The Open Microbiology Journal




ISSN: 1874-2858 ― Volume 14, 2020
REVIEW ARTICLE

The Human Immune System toward Staphylococcus aureus



Rasoul Mirzaei1, Reza Ranjbar2, *, Sajad Karampoor3, Rezvan Goodarzi1, Hamze Hasanvand4
1 Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
2 Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
3 Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
4 School of Medicine, Iran University of Medical Sciences, Tehran, Iran.

Abstract

The immune system is responsible for protecting the host from pathogens, and it has evolved to deal with these pathogens. On the other hand, the co-evolution of pathogenic bacteria with hosts has led to the rise of an array of virulence genes that enable pathogen bacteria to evade or modulate the immune system. Staphylococcus aureus is a significant pathogen of humans that encodes several virulence factors that can modulate or evade from the innate and adaptive arm of the immune system. Overall, the immune reaction toward S. aureus contributes to stimulate innate and adaptive reactions. A profound understanding of the immune response to S. aureus infections will be critical for the development of vaccines and novel therapies. In this review, we summarized and discussed the novel information about the human immune system against S. aureus.

Keywords: Staphylococcus aureus, Innate immunity, Adaptive immunity, Pathogen, Immune system, Methicillin-resistant S. aureus.


Article Information


Identifiers and Pagination:

Year: 2020
Volume: 14
First Page: 164
Last Page: 170
Publisher Id: TOMICROJ-14-164
DOI: 10.2174/1874285802014010164

Article History:

Received Date: 20/02/2020
Revision Received Date: 12/5/2020
Acceptance Date: 13/5/2020
Electronic publication date: 30/07/2020
Collection year: 2020

© 2020 Mirzaei et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Molecular Biology Research Center Research, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran E-mail: ranjbar@bmsu.ac.ir





1. INTRODUCTION

Staphylococcus aureus, a Gram-positive anaerobic bacterium, is the most important medically species in the genus of Staphylococcus [1Taylor TA, Unakal CG. Staphylococcus aureus. StatPearls [Internet]: StatPearls Publishing 2019.]. This organism develops a wide variety of infections ranging from simple skin infections (like corks, scabies, boils, and abscess) to life-threatening diseases (like endocarditis, pneumonia, osteomyelitis, meningitis, septicemia, toxic shock syndrome) [2Lowy FD. Staphylococcus aureus infections. N Engl J Med 1998; 339(8): 520-32.
[http://dx.doi.org/10.1056/NEJM199808203390806] [PMID: 9709046]
]. Methicillin-resistant S. aureus (MRSA) that is resistant to most antibiotics is considered a threat to public health [3Levy SB. Antibiotic resistance-the problem intensifies. Adv Drug Deliv Rev 2005; 57(10): 1446-50.
[http://dx.doi.org/10.1016/j.addr.2005.04.001] [PMID: 15949867]
]. Despite their obvious pathogenic potential, S. aureus strains have the potential to co-exist with their host as a commensal, with approximately 30% of the human population colonized at the mucocutaneous section [4Brown AF, Leech JM, Rogers TR, McLoughlin RM. Staphylococcus aureus Colonization: Modulation of Host Immune Response and Impact on Human Vaccine Design. Front Immunol 2014; 4: 507.
[http://dx.doi.org/10.3389/fimmu.2013.00507] [PMID: 24409186]
, 5Tong SYC, Davis JS, Eichenberger E, Holland TL, Fowler VG Jr. Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev 2015; 28(3): 603-61.
[http://dx.doi.org/10.1128/CMR.00134-14] [PMID: 26016486]
]. The human immune system detects pathogens and destroys them [6Chaplin DD. 1. Overview of the human immune response. J Allergy Clin Immunol 2006; 117(2)(Suppl Mini-Primer): S430-5.
[http://dx.doi.org/10.1016/j.jaci.2005.09.034] [PMID: 16455341]
, 7Rasoul M, Rokhsareh M, Mohammad SM, Sajad K, Ahmadreza M. The Human Immune System against Staphylococcus epidermidis. Critical Reviews™ in Immunology 2019; 39]. In this regard, the immune system includes innate and adaptive sections [6Chaplin DD. 1. Overview of the human immune response. J Allergy Clin Immunol 2006; 117(2)(Suppl Mini-Primer): S430-5.
[http://dx.doi.org/10.1016/j.jaci.2005.09.034] [PMID: 16455341]
, 7Rasoul M, Rokhsareh M, Mohammad SM, Sajad K, Ahmadreza M. The Human Immune System against Staphylococcus epidermidis. Critical Reviews™ in Immunology 2019; 39]. The innate or nonspecific immune system or natural immunity is the first level of protection and consists of cells that commonly find and destroy pathogens in the body [8Müller U, Vogel P, Alber G, Schaub GA. The innate immune system of mammals and insects Trends in innate immunity 2008; 21-44.]. As the primary class of defense in bacterial infections, the innate immune reactions are rapidly induced by pattern recognition routes that recognize non-specific markers of bacterial infection [9Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010; 11(5): 373-84.
[http://dx.doi.org/10.1038/ni.1863] [PMID: 20404851]
]. A major consequence is the stimulation of phagocytic immune cells like neutrophils and macrophages [9Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010; 11(5): 373-84.
[http://dx.doi.org/10.1038/ni.1863] [PMID: 20404851]
]. The innate immune cells can be induced via Toll-like Receptors that enhance antibacterial reactions, stimulate inflammation, and trigger effector cells. This process finally results in the production of interferons, pro-inflammatory as well as cytokines. Pro-inflammatory cytokines are produced by resident host cells that cause the fever [10Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 2011; 11(8): 519-31.
[http://dx.doi.org/10.1038/nri3024] [PMID: 21785456]
].

Acquired (adaptive) host immunity is the second type of immunity that is much more evolved than innate immunity and is induced with each encounter with infectious agents and with each repeated exposure to a particular pathogen that increases its defense capacity and capabilities [11Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Clin Immunol 2010; 125(2)(Suppl. 2): S33-40.
[http://dx.doi.org/10.1016/j.jaci.2009.09.017] [PMID: 20061006]
]. An important feature of this type of immunity is that it has a specific response for each external factor and that it is also a faster and stronger response [11Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Clin Immunol 2010; 125(2)(Suppl. 2): S33-40.
[http://dx.doi.org/10.1016/j.jaci.2009.09.017] [PMID: 20061006]
]. Via activation of T cells and antibodies formation by B cells, the adaptive host immune reaction targets particular microbial antigens and could be recalled in subsequent bacterial infections to offer memory toward that specific pathogen [11Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Clin Immunol 2010; 125(2)(Suppl. 2): S33-40.
[http://dx.doi.org/10.1016/j.jaci.2009.09.017] [PMID: 20061006]
]. In this review, we summarized and discussed the novel information about the human immune system against S. aureus.

2. INNATE IMMUNE RESPONSES TOWARD S. AUREUS

The skin is the largest organ in the body and the main physical barrier between the organism and its environment [12Nestle FO, Di Meglio P, Qin J-Z, Nickoloff BJ. Skin immune sentinels in health and disease. Nat Rev Immunol 2009; 9(10): 679-91.
[http://dx.doi.org/10.1038/nri2622] [PMID: 19763149]
]. It also plays an active role in the defense of the host and, therefore, plays a role in the development and maintenance of local immune and inflammatory responses [12Nestle FO, Di Meglio P, Qin J-Z, Nickoloff BJ. Skin immune sentinels in health and disease. Nat Rev Immunol 2009; 9(10): 679-91.
[http://dx.doi.org/10.1038/nri2622] [PMID: 19763149]
]. Many immune responses originate from this tissue as the gateway to many alien antigens [12Nestle FO, Di Meglio P, Qin J-Z, Nickoloff BJ. Skin immune sentinels in health and disease. Nat Rev Immunol 2009; 9(10): 679-91.
[http://dx.doi.org/10.1038/nri2622] [PMID: 19763149]
]. The skin contains important cells like melanocytes, keratinocytes, and Langerhans and T lymphocytes. Langerhans is immature Dendritic Cells (DCs) of the immune system and its function is to trap the antigens that enter the host skin [13Di Meglio P, Perera GK, Nestle FO. The multitasking organ: recent insights into skin immune function. Immunity 2011; 35(6): 857-69.
[http://dx.doi.org/10.1016/j.immuni.2011.12.003] [PMID: 22195743]
]. The epidermis layer of skin is organized by keratinocyte cells in various maturation levels, T lymphocytes as well as Langerhans cells. The dermis layer comprises extracellular matrix ingredients, like connective tissues, elastin fibers, and collagen [14Matejuk A. Skin Immunity. Arch Immunol Ther Exp (Warsz) 2018; 66(1): 45-54.
[http://dx.doi.org/10.1007/s00005-017-0477-3] [PMID: 28623375]
]. The fibers offer a building skeleton to human blood vessels, fibroblasts, adipocytes, macrophage cells, DCs, mast cells, T cells, B cells, and plasma as well as Natural Killer (NK) cells [14Matejuk A. Skin Immunity. Arch Immunol Ther Exp (Warsz) 2018; 66(1): 45-54.
[http://dx.doi.org/10.1007/s00005-017-0477-3] [PMID: 28623375]
]. As such, inhabitant human immune cells are plentiful in the skin, and these cells are all contributed to the control of infection of S. aureus strains.

