The Open Toxicology Journal




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ISSN: 1874-3404 ― Volume 7, 2021

Blood Hemostasis Dysfunction and Inflammation in COVID-19 Patients: Viral and Host Active Molecules as Therapeutic Targets



Mourad Errasfa1, *
1 Department of Pharmacology, Faculty of Medicine and Pharmacy, University of Sidi Mohamed Ben Abdellah, Fez, Morocco

Abstract

The COVID-19 pandemic is challenging world health authorities and researchers. WHO is supervising many clinical studies to ascertain whether some known drugs can be effective against the disease. Meanwhile, researchers around the globe are working on cellular and molecular mechanisms that are key steps of SARS-Cov-2 associated infection. Blood hemostasis dysfunction, inflammation, hypoxia and venous thrombotic events are reported to be involved in the pathophysiology of COVID-19 patients at early and late severe stages of the disease. It is of high relevance to understand how SARS-Cov-2 triggers negative cellular and biochemical events in infected persons. A large number of cell species and active molecules, such as blood and tissue enzymes, cytokines, and other active amines and lipid inflammatory molecular species, can be involved in immune reactions and host defense mechanisms upon human infectious diseases or other kinds of health issues such as trauma or snake envenomation. Possible physiopathology trends of COVID-19 and some therapeutic perspectives are discussed in the present minireview.

Keywords: SARS-Cov-2, COVID-19, Hemostasis, Blood, Coagulation, Fibrinolysis, Inflammation, Serine proteases.


Article Information


Identifiers and Pagination:

Year: 2021
Volume: 7
First Page: 1
Last Page: 7
Publisher Id: TOTOXIJ-7-1
DOI: 10.2174/1874340402107010001

Article History:

Received Date: 07/05/2020
Revision Received Date: 18/09/2020
Acceptance Date: 11/11/2020
Electronic publication date: 02/03/2021
Collection year: 2021

© 2021 Mourad Errasfa.

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 Department of Pharmacology, Faculty of Medicine and Pharmacy, University of Sidi Mohamed Ben Abdellah, Fez, Morocco; E-mail: mourad.er-rasfa@usmba.ac.ma





1. INTRODUCTION

The COVID-19 pandemic caused by SARS-Cov-2 took place early this year after a first patient was diagnosed with ARSD in Wuhan (China). The virus molecular characterization was reported and its target receptor was identified [1Wu F, Zhao S, Yu B, et al. A new coronavirus associated with human respiratory disease in China. Nature 2020; 579(7798): 265-9.
[http://dx.doi.org/10.1038/s41586-020-2008-3] [PMID: 32015508]
, 2Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020; 181(2): 281-292.e6.
[http://dx.doi.org/10.1016/j.cell.2020.02.058] [PMID: 32155444]
] as the membrane angiotensin-converting enzyme-2. Researches on effective drug therapy were launched in clinical studies like the Solidarity Trial and the Discovery Trial in Europe. Both clinical trial studies include many classic antiviral and antiretroviral molecules, anti-malaria drugs, cytokines, antibodies and Chinese plant extracts [3Aronson KJ, Ferner RE, DeVito N, Heneghan C. COVID-19 trials registered up to 8 March 2020: An analysis of 382 studies. The Centre for Evidence-Based Medicine 2020. https://www.cebm.net/covid- 19/registered-trials-and-analysis/-5Who.int. 2021. “Solidarity” clinical trial for COVID-19 treatments. [online] Available at:. https://www.who.int/emergencies/diseases /novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-COVID-19-treatments]. Recent clinical findings have found that COVID-19 patients can suffer from hypoxia [6Xie J, Covassin N, Fan Z, et al. Association between hypoxemia and mortality in patients with COVID-19. Mayo Clin Proc 2020; 95(6): 1138-47.
[http://dx.doi.org/10.1016/j.mayocp.2020.04.006] [PMID: 32376101]
], pulmonary venous thromboembolism [7Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost 2020; 18(6): 1421-4.
[http://dx.doi.org/10.1111/jth.14830] [PMID: 32271988]
], and gut dysbiosis [8Zuo T, Zhang F, Lui GCY, et al. Alterations in gut microbiota of patients with COVID-19 during time of hospitalization [published online ahead of print, 2020 May 20]. Gastroenterology 2020; S0016-5085(20): 34701-6.-10Chan JF, Yuan S, Kok KH, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster. Lancet 2020; 395(10223): 514-23.
[http://dx.doi.org/10.1016/S0140-6736(20)30154-9] [PMID: 31986261]
]. Similar viral infection-associated dysbiosis was described earlier upon viral infections [11Hanada S, Pirzadeh M, Carver KY, Deng JC. Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia. Front Immunol 2018; 9: 2640.
[http://dx.doi.org/10.3389/fimmu.2018.02640] [PMID: 30505304]
]. SARS-Cov-2 -associated respiratory distress syndrome is the leading cause of death in COVID-19 patients. However, the underlying mechanisms that cause death are still not totally known.