Keratinocyte cells are the central cells of the epidermis and have a protective function against external factors such as bacteria [15Ibrahim F, Khan T, Pujalte GG. Bacterial Skin Infections. Prim Care 2015; 42(4): 485-99.
[http://dx.doi.org/10.1016/j.pop.2015.08.001] [PMID: 26612370]
]. Keratinocyte cells are usually the first cells that encounter microbial pathogens, and detect Pathogen-Associated Molecular Patterns (PAMPs) through various Pattern-Recognition Receptors (PRRs), like nucleotide-binding oligomerization domain-1 (NOD-1), nucleotide-binding oligomerization domain -2 (NOD -2), TLRs as well as the scavenger receptors CD36 [15Ibrahim F, Khan T, Pujalte GG. Bacterial Skin Infections. Prim Care 2015; 42(4): 485-99.
[http://dx.doi.org/10.1016/j.pop.2015.08.001] [PMID: 26612370]
-17Amarante-Mendes GP, Adjemian S, Branco LM, Zanetti LC, Weinlich R, Bortoluci KR. Pattern recognition receptors and the host cell death molecular machinery. Front Immunol 2018; 9: 2379.
[http://dx.doi.org/10.3389/fimmu.2018.02379] [PMID: 30459758]
]. Signaling via these human receptors stimulates transcription factors like AP1, NF-kB as well as CREB to produce chemokines, cytokines, and antimicrobial effectors, like Antimicrobial Peptides (AMPs) and inducible Nitric Oxide synthase [16Miller LS. Toll-like receptors in skin. Adv Dermatol 2008; 24: 71-87.
[http://dx.doi.org/10.1016/j.yadr.2008.09.004] [PMID: 19256306]
, 18Pasparakis M, Haase I, Nestle FO. Mechanisms regulating skin immunity and inflammation. Nat Rev Immunol 2014; 14(5): 289-301.
[http://dx.doi.org/10.1038/nri3646] [PMID: 24722477]
, 19Bitschar K, Wolz C, Krismer B, Peschel A, Schittek B. Keratinocytes as sensors and central players in the immune defense against Staphylococcus aureus in the skin. J Dermatol Sci 2017; 87(3): 215-20.
[http://dx.doi.org/10.1016/j.jdermsci.2017.06.003] [PMID: 28655473]
]. TLR-1, TLR-2, and TLR-6 detect the cell wall components S. aureus, particularly peptidoglycan and lipopeptides [20Fournier B. The function of TLR2 during staphylococcal diseases. Front Cell Infect Microbiol 2013; 2: 167.
[http://dx.doi.org/10.3389/fcimb.2012.00167] [PMID: 23316483]
, 21Ozinsky A, Underhill DM, Fontenot JD, et al. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci USA 2000; 97(25): 13766-71.
[http://dx.doi.org/10.1073/pnas.250476497] [PMID: 11095740]
]. These TLRs apply the signaling adapter MyD88 to stimulate efficient and robust transcriptional programs that trigger inflammatory reactions [22Verstak B, Stack J, Ve T, et al. The TLR signaling adaptor TRAM interacts with TRAF6 to mediate activation of the inflammatory response by TLR4. J Leukoc Biol 2014; 96(3): 427-36.
[http://dx.doi.org/10.1189/jlb.2A0913-487R] [PMID: 24812060]
]. TLR-1, TLR-2, and TLR-6, contribute in different stages of infection caused by S. aureus. Primarily, TLR-2 on Keratinocyte cell detect bacterial pathogens to release neutrophil antimicrobial peptides and chemo-attractants, like the defensins and cathelicidin LL-37, which produce pores in the membrane of bacteria [19Bitschar K, Wolz C, Krismer B, Peschel A, Schittek B. Keratinocytes as sensors and central players in the immune defense against Staphylococcus aureus in the skin. J Dermatol Sci 2017; 87(3): 215-20.
[http://dx.doi.org/10.1016/j.jdermsci.2017.06.003] [PMID: 28655473]
]. TLR-2 molecules are formed on inhabitant recruited neutrophils, monocytes, and macrophages, which immediately react to S. aureus and further activate cytokine formation and phagocytosis [23Yimin KM, Kohanawa M, Zhao S, et al. Contribution of toll-like receptor 2 to the innate response against Staphylococcus aureus infection in mice. PLoS One 2013; 8(9)e74287
[http://dx.doi.org/10.1371/journal.pone.0074287] [PMID: 24058538]
]. It is supposed that TLR2 molecules are essential for localized and systemic S. aureus infection. Mouse deficient in TLR-1, TLR-2, TLR-6, and MyD88 is very susceptible to intranasal infection of S. aureus, as documented by the raised load of bacteria, poor inflammatory reactions, and increased morbidity and mortality in different models of disease [24Feuerstein R, Seidl M, Prinz M, Henneke P. MyD88 in macrophages is critical for abscess resolution in staphylococcal skin infection. Journal of immunology (Baltimore, Md : 1950) 2015; 194: 2735-45.
[http://dx.doi.org/10.4049/jimmunol.1402566]
]. In human skin, the TLR2 activity is controversial due to variation in virulence of microbial strains, measured endpoints as well as infectious dose (Fig. 1).

Neutrophils are a type of phagocytic white cells that have chemotaxis and are in the second line of nonspecific defense in the human immune system [25Smith JA. Neutrophils, host defense, and inflammation: a double-edged sword. J Leukoc Biol 1994; 56(6): 672-86.
[http://dx.doi.org/10.1002/jlb.56.6.672] [PMID: 7996043]
]. The neutrophil is a crucial section of the acute reaction and centrally relevant toward S. aureus [26Rigby KM, DeLeo FR. Neutrophils in innate host defense against Staphylococcus aureus infections. Semin Immunopathol 2012; 34(2): 237-59.
[http://dx.doi.org/10.1007/s00281-011-0295-3] [PMID: 22080185]
]. The NOD-1, NOD-2 and intracellular PRRs that recognized microbial peptidoglycan stimulate antimicrobial peptide formation, inflammation, and phagocytic effector activities [27Takada H, Uehara A. Enhancement of TLR-mediated innate immune responses by peptidoglycans through NOD signaling. Curr Pharm Des 2006; 12(32): 4163-72.
[http://dx.doi.org/10.2174/138161206778743510] [PMID: 17100619]
]. NOD-2 molecules detect muramyl-dipeptide from the peptidoglycan of S. aureus [28Girardin SE, Boneca IG, Viala J, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 2003; 278(11): 8869-72.
[http://dx.doi.org/10.1074/jbc.C200651200] [PMID: 12527755]
, 29Schäffler H, Demircioglu DD, Kühner D, et al. NOD2 stimulation by Staphylococcus aureus-derived peptidoglycan is boosted by Toll-like receptor 2 costimulation with lipoproteins in dendritic cells. Infect Immun 2014; 82(11): 4681-8.
[http://dx.doi.org/10.1128/IAI.02043-14] [PMID: 25156723]
]. The NOD2-deficient mouse is very susceptible to systemic and skin infections of S. aureus when compared with wild type counterparts [29Schäffler H, Demircioglu DD, Kühner D, et al. NOD2 stimulation by Staphylococcus aureus-derived peptidoglycan is boosted by Toll-like receptor 2 costimulation with lipoproteins in dendritic cells. Infect Immun 2014; 82(11): 4681-8.
[http://dx.doi.org/10.1128/IAI.02043-14] [PMID: 25156723]
, 30Parker D, Planet PJ, Soong G, Narechania A, Prince A. Induction of type I interferon signaling determines the relative pathogenicity of Staphylococcus aureus strains. PLoS Pathog 2014; 10(2)e1003951
[http://dx.doi.org/10.1371/journal.ppat.1003951] [PMID: 24586160]
]. Eventually, scavenger receptors SRBII, CD36, as well as MARCO are required for optimal skin host defense against S. aureus [31Castleman MJ, Febbraio M, Hall PR. CD36 Is Essential for Regulation of the Host Innate Response to Staphylococcus aureus α-Toxin-Mediated Dermonecrosis. J Immunol 2015; 195(5): 2294-302.
[http://dx.doi.org/10.4049/jimmunol.1500500] [PMID: 26223653]
, 32Blanchet C, Jouvion G, Fitting C, Cavaillon J-M, Adib-Conquy M. Protective or deleterious role of scavenger receptors SR-A and CD36 on host resistance to Staphylococcus aureus depends on the site of infection. PLoS One 2014; 9(1)e87927
[http://dx.doi.org/10.1371/journal.pone.0087927] [PMID: 24498223]
]. As a result, CD36 2/2 mouse shows raised bacterial loads and enhances severe dermonecrosis induced by α-toxin [31Castleman MJ, Febbraio M, Hall PR. CD36 Is Essential for Regulation of the Host Innate Response to Staphylococcus aureus α-Toxin-Mediated Dermonecrosis. J Immunol 2015; 195(5): 2294-302.
[http://dx.doi.org/10.4049/jimmunol.1500500] [PMID: 26223653]
].

Macrophages have spread throughout the body [33Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 2014; 15(5): 300-12.
[http://dx.doi.org/10.1038/nrn3722] [PMID: 24713688]
]. Immature macrophages in the bloodstream are called monocytes [33Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 2014; 15(5): 300-12.
[http://dx.doi.org/10.1038/nrn3722] [PMID: 24713688]
]. Skin-inhabitant macrophage cells assist in the first S. aureus clearance, and in conjunction with perivascular macrophage cells. Moreover, they control the recruitment of monocytes and neutrophils to the location of infection [34Abtin A, Jain R, Mitchell AJ, et al. Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection. Nat Immunol 2014; 15(1): 45-53.
[http://dx.doi.org/10.1038/ni.2769] [PMID: 24270515]
]. Dermal macrophage cells could phagocytose and kill S. aureus efficiently by forming antimicrobial peptides, reactive nitrogen, and oxygen species as well as chelating proteins that starve microbes of essential micronutrients [35Kobayashi SD, Malachowa N, DeLeo FR. Pathogenesis of Staphylococcus aureus abscesses. Am J Pathol 2015; 185(6): 1518-27.
[http://dx.doi.org/10.1016/j.ajpath.2014.11.030] [PMID: 25749135]
, 36Feuerstein R, Kolter J, Henneke P. Dynamic interactions between dermal macrophages and Staphylococcus aureus. J Leukoc Biol 2017; 101(1): 99-106.
[http://dx.doi.org/10.1189/jlb.3MR0316-097RR] [PMID: 27733573]
]. Additionally, dermal macrophage cells release various chemo-attractant molecules that offer signals for the recruitment of neutrophil cells in a manner mediated to MyD88, IL-1-R [37Miller LS, O’Connell RM, Gutierrez MA, et al. MyD88 mediates neutrophil recruitment initiated by IL-1R but not TLR2 activation in immunity against Staphylococcus aureus. Immunity 2006; 24(1): 79-91.
[http://dx.doi.org/10.1016/j.immuni.2005.11.011] [PMID: 16413925]
]. Moreover, these cells contribute to the dead cell-clearance at the site of bacterial infection, which is vital for the resolution of the disorder [35Kobayashi SD, Malachowa N, DeLeo FR. Pathogenesis of Staphylococcus aureus abscesses. Am J Pathol 2015; 185(6): 1518-27.
[http://dx.doi.org/10.1016/j.ajpath.2014.11.030] [PMID: 25749135]
, 36Feuerstein R, Kolter J, Henneke P. Dynamic interactions between dermal macrophages and Staphylococcus aureus. J Leukoc Biol 2017; 101(1): 99-106.
[http://dx.doi.org/10.1189/jlb.3MR0316-097RR] [PMID: 27733573]
]. When the neutrophil cell reaches the location of the infection, it engulfs the S. aureus and attempts to control bacterial growth by forming various antimicrobial effector molecules [35Kobayashi SD, Malachowa N, DeLeo FR. Pathogenesis of Staphylococcus aureus abscesses. Am J Pathol 2015; 185(6): 1518-27.
[http://dx.doi.org/10.1016/j.ajpath.2014.11.030] [PMID: 25749135]
]. The neutrophil is a short-lived immune cell that quickly triggers apoptosis and requires to be eradicated from the location of the infection. Nevertheless, S. aureus cells form different toxins, like Panton-Valentine leukocidin, phenol soluble modulins, α-toxin as well as γ-hemolysin, and that could hasten neutrophil death by stimulating necrosis and cause to liberate the danger-mediated molecular patterns [35Kobayashi SD, Malachowa N, DeLeo FR. Pathogenesis of Staphylococcus aureus abscesses. Am J Pathol 2015; 185(6): 1518-27.
[http://dx.doi.org/10.1016/j.ajpath.2014.11.030] [PMID: 25749135]
, 38Guerra FE, Borgogna TR, Patel DM, Sward EW, Voyich JM. Epic immune battles of history: neutrophils vs. Staphylococcus aureus. Front Cell Infect Microbiol 2017; 7: 286.
[http://dx.doi.org/10.3389/fcimb.2017.00286] [PMID: 28713774]
]. Danger-mediated molecular patterns freed in S. aureus infection like IL-1α, IL-33, HGMB1, ATP, as well as calprotectin [39Parker D, Prince A. Immunoregulatory effects of necroptosis in bacterial infections. Cytokine 2016; 88: 274-5.
[http://dx.doi.org/10.1016/j.cyto.2016.09.024] [PMID: 27710879]
]. DCs and Langerhans cells capture the microbial antigens before contact with skin-draining lymph nodes [40Kashem SW, Haniffa M, Kaplan DH. Antigen-presenting cells in the skin. Annu Rev Immunol 2017; 35: 469-99.
[http://dx.doi.org/10.1146/annurev-immunol-051116-052215] [PMID: 28226228]
, 41Kaplan DH. Ontogeny and function of murine epidermal Langerhans cells. Nat Immunol 2017; 18(10): 1068-75.
[http://dx.doi.org/10.1038/ni.3815] [PMID: 28926543]
]. The study has found that in skin S. aureus infection, Langerhans cells that engulf the bacteria are stimulated by PAMPs, and subsequently migrate to draining lymph nodes where Langerhans cells elicit adaptive reactions specific to S. aureus [42Dejani NN, Brandt SL, Piñeros A, et al. Topical Prostaglandin E Analog Restores Defective Dendritic Cell-Mediated Th17 Host Defense Against Methicillin-Resistant Staphylococcus Aureus in the Skin of Diabetic Mice. Diabetes 2016; 65(12): 3718-29.
[http://dx.doi.org/10.2337/db16-0565] [PMID: 27605625]
, 43Ouchi T, Kubo A, Yokouchi M, et al. Langerhans cell antigen capture through tight junctions confers preemptive immunity in experimental staphylococcal scalded skin syndrome. J Exp Med 2011; 208(13): 2607-13.
[http://dx.doi.org/10.1084/jem.20111718] [PMID: 22143886]
]. Although there are various distinct sub-kinds of dendritic cells in the human skin, its activity against S. aureus infection in the skin is not well-defined [44Darisipudi MN, Nordengrün M, Bröker BM, Péton V. Messing with the Sentinels-The Interaction of Staphylococcus aureus with Dendritic Cells. Microorganisms 2018; 6(3): 87.
[http://dx.doi.org/10.3390/microorganisms6030087] [PMID: 30111706]
].

S. aureus cells can be engulfed by receptors that detect non-opsonized and opsonized bacteria [35Kobayashi SD, Malachowa N, DeLeo FR. Pathogenesis of Staphylococcus aureus abscesses. Am J Pathol 2015; 185(6): 1518-27.
[http://dx.doi.org/10.1016/j.ajpath.2014.11.030] [PMID: 25749135]
, 38Guerra FE, Borgogna TR, Patel DM, Sward EW, Voyich JM. Epic immune battles of history: neutrophils vs. Staphylococcus aureus. Front Cell Infect Microbiol 2017; 7: 286.
[http://dx.doi.org/10.3389/fcimb.2017.00286] [PMID: 28713774]
, 45Harrison CJ. Innate immunity as a key element in host defense against methicillin resistant Staphylococcus aureus. Minerva Pediatr 2009; 61(5): 503-14.
[PMID: 19794376]
]. S. aureus cells trigger different antimicrobial effector activities, when coated with opsonins like C3b and IgG [44Darisipudi MN, Nordengrün M, Bröker BM, Péton V. Messing with the Sentinels-The Interaction of Staphylococcus aureus with Dendritic Cells. Microorganisms 2018; 6(3): 87.
[http://dx.doi.org/10.3390/microorganisms6030087] [PMID: 30111706]
]. Reactive oxygen species are produced via the actions of myeloperoxidase and NADPH oxidase following phagocytosis, which can directly kill microbes [46Nauseef WM. The phagocyte NOX2 NADPH oxidase in microbial killing and cell signaling. Curr Opin Immunol 2019; 60: 130-40.
[http://dx.doi.org/10.1016/j.coi.2019.05.006] [PMID: 31302569]
]. Nitric oxide molecules are a main reactive nitrogen species that formed from nitric oxide synthase with immunomodulatory and antimicrobial activity [46Nauseef WM. The phagocyte NOX2 NADPH oxidase in microbial killing and cell signaling. Curr Opin Immunol 2019; 60: 130-40.
[http://dx.doi.org/10.1016/j.coi.2019.05.006] [PMID: 31302569]
]. Pharmacologic inhibition and genetic deletion of nitric oxide production render mice susceptible to S. aureus infection [47Li C, Li H, Jiang Z, et al. Interleukin-33 increases antibacterial defense by activation of inducible nitric oxide synthase in skin. PLoS Pathog 2014; 10(2)e1003918
[http://dx.doi.org/10.1371/journal.ppat.1003918] [PMID: 24586149]
].

Fig. (1)
The immune system toward Staphylococcus aureus. Human immunity toward S. aureus heavily relies on complement and neutrophil and stimulation of TLR2. The immune reaction toward S. aureus contributes to the stimulation of both innate and adaptive reactions. S aureus, Staphylococcus aureus; PMN, Polymorphonuclear neutrophils; MQ, Macrophage; T cell, T lymphocyte; B cell, B lymphocyte.


Nevertheless, high levels of nitric oxide could exert anti-inflammatory impacts. High concentrations of nitric oxide can, therefore, predispose to bacterial infection via inhibiting the proliferation of the cell, stimulating host cell death, and preventing TNF-α formation induced by phagocyte and presentation of Ags.

Additionally, S. aureus cells use nitric oxide to proliferate and preclude stimulation of the stress regulon through the fermentation of lactic acid [48Grosser MR, Weiss A, Shaw LN, Richardson AR. Regulatory requirements for Staphylococcus aureus nitric oxide resistance. J Bacteriol 2016; 198(15): 2043-55.
[http://dx.doi.org/10.1128/JB.00229-16] [PMID: 27185828]
, 49Vitko NP, Spahich NA, Richardson AR. Glycolytic dependency of high-level nitric oxide resistance and virulence in Staphylococcus aureus. MBio 2015; 6(2): e00045-15.
[http://dx.doi.org/10.1128/mBio.00045-15] [PMID: 25852157]
].

Neutrophils kill pathogens by degranulation of toxic components [50Kobayashi Y. Neutrophil biology: an update. EXCLI J 2015; 14: 220-7.
[PMID: 26600743]
]. Degranulation stimulates the formation of particular granules containing antimicrobial peptides, like LL37, defensins, and cathelicidin-related antimicrobial peptide. Moreover, degranulation diffuses cathepsin, azurocidin, lysozymes, lactoferrin, elastase, and proteinase-3 [51Greenlee-Wacker M, DeLeo FR, Nauseef WM. How methicillin-resistant Staphylococcus aureus evade neutrophil killing. Curr Opin Hematol 2015; 22(1): 30-5.
[http://dx.doi.org/10.1097/MOH.0000000000000096] [PMID: 25394313]
, 52van Kessel KP, Bestebroer J, van Strijp JA. Neutrophil-mediated phagocytosis of Staphylococcus aureus. Front Immunol 2014; 5: 467.
[http://dx.doi.org/10.3389/fimmu.2014.00467] [PMID: 25309547]
]. Neutrophils liberate structures of DNA named NET (neutrophil extracellular trap), as an additional effector mechanism to control S. aureus infection, that formed in a mechanism dependent on a TLR2 and MyD88 and is necessary for containing S. aureus in the host skin to prevent bacteremia [53Yipp BG, Petri B, Salina D, et al. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med 2012; 18(9): 1386-93.
[http://dx.doi.org/10.1038/nm.2847] [PMID: 22922410]
]. NET finites the spread of bacteria because it is rich in antimicrobial agents like cathepsin, antimicrobial peptides, histones, elastase, as well as proteases [54Boeltz S, Amini P, Anders H-J, et al. To NET or not to NET:current opinions and state of the science regarding the formation of neutrophil extracellular traps. Cell Death Differ 2019; 26(3): 395-408.
[http://dx.doi.org/10.1038/s41418-018-0261-x] [PMID: 30622307]
]. Nevertheless, S. aureus cells can destroy NET, and the degradation product 2’-deoxyadenosine that stimulates apoptosis in macrophage cells, which raise bacterial survival in the abscess [55Sultan AR, Hoppenbrouwers T, Lemmens-den Toom NA, et al. During the Early Stages of Staphylococcus aureus Biofilm Formation, Induced Neutrophil Extracellular Traps Are Degraded by Autologous Thermonuclease. Infect Immun 2019; 87(12): 87.
[http://dx.doi.org/10.1128/IAI.00605-19] [PMID: 31527127]
].