Recent scientific reports have shown that the severity of COVID-19 symptoms, as well as the mortality caused by COVID-19, would significantly affect the population after 40 years of age, and this incidence increases with age [12The Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus Diseases (COVID-19) — China. http://weekly.chinacdc .cn/en/article/id/e53946e2-c6c4-41e9-9a9b-fea8db1a8f51]. The highest death figures (virus fatality index) are among those over 60 years of age, reaching 15.6% in those over 80 years of age [13Verity R, Okell LC, Dorigatti I, et al. Estimates of the severity of coronavirus disease 2019: A model-based analysis. Lancet Infect Dis 2020; 20(6): 669-77.
[http://dx.doi.org/10.1016/S1473-3099(20)30243-7] [PMID: 32240634]
]. On the other hand, individuals with underlying health conditions are more vulnerable than those without. Obese patients and those who have health issues such as cardiovascular diseases, diabetes, chronic respiratory diseases, hypertension or cancer have a higher case fatality rate for COVID-19 [14 Mortality Risk of COVID-19 - Statistics and Research [Internet]. Our World in Data. 2021 [cited 11 February 2021]. Available from:. https://ourworldindata.org/mortality-risk-covid].

2. PHYSIOPATHOLOGY ASSOCIATED WITH SARS-COV-2 INFECTION

2.1. Inflammation

Blood analyses of patients have shown “cytokines storm”, which might be leading to a serious general inflammation [15Mogensen TH, Paludan SR. Molecular pathways in virus-induced cytokine production. Microbiol Mol Biol Rev 2001; 65(1): 131-50.
[http://dx.doi.org/10.1128/MMBR.65.1.131-150.2001] [PMID: 11238989]
, 16Jose RJ, Manuel A. COVID-19 cytokine storm: The interplay between inflammation and coagulation. Lancet Respir Med 2020; 8(6): e46-7.
[http://dx.doi.org/10.1016/S2213-2600(20)30216-2] [PMID: 32353251]
]. A very large number of pro-inflammatory cytokines are described in viral infections. Pro-inflammatory cytokines are released by specialized immune cells (Fig. 1), and this phenomenon might exacerbate a patient's health weakness. It is likely that in COVID-19 patients, many blood cell species are activated, such as platelets, monocytes and neutrophils. Other tissue resident cells such as alveolar macrophages, mesangial cells or glial cells might be activated as well. A large number of active lipid [17Serhan CN. Novel lipid mediators and resolution mechanisms in acute inflammation: To resolve or not? Am J Pathol 2010; 177(4): 1576-91.
[http://dx.doi.org/10.2353/ajpath.2010.100322] [PMID: 20813960]
] inflammatory mediators (prostaglandins, leukotrienes, platelet activating factor) and edema associated molecules (histamine, serotonin and bradykinin) can play a role in the inflammatory process of COVID-19. Macrophages and neutrophils are the main cell species that release NADPH-Oxidase dependent oxygen free radicals upon their activation. Hence, oxidative stress might be an additional burden in the physiopathology of SARS-Cov-2 infection [18Schwarz KB. Oxidative stress during viral infection: A review. Free Radic Biol Med 1996; 21(5): 641-9.
[http://dx.doi.org/10.1016/0891-5849(96)00131-1] [PMID: 8891667]
]. Interestingly, recent studies, including a meta-analysis investigation [19Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: A Meta-analysis. JAMA 324(13): 1330-41.
[http://dx.doi.org/10.1001/jama.2020.17023]
], have shown that intravenous corticoid (anti-inflammatory steroids) treatment was associated with a better outcome of COVID-19 severe cases.