Some AMPs exist in the human skin with activity toward S. aureus cells, for example, Alpha-defensins (named HNPs (human neutrophil peptides)), dermcidin, Beta-defensins, cathelicidin, as well as RNase7 [56van der Does AM, Hiemstra PS, Mookherjee N. Antimicrobial Host Defence Peptides: Immunomodulatory Functions and Translational Prospects Antimicrobial Peptides 2019; 149-71.
[http://dx.doi.org/10.1007/978-981-13-3588-4_10]
, 57Prasad SV, Fiedoruk K, Daniluk T, Piktel E, Bucki R. Expression and Function of Host Defense Peptides at Inflammation Sites. Int J Mol Sci 2019; 21(1): 104.
[http://dx.doi.org/10.3390/ijms21010104] [PMID: 31877866]
]. Neutrophil releases high rates of HNPs, which included nearly half of the peptides inside granules of neutrophils [58Glenthøj A, Nickles K, Cowland J, Borregaard N. Processing of neutrophil α-defensins does not rely on serine proteases in vivo. PLoS One 2015; 10(5)e0125483
[http://dx.doi.org/10.1371/journal.pone.0125483] [PMID: 25945506]
]. Amongst HNPs, HNP2 peptides have the highest degree of antibacterial role toward S. aureus cells [59Ericksen B, Wu Z, Lu W, Lehrer RI. Antibacterial activity and specificity of the six human α-defensins. Antimicrob Agents Chemother 2005; 49(1): 269-75.
[http://dx.doi.org/10.1128/AAC.49.1.269-275.2005] [PMID: 15616305]
]. In humans, there are four human β-defensins (hBDs), including hBD1, hBD2, hBD3, hBD4, which are formed by keratinocytes, macrophages, as well as DCs [60Kiatsurayanon C, Ogawa H, Niyonsaba F. The role of host defense peptide human β-defensins in the maintenance of skin barriers. Curr Pharm Des 2018; 24(10): 1092-9.
[http://dx.doi.org/10.2174/1381612824666180327164445] [PMID: 29589537]
, 61Schauber J, Gallo RL. Antimicrobial peptides and the skin immune defense system. J Allergy Clin Immunol 2008; 122(2): 261-6.
[http://dx.doi.org/10.1016/j.jaci.2008.03.027] [PMID: 18439663]
]. Amongst hBDs, hBD3 has a potent activity toward S. aureus [62Otto M. Staphylococcus colonization of the skin and antimicrobial peptides. Expert Rev Dermatol 2010; 5(2): 183-95.
[http://dx.doi.org/10.1586/edm.10.6] [PMID: 20473345]
]. Cathelicidin is also called LL-37 as it has 37 amino acid released from the cationic antimicrobial protein 18 kDa [63Zhang M, Liang W, Gong W, Yoshimura T, Chen K, Wang JM. The Critical Role of the Antimicrobial Peptide LL-37/CRAMP in Protection of Colon Microbiota Balance, Mucosal Homeostasis, Anti-Inflammatory Responses, and Resistance to Carcinogenesis. Critical Reviews™ in Immunology 2019; 39] similar to hBD3, which has strong activity against S. aureus [64Febriza A, Hatta M, Natzir R, Kasim VN, Idrus HH. Activity of Antimicrobial Peptide; Cathelicidin, on Bacterial Infection. Open Biochem J 2019; 13.
[http://dx.doi.org/10.2174/1874091X01913010045]
]. This AMP is formed in neutrophil cells and could be stimulated in keratinocyte cells [64Febriza A, Hatta M, Natzir R, Kasim VN, Idrus HH. Activity of Antimicrobial Peptide; Cathelicidin, on Bacterial Infection. Open Biochem J 2019; 13.
[http://dx.doi.org/10.2174/1874091X01913010045]
]. Another AMP, RNase 7, is formed by human keratinocyte cells and has activity toward S. aureus [65Rademacher F, Dreyer S, Kopfnagel V, Gläser R, Werfel T, Harder J. The antimicrobial and immunomodulatory function of RNase 7 in skin. Front Immunol 2019; 10: 2553.
[http://dx.doi.org/10.3389/fimmu.2019.02553] [PMID: 31749808]
]. A current work discovered that high levels of RNase7 could stop S. aureus skin colonization in the host stratum corneum [66Simanski M, Dressel S, Gläser R, Harder J. RNase 7 protects healthy skin from Staphylococcus aureus colonization. J Invest Dermatol 2010; 130(12): 2836-8.
[http://dx.doi.org/10.1038/jid.2010.217] [PMID: 20668470]
]. Additionally, dermcidin is formed by eccrine sweat glands with activity toward S. aureus [67Liu Q, Mazhar M, Miller LS. Immune and Inflammatory Reponses to Staphylococcus aureus Skin Infections. Curr Dermatol Rep 2018; 7(4): 338-49.
[http://dx.doi.org/10.1007/s13671-018-0235-8] [PMID: 30989002]
]. The keratinocyte cells form the LL-37, hBD2 as well as hBD3 in S. aureus infections for prompt clearance of the bacterial cells [68Herman A, Herman AP. Antimicrobial peptides activity in the skin. Skin Res Technol 2019; 25(2): 111-7.
[http://dx.doi.org/10.1111/srt.12626] [PMID: 30320469]
]. In addition, stimulation of the EGFR (epidermal growth factor receptor) by wounding of skin cause in enhanced hBD3 formation offers another strategy for increasing antibacterial role toward S. aureus [69Felgueiras HP, Amorim M. Antimicrobial peptides in infected wounds 2019.
[http://dx.doi.org/10.33582/research-trends-of-microbiology/antimicrobial-peptides-in-infected-wounds]
].

Four PGRPs (peptidoglycan recognition proteins) exist in humans, including PGRP1-4 that secrete proteins [70Wolf AJ, Underhill DM. Peptidoglycan recognition by the innate immune system. Nat Rev Immunol 2018; 18(4): 243-54.
[http://dx.doi.org/10.1038/nri.2017.136] [PMID: 29292393]
]. PGRP1 molecules are formed in neutrophil cells, where they bind peptidoglycan S. aureus inside tertiary granules and apply their bactericidal activity [71Cho JH, Fraser IP, Fukase K, et al. Human peptidoglycan recognition protein S is an effector of neutrophil-mediated innate immunity. Blood 2005; 106(7): 2551-8.
[http://dx.doi.org/10.1182/blood-2005-02-0530] [PMID: 15956276]
]. PGRP2 molecules are formed by keratinocyte cells and are distinct that they have the active amidases that cleave the peptidoglycan of S. aureus [72Dziarski R, Royet J, Gupta D. Peptidoglycan recognition proteins and lysozyme Molecular Immunology 2016; 389-403., 73Wang Z-M, Li X, Cocklin RR, et al. Human peptidoglycan recognition protein-L is an N-acetylmuramoyl-L-alanine amidase. J Biol Chem 2003; 278(49): 49044-52.
[http://dx.doi.org/10.1074/jbc.M307758200] [PMID: 14506276]
]. Finally, PGRP3 and PGRP4 produce in the hair follicles, epidermis, sebaceous glands, as well as sweat glands and their relevance to S. aureus infection is unknown [74Dziarski R, Gupta D. Review: Mammalian peptidoglycan recognition proteins (PGRPs) in innate immunity. Innate Immun 2010; 16(3): 168-74.
[http://dx.doi.org/10.1177/1753425910366059] [PMID: 20418257]
]. Complement activation, as a crucial section of the innate immune defense, triggers cytolytic reactions and acute inflammatory responses. Furthermore, it involved in the regulation of host adaptive immune defenses [75Parnham MJ, Rossi AG. Innate Immunity: Phagocytes, Natural Killer Cells, and the Complement System Nijkamp and Parnham’s Principles of Immunopharmacology 2019; 117-37.
[http://dx.doi.org/10.1007/978-3-030-10811-3_8]
, 76Rich RR, Chaplin DD. The human immune response.Clinical Immunology: Elsevier 2019; 3-17.]. The complement is stimulated through particular recognition routes, including the classical and the alternative and the lectin pathway [75Parnham MJ, Rossi AG. Innate Immunity: Phagocytes, Natural Killer Cells, and the Complement System Nijkamp and Parnham’s Principles of Immunopharmacology 2019; 117-37.
[http://dx.doi.org/10.1007/978-3-030-10811-3_8]
]. All pathways form the active protease complexes, the C3 convertase, on the bacterial surface [77Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT. Complement System Part I - Molecular Mechanisms of Activation and Regulation. Front Immunol 2015; 6: 262.
[http://dx.doi.org/10.3389/fimmu.2015.00262] [PMID: 26082779]
]. C3 convertase activity leads the labeling of microbial antigens with a high amount of C3b, as well as iC3b [75Parnham MJ, Rossi AG. Innate Immunity: Phagocytes, Natural Killer Cells, and the Complement System Nijkamp and Parnham’s Principles of Immunopharmacology 2019; 117-37.
[http://dx.doi.org/10.1007/978-3-030-10811-3_8]
]. This process is named opsonization that is crucial for impressive phagocytic uptake through complement receptors by phagocytic cells [78Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140(6): 805-20.
[http://dx.doi.org/10.1016/j.cell.2010.01.022] [PMID: 20303872]
]. It must be noted that a highly particular factor called staphylococcal complement inhibitor produced by S. aureus cells attaches to and stops the role of the C3 convertases on the staphylococcus surface [79Wanke I, Steffen H, Christ C, et al. Skin commensals amplify the innate immune response to pathogens by activation of distinct signaling pathways. J Invest Dermatol 2011; 131(2): 382-90.
[http://dx.doi.org/10.1038/jid.2010.328] [PMID: 21048787]
].

3. ADAPTIVE IMMUNITY AGAINST S. AUREUS

It is unclear whether the limited association of B cells and S. aureus affects the pathogenesis and/or host immune response, but, it has been shown that the binding of CR2 expressed by B lymphocyte with C3d on the antigen surface has several roles useful for the antibody action [80Nygaard TK, Kobayashi SD, Freedman B, Porter AR, Voyich JM, Otto M, et al. Interaction of Staphylococci with Human B cells. PloS one 2016; e0164410-e.]. For cognitive B cells, the simultaneous binding of CR2 with C3b with the B lymphocyte antigen receptor complex reduces the B cell activation threshold by several orders of magnitude. It is required for proper B cell activation [80Nygaard TK, Kobayashi SD, Freedman B, Porter AR, Voyich JM, Otto M, et al. Interaction of Staphylococci with Human B cells. PloS one 2016; e0164410-e.]. On the other hand, non-cognitive B cells in the lymph nodes and spleen of mice play an important role in the transfer of immune complexes containing Immunoglobulin M to follicle DCs [80Nygaard TK, Kobayashi SD, Freedman B, Porter AR, Voyich JM, Otto M, et al. Interaction of Staphylococci with Human B cells. PloS one 2016; e0164410-e.]. This process is dependent on the receptor and complement that is essential for the efficient formation of the germination center and maturation of the antibody affinity [80Nygaard TK, Kobayashi SD, Freedman B, Porter AR, Voyich JM, Otto M, et al. Interaction of Staphylococci with Human B cells. PloS one 2016; e0164410-e.]. Unrecognized CR2 B cells attached to antigen-containing immune complexes can also deliver these immune complexes to antigen-specific T cells to enable appropriate T-cell activation [80Nygaard TK, Kobayashi SD, Freedman B, Porter AR, Voyich JM, Otto M, et al. Interaction of Staphylococci with Human B cells. PloS one 2016; e0164410-e.]. Thus, molecules secreted by S. aureus that inhibit the association of C3d-containing immune complexes with CR2 can influence the host's adaptive immune response against this bacterium [80Nygaard TK, Kobayashi SD, Freedman B, Porter AR, Voyich JM, Otto M, et al. Interaction of Staphylococci with Human B cells. PloS one 2016; e0164410-e.].

B lymphocytes are immune cells that produce antibodies against pathogens, such as viruses [81Cooper MD, Alder MN. The evolution of adaptive immune systems. Cell 2006; 124(4): 815-22.
[http://dx.doi.org/10.1016/j.cell.2006.02.001] [PMID: 16497590]
]. These lymphocytes are involved in humoral immunity, which, together with cellular immunity, form a specific defense mechanism [81Cooper MD, Alder MN. The evolution of adaptive immune systems. Cell 2006; 124(4): 815-22.
[http://dx.doi.org/10.1016/j.cell.2006.02.001] [PMID: 16497590]
]. B lymphocytes act in a specific way; that is, they identify and eliminate a particular type of alien agent [81Cooper MD, Alder MN. The evolution of adaptive immune systems. Cell 2006; 124(4): 815-22.
[http://dx.doi.org/10.1016/j.cell.2006.02.001] [PMID: 16497590]
]. These cells have a major role in humoral immunity [82Rossetti RAM, Lorenzi NPC, Yokochi K, et al. B lymphocytes can be activated to act as antigen presenting cells to promote anti-tumor responses. PLoS One 2018; 13(7)e0199034
[http://dx.doi.org/10.1371/journal.pone.0199034] [PMID: 29975708]
]. The primary function of antibody-deficient lymphocytes against antigens is to function as Antigen-Presenting Cells (APCs), and eventually to evolve into memory cells after activation by antigenic interactions [82Rossetti RAM, Lorenzi NPC, Yokochi K, et al. B lymphocytes can be activated to act as antigen presenting cells to promote anti-tumor responses. PLoS One 2018; 13(7)e0199034
[http://dx.doi.org/10.1371/journal.pone.0199034] [PMID: 29975708]
]. Memory cells produce more antibodies in a shorter time after re-encountering the same antigen [83Kurosaki T, Kometani K, Ise W. Memory B cells. Nat Rev Immunol 2015; 15(3): 149-59.
[http://dx.doi.org/10.1038/nri3802] [PMID: 25677494]
]. The main activity of B lymphocytes is to form immunoglobulins that neutralize the action of target proteins (like toxin) or opsonize microbial pathogens to optimize clearance and phagocytosis [83Kurosaki T, Kometani K, Ise W. Memory B cells. Nat Rev Immunol 2015; 15(3): 149-59.
[http://dx.doi.org/10.1038/nri3802] [PMID: 25677494]
]. The significance of antibody-mediated protection toward microbial infectious agents is found by demonstrating this event that the absence of B lymphocyte maturation causes susceptibility against infections with encapsulated bacteria and viruses [84Bruton OC. Agammaglobulinemia. Pediatrics 1952; 9(6): 722-8.
[PMID: 14929630]
]. The notable absence of raised susceptibility in this regard to S. aureus argues that antibody is un-significant in protection toward infection of S. aureus. Nevertheless, it has found that early cutaneous S. aureus infection could stimulate antibody-mediated support toward a subsequent microbial infection in certain mouse strains, and many pre-clinical works have found at least partial support from subsequent microbial infection subsequent stimulation of antibodies by vaccination [85Montgomery CP, Daniels M, Zhao F, Alegre M-L, Chong AS, Daum RS. Protective immunity against recurrent Staphylococcus aureus skin infection requires antibody and interleukin-17A. Infect Immun 2014; 82(5): 2125-34.
[http://dx.doi.org/10.1128/IAI.01491-14] [PMID: 24614654]
].

In the opsonophagocytosis, T lymphocyte has a dual function: (1) it is important for the production of opposing antibodies because T cell is essential for maturation of antibody affinity as well as class switches, (2) T cells promote phagocytosis by absorbing neutrophils and macrophages from the bone marrow to the site of infection [86McHeyzer-Williams M, Okitsu S, Wang N, McHeyzer-Williams L. Molecular programming of B cell memory. Nat Rev Immunol 2011; 12(1): 24-34.
[http://dx.doi.org/10.1038/nri3128] [PMID: 22158414]
, 87Hirahara K, Vahedi G, Ghoreschi K, et al. Helper T-cell differentiation and plasticity: insights from epigenetics. Immunology 2011; 134(3): 235-45.
[http://dx.doi.org/10.1111/j.1365-2567.2011.03483.x] [PMID: 21977994]
]. As long as the S. aureus resides in the macrophage phagosome, its elimination by T-cell cytokines is more pronounced by IFN-γ [87Hirahara K, Vahedi G, Ghoreschi K, et al. Helper T-cell differentiation and plasticity: insights from epigenetics. Immunology 2011; 134(3): 235-45.
[http://dx.doi.org/10.1111/j.1365-2567.2011.03483.x] [PMID: 21977994]
]. The infected cell must now be lysed by Cytotoxic Cells (CT) cells and/or NK cells [88Bröker BM, Mrochen D, Péton V. The T cell response to Staphylococcus aureus. Pathogens 2016; 5(1): 31.
[http://dx.doi.org/10.3390/pathogens5010031] [PMID: 26999219]
]. Finally, T cells are essential for the (re) establishment of immune homeostasis by blocking inflammatory processes [88Bröker BM, Mrochen D, Péton V. The T cell response to Staphylococcus aureus. Pathogens 2016; 5(1): 31.
[http://dx.doi.org/10.3390/pathogens5010031] [PMID: 26999219]
]. Treg regulatory (T-reg) cells specialize in this critical immune function [88Bröker BM, Mrochen D, Péton V. The T cell response to Staphylococcus aureus. Pathogens 2016; 5(1): 31.
[http://dx.doi.org/10.3390/pathogens5010031] [PMID: 26999219]
]. T lymphocytes proliferate upon binding to the antigen, producing a variety of T cells, including some lethal T and some T memory [89Smith-Garvin JE, Koretzky GA, Jordan MS. T cell activation. Annu Rev Immunol 2009; 27: 591-619.
[http://dx.doi.org/10.1146/annurev.immunol.021908.132706] [PMID: 19132916]
, 90Wagner C, Kotsougiani D, Pioch M, Prior B, Wentzensen A, Hänsch GM. T lymphocytes in acute bacterial infection: increased prevalence of CD11b(+) cells in the peripheral blood and recruitment to the infected site. Immunology 2008; 125(4): 503-9.
[http://dx.doi.org/10.1111/j.1365-2567.2008.02863.x] [PMID: 18479349]
]. Lethal T cells directly invade virus-infected cells and cancer cells and kill them [90Wagner C, Kotsougiani D, Pioch M, Prior B, Wentzensen A, Hänsch GM. T lymphocytes in acute bacterial infection: increased prevalence of CD11b(+) cells in the peripheral blood and recruitment to the infected site. Immunology 2008; 125(4): 503-9.
[http://dx.doi.org/10.1111/j.1365-2567.2008.02863.x] [PMID: 18479349]
]. That is why this type of immune response to cellular immunity is known [90Wagner C, Kotsougiani D, Pioch M, Prior B, Wentzensen A, Hänsch GM. T lymphocytes in acute bacterial infection: increased prevalence of CD11b(+) cells in the peripheral blood and recruitment to the infected site. Immunology 2008; 125(4): 503-9.
[http://dx.doi.org/10.1111/j.1365-2567.2008.02863.x] [PMID: 18479349]
]. T lymphocyte is thymic-derived cells that form particular TCR receptors that detect peptides derived from antigen in terms of MHC molecules on antigen APC cells. Similar to antibody and B lymphocytes, a case could be formed for an activity for T lymphocytes in S. aureus infection according to the presence of detectable T lymphocytes reactions in humans and the capacity of the bacteria to modulate T lymphocytes as exemplified by their formation of a multitude of T lymphocyte super-antigens [91Kolata JB, Kühbandner I, Link C, et al. The fall of a dogma? Unexpected high T-cell memory response to Staphylococcus aureus in humans. J Infect Dis 2015; 212(5): 830-8.
[http://dx.doi.org/10.1093/infdis/jiv128] [PMID: 25737563]
, 92Spaulding AR, Salgado-Pabón W, Kohler PL, Horswill AR, Leung DY, Schlievert PM. Staphylococcal and streptococcal superantigen exotoxins. Clin Microbiol Rev 2013; 26(3): 422-47.
[http://dx.doi.org/10.1128/CMR.00104-12] [PMID: 23824366]
]. Nevertheless, it has been found that T lymphocyte is not essential for protection toward S. aureus in mice [93Schmaler M, Jann NJ, Ferracin F, Landmann R. T and B cells are not required for clearing Staphylococcus aureus in systemic infection despite a strong TLR2-MyD88-dependent T cell activation. J Immunol 2011; 186(1): 443-52.
[http://dx.doi.org/10.4049/jimmunol.1001407] [PMID: 21131426]
]. Different sets of T lymphocyte have differing activities, and further nuanced activities for these sets have become a document in mouse evaluations and with the detected susceptibility to various staphylococcal infections of individuals with Human Immunodeficiency Viruses (HIV) disorder [94Hidron AI, Kempker R, Moanna A, Rimland D. Methicillin-resistant Staphylococcus aureus in HIV-infected patients. Infect Drug Resist 2010; 3: 73-86.
[http://dx.doi.org/10.2147/IDR.S7641] [PMID: 21694896]
]. Most of T lymphocytes like CD4 (positive) and CD8 (positive) T lymphocytes have long been detected as a main cellular weapon of adaptive immunity of host [95Pennock ND, White JT, Cross EW, Cheney EE, Tamburini BA, Kedl RM. T cell responses: naive to memory and everything in between. Adv Physiol Educ 2013; 37(4): 273-83.
[http://dx.doi.org/10.1152/advan.00066.2013] [PMID: 24292902]
]. The main activity of CD8 (positive) T lymphocytes is to kill intracellular microbial pathogens by the cytolytic killing of the infected human cell [96Stenger S, Modlin RL. Cytotoxic T cell responses to intracellular pathogens. Curr Opin Immunol 1998; 10(4): 471-7.
[http://dx.doi.org/10.1016/S0952-7915(98)80123-4] [PMID: 9722925]
]. Consistent with S. aureus cells being an early extracellular microbial pathogen, the clear activities for CD8 (positive) T lymphocytes have not been found, although activation of CD8 positive T lymphocytes could be found in staphylococcal super-antigen exposure and S. aureus infection. Naive CD4 positive T lymphocytes are polarized against different effector activities mediated to the cytokine milieu in which stimulation of their TCR receptor occurs. These Th lymphocytes are functionally determined by their cytokine formation profiles. A rate of these polarized lymphocytes will exist in the human as memory lymphocytes awaiting re-stimulation by next exposure to antigen. More recently, in addition to CD4 positive and CD8 positive T lymphocytes, a set of T lymphocytes has been described, such as γδ T lymphocytes, NK cells, and innate lymphoid cells, that involve mostly in the innate immune reactions at mucosal locations instead of memory specific to the antigen, although current works have proposed the potential for γδ T lymphocytes to involve in a memory reaction under some conditions [97Murphy AG, O’Keeffe KM, Lalor SJ, Maher BM, Mills KH, McLoughlin RM. Staphylococcus aureus infection of mice expands a population of memory γδ T cells that are protective against subsequent infection. J Immunol 2014; 192(8): 3697-708.
[http://dx.doi.org/10.4049/jimmunol.1303420] [PMID: 24623128]
].

CONCLUSION

In summary, host immunity in S. aureus infections is tissue-specific and it significantly is mediated to PRRs, like NOD-2, TLR-2, and for particular cytokine signaling mechanisms, like IL-1. Nevertheless, adaptive host immunity (B and T lymphocyte reactions) can impact this defense. Overall, the immune reaction toward S. aureus contributes to the stimulation of both innate and adaptive reactions. Adaptive immunity of the host may impact susceptibility to infections of S. aureus and its ability has specific significance in determining the results of chronic persistent human infections. Finally, a profound understanding of the human immune response to S. aureus infections will be critical for the development of vaccines and novel therapies.

AUTHOR'S CONTRIBUTIONS

R.M, S.K, R.G, S.G prepared the manuscript, and R. R edited the manuscript and H.H designed the figure.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None declared.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Thanks to guidance and advice from the “Clinical Research Development Unit of Baqiyatallah Hospital”. The authors also thank the Department of Microbiology of Hamadan, Hamadan University of Medical Sciences, Iran.

REFERENCES

[1] Taylor TA, Unakal CG. Staphylococcus aureus. StatPearls [Internet]: StatPearls Publishing 2019.
[2] Lowy FD. Staphylococcus aureus infections. N Engl J Med 1998; 339(8): 520-32.
[http://dx.doi.org/10.1056/NEJM199808203390806] [PMID: 9709046]
[3] Levy SB. Antibiotic resistance-the problem intensifies. Adv Drug Deliv Rev 2005; 57(10): 1446-50.
[http://dx.doi.org/10.1016/j.addr.2005.04.001] [PMID: 15949867]
[4] Brown AF, Leech JM, Rogers TR, McLoughlin RM. Staphylococcus aureus Colonization: Modulation of Host Immune Response and Impact on Human Vaccine Design. Front Immunol 2014; 4: 507.
[http://dx.doi.org/10.3389/fimmu.2013.00507] [PMID: 24409186]
[5] Tong SYC, Davis JS, Eichenberger E, Holland TL, Fowler VG Jr. Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev 2015; 28(3): 603-61.
[http://dx.doi.org/10.1128/CMR.00134-14] [PMID: 26016486]
[6] Chaplin DD. 1. Overview of the human immune response. J Allergy Clin Immunol 2006; 117(2)(Suppl Mini-Primer): S430-5.
[http://dx.doi.org/10.1016/j.jaci.2005.09.034] [PMID: 16455341]
[7] Rasoul M, Rokhsareh M, Mohammad SM, Sajad K, Ahmadreza M. The Human Immune System against Staphylococcus epidermidis. Critical Reviews™ in Immunology 2019; 39
[8] Müller U, Vogel P, Alber G, Schaub GA. The innate immune system of mammals and insects Trends in innate immunity 2008; 21-44.
[9] Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010; 11(5): 373-84.
[http://dx.doi.org/10.1038/ni.1863] [PMID: 20404851]
[10] Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 2011; 11(8): 519-31.
[http://dx.doi.org/10.1038/nri3024] [PMID: 21785456]
[11] Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Clin Immunol 2010; 125(2)(Suppl. 2): S33-40.
[http://dx.doi.org/10.1016/j.jaci.2009.09.017] [PMID: 20061006]
[12] Nestle FO, Di Meglio P, Qin J-Z, Nickoloff BJ. Skin immune sentinels in health and disease. Nat Rev Immunol 2009; 9(10): 679-91.
[http://dx.doi.org/10.1038/nri2622] [PMID: 19763149]
[13] Di Meglio P, Perera GK, Nestle FO. The multitasking organ: recent insights into skin immune function. Immunity 2011; 35(6): 857-69.
[http://dx.doi.org/10.1016/j.immuni.2011.12.003] [PMID: 22195743]
[14] Matejuk A. Skin Immunity. Arch Immunol Ther Exp (Warsz) 2018; 66(1): 45-54.
[http://dx.doi.org/10.1007/s00005-017-0477-3] [PMID: 28623375]
[15] Ibrahim F, Khan T, Pujalte GG. Bacterial Skin Infections. Prim Care 2015; 42(4): 485-99.
[http://dx.doi.org/10.1016/j.pop.2015.08.001] [PMID: 26612370]
[16] Miller LS. Toll-like receptors in skin. Adv Dermatol 2008; 24: 71-87.
[http://dx.doi.org/10.1016/j.yadr.2008.09.004] [PMID: 19256306]
[17] Amarante-Mendes GP, Adjemian S, Branco LM, Zanetti LC, Weinlich R, Bortoluci KR. Pattern recognition receptors and the host cell death molecular machinery. Front Immunol 2018; 9: 2379.
[http://dx.doi.org/10.3389/fimmu.2018.02379] [PMID: 30459758]
[18] Pasparakis M, Haase I, Nestle FO. Mechanisms regulating skin immunity and inflammation. Nat Rev Immunol 2014; 14(5): 289-301.
[http://dx.doi.org/10.1038/nri3646] [PMID: 24722477]
[19] Bitschar K, Wolz C, Krismer B, Peschel A, Schittek B. Keratinocytes as sensors and central players in the immune defense against Staphylococcus aureus in the skin. J Dermatol Sci 2017; 87(3): 215-20.
[http://dx.doi.org/10.1016/j.jdermsci.2017.06.003] [PMID: 28655473]
[20] Fournier B. The function of TLR2 during staphylococcal diseases. Front Cell Infect Microbiol 2013; 2: 167.
[http://dx.doi.org/10.3389/fcimb.2012.00167] [PMID: 23316483]
[21] Ozinsky A, Underhill DM, Fontenot JD, et al. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci USA 2000; 97(25): 13766-71.
[http://dx.doi.org/10.1073/pnas.250476497] [PMID: 11095740]
[22] Verstak B, Stack J, Ve T, et al. The TLR signaling adaptor TRAM interacts with TRAF6 to mediate activation of the inflammatory response by TLR4. J Leukoc Biol 2014; 96(3): 427-36.
[http://dx.doi.org/10.1189/jlb.2A0913-487R] [PMID: 24812060]
[23] Yimin KM, Kohanawa M, Zhao S, et al. Contribution of toll-like receptor 2 to the innate response against Staphylococcus aureus infection in mice. PLoS One 2013; 8(9)e74287
[http://dx.doi.org/10.1371/journal.pone.0074287] [PMID: 24058538]
[24] Feuerstein R, Seidl M, Prinz M, Henneke P. MyD88 in macrophages is critical for abscess resolution in staphylococcal skin infection. Journal of immunology (Baltimore, Md : 1950) 2015; 194: 2735-45.
[http://dx.doi.org/10.4049/jimmunol.1402566]
[25] Smith JA. Neutrophils, host defense, and inflammation: a double-edged sword. J Leukoc Biol 1994; 56(6): 672-86.
[http://dx.doi.org/10.1002/jlb.56.6.672] [PMID: 7996043]
[26] Rigby KM, DeLeo FR. Neutrophils in innate host defense against Staphylococcus aureus infections. Semin Immunopathol 2012; 34(2): 237-59.
[http://dx.doi.org/10.1007/s00281-011-0295-3] [PMID: 22080185]
[27] Takada H, Uehara A. Enhancement of TLR-mediated innate immune responses by peptidoglycans through NOD signaling. Curr Pharm Des 2006; 12(32): 4163-72.
[http://dx.doi.org/10.2174/138161206778743510] [PMID: 17100619]
[28] Girardin SE, Boneca IG, Viala J, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 2003; 278(11): 8869-72.
[http://dx.doi.org/10.1074/jbc.C200651200] [PMID: 12527755]
[29] Schäffler H, Demircioglu DD, Kühner D, et al. NOD2 stimulation by Staphylococcus aureus-derived peptidoglycan is boosted by Toll-like receptor 2 costimulation with lipoproteins in dendritic cells. Infect Immun 2014; 82(11): 4681-8.
[http://dx.doi.org/10.1128/IAI.02043-14] [PMID: 25156723]
[30] Parker D, Planet PJ, Soong G, Narechania A, Prince A. Induction of type I interferon signaling determines the relative pathogenicity of Staphylococcus aureus strains. PLoS Pathog 2014; 10(2)e1003951
[http://dx.doi.org/10.1371/journal.ppat.1003951] [PMID: 24586160]
[31] Castleman MJ, Febbraio M, Hall PR. CD36 Is Essential for Regulation of the Host Innate Response to Staphylococcus aureus α-Toxin-Mediated Dermonecrosis. J Immunol 2015; 195(5): 2294-302.
[http://dx.doi.org/10.4049/jimmunol.1500500] [PMID: 26223653]
[32] Blanchet C, Jouvion G, Fitting C, Cavaillon J-M, Adib-Conquy M. Protective or deleterious role of scavenger receptors SR-A and CD36 on host resistance to Staphylococcus aureus depends on the site of infection. PLoS One 2014; 9(1)e87927
[http://dx.doi.org/10.1371/journal.pone.0087927] [PMID: 24498223]
[33] Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 2014; 15(5): 300-12.
[http://dx.doi.org/10.1038/nrn3722] [PMID: 24713688]
[34] Abtin A, Jain R, Mitchell AJ, et al. Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection. Nat Immunol 2014; 15(1): 45-53.
[http://dx.doi.org/10.1038/ni.2769] [PMID: 24270515]
[35] Kobayashi SD, Malachowa N, DeLeo FR. Pathogenesis of Staphylococcus aureus abscesses. Am J Pathol 2015; 185(6): 1518-27.
[http://dx.doi.org/10.1016/j.ajpath.2014.11.030] [PMID: 25749135]
[36] Feuerstein R, Kolter J, Henneke P. Dynamic interactions between dermal macrophages and Staphylococcus aureus. J Leukoc Biol 2017; 101(1): 99-106.
[http://dx.doi.org/10.1189/jlb.3MR0316-097RR] [PMID: 27733573]
[37] Miller LS, O’Connell RM, Gutierrez MA, et al. MyD88 mediates neutrophil recruitment initiated by IL-1R but not TLR2 activation in immunity against Staphylococcus aureus. Immunity 2006; 24(1): 79-91.
[http://dx.doi.org/10.1016/j.immuni.2005.11.011] [PMID: 16413925]
[38] Guerra FE, Borgogna TR, Patel DM, Sward EW, Voyich JM. Epic immune battles of history: neutrophils vs. Staphylococcus aureus. Front Cell Infect Microbiol 2017; 7: 286.
[http://dx.doi.org/10.3389/fcimb.2017.00286] [PMID: 28713774]
[39] Parker D, Prince A. Immunoregulatory effects of necroptosis in bacterial infections. Cytokine 2016; 88: 274-5.
[http://dx.doi.org/10.1016/j.cyto.2016.09.024] [PMID: 27710879]
[40] Kashem SW, Haniffa M, Kaplan DH. Antigen-presenting cells in the skin. Annu Rev Immunol 2017; 35: 469-99.
[http://dx.doi.org/10.1146/annurev-immunol-051116-052215] [PMID: 28226228]
[41] Kaplan DH. Ontogeny and function of murine epidermal Langerhans cells. Nat Immunol 2017; 18(10): 1068-75.
[http://dx.doi.org/10.1038/ni.3815] [PMID: 28926543]
[42] Dejani NN, Brandt SL, Piñeros A, et al. Topical Prostaglandin E Analog Restores Defective Dendritic Cell-Mediated Th17 Host Defense Against Methicillin-Resistant Staphylococcus Aureus in the Skin of Diabetic Mice. Diabetes 2016; 65(12): 3718-29.
[http://dx.doi.org/10.2337/db16-0565] [PMID: 27605625]
[43] Ouchi T, Kubo A, Yokouchi M, et al. Langerhans cell antigen capture through tight junctions confers preemptive immunity in experimental staphylococcal scalded skin syndrome. J Exp Med 2011; 208(13): 2607-13.
[http://dx.doi.org/10.1084/jem.20111718] [PMID: 22143886]
[44] Darisipudi MN, Nordengrün M, Bröker BM, Péton V. Messing with the Sentinels-The Interaction of Staphylococcus aureus with Dendritic Cells. Microorganisms 2018; 6(3): 87.
[http://dx.doi.org/10.3390/microorganisms6030087] [PMID: 30111706]
[45] Harrison CJ. Innate immunity as a key element in host defense against methicillin resistant Staphylococcus aureus. Minerva Pediatr 2009; 61(5): 503-14.
[PMID: 19794376]
[46] Nauseef WM. The phagocyte NOX2 NADPH oxidase in microbial killing and cell signaling. Curr Opin Immunol 2019; 60: 130-40.
[http://dx.doi.org/10.1016/j.coi.2019.05.006] [PMID: 31302569]
[47] Li C, Li H, Jiang Z, et al. Interleukin-33 increases antibacterial defense by activation of inducible nitric oxide synthase in skin. PLoS Pathog 2014; 10(2)e1003918
[http://dx.doi.org/10.1371/journal.ppat.1003918] [PMID: 24586149]
[48] Grosser MR, Weiss A, Shaw LN, Richardson AR. Regulatory requirements for Staphylococcus aureus nitric oxide resistance. J Bacteriol 2016; 198(15): 2043-55.
[http://dx.doi.org/10.1128/JB.00229-16] [PMID: 27185828]
[49] Vitko NP, Spahich NA, Richardson AR. Glycolytic dependency of high-level nitric oxide resistance and virulence in Staphylococcus aureus. MBio 2015; 6(2): e00045-15.
[http://dx.doi.org/10.1128/mBio.00045-15] [PMID: 25852157]
[50] Kobayashi Y. Neutrophil biology: an update. EXCLI J 2015; 14: 220-7.
[PMID: 26600743]
[51] Greenlee-Wacker M, DeLeo FR, Nauseef WM. How methicillin-resistant Staphylococcus aureus evade neutrophil killing. Curr Opin Hematol 2015; 22(1): 30-5.
[http://dx.doi.org/10.1097/MOH.0000000000000096] [PMID: 25394313]
[52] van Kessel KP, Bestebroer J, van Strijp JA. Neutrophil-mediated phagocytosis of Staphylococcus aureus. Front Immunol 2014; 5: 467.
[http://dx.doi.org/10.3389/fimmu.2014.00467] [PMID: 25309547]
[53] Yipp BG, Petri B, Salina D, et al. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med 2012; 18(9): 1386-93.
[http://dx.doi.org/10.1038/nm.2847] [PMID: 22922410]
[54] Boeltz S, Amini P, Anders H-J, et al. To NET or not to NET:current opinions and state of the science regarding the formation of neutrophil extracellular traps. Cell Death Differ 2019; 26(3): 395-408.
[http://dx.doi.org/10.1038/s41418-018-0261-x] [PMID: 30622307]
[55] Sultan AR, Hoppenbrouwers T, Lemmens-den Toom NA, et al. During the Early Stages of Staphylococcus aureus Biofilm Formation, Induced Neutrophil Extracellular Traps Are Degraded by Autologous Thermonuclease. Infect Immun 2019; 87(12): 87.
[http://dx.doi.org/10.1128/IAI.00605-19] [PMID: 31527127]
[56] van der Does AM, Hiemstra PS, Mookherjee N. Antimicrobial Host Defence Peptides: Immunomodulatory Functions and Translational Prospects Antimicrobial Peptides 2019; 149-71.
[http://dx.doi.org/10.1007/978-981-13-3588-4_10]
[57] Prasad SV, Fiedoruk K, Daniluk T, Piktel E, Bucki R. Expression and Function of Host Defense Peptides at Inflammation Sites. Int J Mol Sci 2019; 21(1): 104.
[http://dx.doi.org/10.3390/ijms21010104] [PMID: 31877866]
[58] Glenthøj A, Nickles K, Cowland J, Borregaard N. Processing of neutrophil α-defensins does not rely on serine proteases in vivo. PLoS One 2015; 10(5)e0125483
[http://dx.doi.org/10.1371/journal.pone.0125483] [PMID: 25945506]
[59] Ericksen B, Wu Z, Lu W, Lehrer RI. Antibacterial activity and specificity of the six human α-defensins. Antimicrob Agents Chemother 2005; 49(1): 269-75.
[http://dx.doi.org/10.1128/AAC.49.1.269-275.2005] [PMID: 15616305]
[60] Kiatsurayanon C, Ogawa H, Niyonsaba F. The role of host defense peptide human β-defensins in the maintenance of skin barriers. Curr Pharm Des 2018; 24(10): 1092-9.
[http://dx.doi.org/10.2174/1381612824666180327164445] [PMID: 29589537]
[61] Schauber J, Gallo RL. Antimicrobial peptides and the skin immune defense system. J Allergy Clin Immunol 2008; 122(2): 261-6.
[http://dx.doi.org/10.1016/j.jaci.2008.03.027] [PMID: 18439663]
[62] Otto M. Staphylococcus colonization of the skin and antimicrobial peptides. Expert Rev Dermatol 2010; 5(2): 183-95.
[http://dx.doi.org/10.1586/edm.10.6] [PMID: 20473345]
[63] Zhang M, Liang W, Gong W, Yoshimura T, Chen K, Wang JM. The Critical Role of the Antimicrobial Peptide LL-37/CRAMP in Protection of Colon Microbiota Balance, Mucosal Homeostasis, Anti-Inflammatory Responses, and Resistance to Carcinogenesis. Critical Reviews™ in Immunology 2019; 39
[64] Febriza A, Hatta M, Natzir R, Kasim VN, Idrus HH. Activity of Antimicrobial Peptide; Cathelicidin, on Bacterial Infection. Open Biochem J 2019; 13.
[http://dx.doi.org/10.2174/1874091X01913010045]
[65] Rademacher F, Dreyer S, Kopfnagel V, Gläser R, Werfel T, Harder J. The antimicrobial and immunomodulatory function of RNase 7 in skin. Front Immunol 2019; 10: 2553.
[http://dx.doi.org/10.3389/fimmu.2019.02553] [PMID: 31749808]
[66] Simanski M, Dressel S, Gläser R, Harder J. RNase 7 protects healthy skin from Staphylococcus aureus colonization. J Invest Dermatol 2010; 130(12): 2836-8.
[http://dx.doi.org/10.1038/jid.2010.217] [PMID: 20668470]
[67] Liu Q, Mazhar M, Miller LS. Immune and Inflammatory Reponses to Staphylococcus aureus Skin Infections. Curr Dermatol Rep 2018; 7(4): 338-49.
[http://dx.doi.org/10.1007/s13671-018-0235-8] [PMID: 30989002]
[68] Herman A, Herman AP. Antimicrobial peptides activity in the skin. Skin Res Technol 2019; 25(2): 111-7.
[http://dx.doi.org/10.1111/srt.12626] [PMID: 30320469]
[69] Felgueiras HP, Amorim M. Antimicrobial peptides in infected wounds 2019.
[http://dx.doi.org/10.33582/research-trends-of-microbiology/antimicrobial-peptides-in-infected-wounds]
[70] Wolf AJ, Underhill DM. Peptidoglycan recognition by the innate immune system. Nat Rev Immunol 2018; 18(4): 243-54.
[http://dx.doi.org/10.1038/nri.2017.136] [PMID: 29292393]
[71] Cho JH, Fraser IP, Fukase K, et al. Human peptidoglycan recognition protein S is an effector of neutrophil-mediated innate immunity. Blood 2005; 106(7): 2551-8.
[http://dx.doi.org/10.1182/blood-2005-02-0530] [PMID: 15956276]
[72] Dziarski R, Royet J, Gupta D. Peptidoglycan recognition proteins and lysozyme Molecular Immunology 2016; 389-403.
[73] Wang Z-M, Li X, Cocklin RR, et al. Human peptidoglycan recognition protein-L is an N-acetylmuramoyl-L-alanine amidase. J Biol Chem 2003; 278(49): 49044-52.
[http://dx.doi.org/10.1074/jbc.M307758200] [PMID: 14506276]
[74] Dziarski R, Gupta D. Review: Mammalian peptidoglycan recognition proteins (PGRPs) in innate immunity. Innate Immun 2010; 16(3): 168-74.
[http://dx.doi.org/10.1177/1753425910366059] [PMID: 20418257]
[75] Parnham MJ, Rossi AG. Innate Immunity: Phagocytes, Natural Killer Cells, and the Complement System Nijkamp and Parnham’s Principles of Immunopharmacology 2019; 117-37.
[http://dx.doi.org/10.1007/978-3-030-10811-3_8]
[76] Rich RR, Chaplin DD. The human immune response.Clinical Immunology: Elsevier 2019; 3-17.
[77] Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT. Complement System Part I - Molecular Mechanisms of Activation and Regulation. Front Immunol 2015; 6: 262.
[http://dx.doi.org/10.3389/fimmu.2015.00262] [PMID: 26082779]
[78] Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140(6): 805-20.
[http://dx.doi.org/10.1016/j.cell.2010.01.022] [PMID: 20303872]
[79] Wanke I, Steffen H, Christ C, et al. Skin commensals amplify the innate immune response to pathogens by activation of distinct signaling pathways. J Invest Dermatol 2011; 131(2): 382-90.
[http://dx.doi.org/10.1038/jid.2010.328] [PMID: 21048787]
[80] Nygaard TK, Kobayashi SD, Freedman B, Porter AR, Voyich JM, Otto M, et al. Interaction of Staphylococci with Human B cells. PloS one 2016; e0164410-e.
[81] Cooper MD, Alder MN. The evolution of adaptive immune systems. Cell 2006; 124(4): 815-22.
[http://dx.doi.org/10.1016/j.cell.2006.02.001] [PMID: 16497590]
[82] Rossetti RAM, Lorenzi NPC, Yokochi K, et al. B lymphocytes can be activated to act as antigen presenting cells to promote anti-tumor responses. PLoS One 2018; 13(7)e0199034
[http://dx.doi.org/10.1371/journal.pone.0199034] [PMID: 29975708]
[83] Kurosaki T, Kometani K, Ise W. Memory B cells. Nat Rev Immunol 2015; 15(3): 149-59.
[http://dx.doi.org/10.1038/nri3802] [PMID: 25677494]
[84] Bruton OC. Agammaglobulinemia. Pediatrics 1952; 9(6): 722-8.
[PMID: 14929630]
[85] Montgomery CP, Daniels M, Zhao F, Alegre M-L, Chong AS, Daum RS. Protective immunity against recurrent Staphylococcus aureus skin infection requires antibody and interleukin-17A. Infect Immun 2014; 82(5): 2125-34.
[http://dx.doi.org/10.1128/IAI.01491-14] [PMID: 24614654]
[86] McHeyzer-Williams M, Okitsu S, Wang N, McHeyzer-Williams L. Molecular programming of B cell memory. Nat Rev Immunol 2011; 12(1): 24-34.
[http://dx.doi.org/10.1038/nri3128] [PMID: 22158414]
[87] Hirahara K, Vahedi G, Ghoreschi K, et al. Helper T-cell differentiation and plasticity: insights from epigenetics. Immunology 2011; 134(3): 235-45.
[http://dx.doi.org/10.1111/j.1365-2567.2011.03483.x] [PMID: 21977994]
[88] Bröker BM, Mrochen D, Péton V. The T cell response to Staphylococcus aureus. Pathogens 2016; 5(1): 31.
[http://dx.doi.org/10.3390/pathogens5010031] [PMID: 26999219]
[89] Smith-Garvin JE, Koretzky GA, Jordan MS. T cell activation. Annu Rev Immunol 2009; 27: 591-619.
[http://dx.doi.org/10.1146/annurev.immunol.021908.132706] [PMID: 19132916]
[90] Wagner C, Kotsougiani D, Pioch M, Prior B, Wentzensen A, Hänsch GM. T lymphocytes in acute bacterial infection: increased prevalence of CD11b(+) cells in the peripheral blood and recruitment to the infected site. Immunology 2008; 125(4): 503-9.
[http://dx.doi.org/10.1111/j.1365-2567.2008.02863.x] [PMID: 18479349]
[91] Kolata JB, Kühbandner I, Link C, et al. The fall of a dogma? Unexpected high T-cell memory response to Staphylococcus aureus in humans. J Infect Dis 2015; 212(5): 830-8.
[http://dx.doi.org/10.1093/infdis/jiv128] [PMID: 25737563]
[92] Spaulding AR, Salgado-Pabón W, Kohler PL, Horswill AR, Leung DY, Schlievert PM. Staphylococcal and streptococcal superantigen exotoxins. Clin Microbiol Rev 2013; 26(3): 422-47.
[http://dx.doi.org/10.1128/CMR.00104-12] [PMID: 23824366]
[93] Schmaler M, Jann NJ, Ferracin F, Landmann R. T and B cells are not required for clearing Staphylococcus aureus in systemic infection despite a strong TLR2-MyD88-dependent T cell activation. J Immunol 2011; 186(1): 443-52.
[http://dx.doi.org/10.4049/jimmunol.1001407] [PMID: 21131426]
[94] Hidron AI, Kempker R, Moanna A, Rimland D. Methicillin-resistant Staphylococcus aureus in HIV-infected patients. Infect Drug Resist 2010; 3: 73-86.
[http://dx.doi.org/10.2147/IDR.S7641] [PMID: 21694896]
[95] Pennock ND, White JT, Cross EW, Cheney EE, Tamburini BA, Kedl RM. T cell responses: naive to memory and everything in between. Adv Physiol Educ 2013; 37(4): 273-83.
[http://dx.doi.org/10.1152/advan.00066.2013] [PMID: 24292902]
[96] Stenger S, Modlin RL. Cytotoxic T cell responses to intracellular pathogens. Curr Opin Immunol 1998; 10(4): 471-7.
[http://dx.doi.org/10.1016/S0952-7915(98)80123-4] [PMID: 9722925]
[97] Murphy AG, O’Keeffe KM, Lalor SJ, Maher BM, Mills KH, McLoughlin RM. Staphylococcus aureus infection of mice expands a population of memory γδ T cells that are protective against subsequent infection. J Immunol 2014; 192(8): 3697-708.
[http://dx.doi.org/10.4049/jimmunol.1303420] [PMID: 24623128]
Track Your Manuscript:


Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


Browse Contents




Webmaster Contact: info@benthamopen.net
Copyright © 2020 Bentham Open