2.2. Hemostasis Dysfunction

Clinical and laboratory data of COVID-19 patients from many countries have pointed out several molecular and cellular mechanisms that may be crucial in the physiopathology caused by SARS-Cov-2 [20Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 2020; 130(5): 2620-9.
[http://dx.doi.org/10.1172/JCI137244] [PMID: 32217835]
, 21Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395(10229): 1054-62.
[http://dx.doi.org/10.1016/S0140-6736(20)30566-3] [PMID: 32171076]
]. It was observed that patients of COVID-19 have hypoxia and hemoglobin oxygen transport dysfunction. On the other hand, venous thromboembolism might be damaging tissues in several organs, such as kidneys, heart, lungs and brain. The hallmark of SARS-Cov-2 infection and thrombogenic blood parameters was associated with the severity of COVID-19. Blood coagulation dysfunction [22Giannis D, Ziogas IA, Gianni P. Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J Clin Virol 2020; 127: 104362.
[http://dx.doi.org/10.1016/j.jcv.2020.104362] [PMID: 32305883]
, 23Yu HH, Qin C, Chen M, Wang W, Tian DS. D-dimer level is associated with the severity of COVID-19. Thromb Res 2020; 195: 219-25.
[http://dx.doi.org/10.1016/j.thromres.2020.07.047] [PMID: 32777639]
] and thrombocytopenia [24Xu P, Zhou Q, Xu J. Mechanism of thrombocytopenia in COVID-19 patients. Ann Hematol 2020; 99(6): 1205-8.
[http://dx.doi.org/10.1007/s00277-020-04019-0] [PMID: 32296910]
] were reported in COVID-19 patients. Blood clots were found in many organs, and abnormally elevated levels of plasmin [25Ji HL, Zhao R, Matalon S, Matthay MA. Elevated plasmin(ogen) as a common risk factor for COVID-19 susceptibility. Physiol Rev 2020; 100(3): 1065-75.
[http://dx.doi.org/10.1152/physrev.00013.2020] [PMID: 32216698]
] and D-dimers [23Yu HH, Qin C, Chen M, Wang W, Tian DS. D-dimer level is associated with the severity of COVID-19. Thromb Res 2020; 195: 219-25.
[http://dx.doi.org/10.1016/j.thromres.2020.07.047] [PMID: 32777639]
] were found in severe cases of COVID-19 patients, and tissue factor was described as a possible key molecule in coagulation dysfunction in COVID-19 patients [26Bautista-Vargas M, Bonilla-Abadía F, Cañas CA. Potential role for tissue factor in the pathogenesis of hypercoagulability associated with in COVID-19. J Thromb Thrombolysis 2020; 50(3): 479-83. [published online ahead of print, 2020 Jun 9].
[http://dx.doi.org/10.1007/s11239-020-02172-x] [PMID: 32519164]
, 27van der Poll T. Tissue factor as an initiator of coagulation and inflammation in the lung. Crit Care 2008; 126: S3.
[http://dx.doi.org/10.1186/cc7026]
]. Human blood coagulation and fibrinolysis are controlled by many serine protease enzymes (Fig. 1). The physiological process of blood clotting and fibrinolysis is highly regulated by a large number of blood proteins that have enzymatic proteolytic activities, such as thrombin and plasmin, to mention just these two cornerstone enzymes. Blood hemostasis is a specific target in many infectious diseases and health issues such as envenomation. Indeed, it is known that blood clotting induced by snake venom is associated with many serine protease enzymes of the venom [28Ferraz CR, Arrahman A, Xie C, et al. Multifunctional toxins in snake venoms and therapeutic implications: From pain to hemorrhage and necrosis Frontiers in Ecology and Evolution 2019; 7www.front iersin.org]. The toxicity of snake venom is known to be associated with a large number of venom enzymes, such as phospholipases, proteases and other toxins. Among SARS-Cov-2 proteins, papain-like protease and 3-chy motrypsin-like protease are key proteases for their replication and infectivity [29Ye S, Xia H, Dong C, et al. Identification and characterization of Iflavirus 3C-like protease processing activities. Virology 2012; 428(2): 136-45.
[http://dx.doi.org/10.1016/j.virol.2012.04.002] [PMID: 22534091]
-31Xia B, Kang X. Activation and maturation of SARS-CoV main protease. Protein Cell 2011; 2(4): 282-90.
[http://dx.doi.org/10.1007/s13238-011-1034-1] [PMID: 21533772]
]. Blood coagulation and fibrinolysis in COVID-19 patients could be affected by the above viral proteases in the case of their release in the host bloodstream. They would act through similar human blood clotting/fibrinolysis protease cascade (thrombin, plasmin) or that of snake venoms protease-induced hemostasis dysfunctions [28Ferraz CR, Arrahman A, Xie C, et al. Multifunctional toxins in snake venoms and therapeutic implications: From pain to hemorrhage and necrosis Frontiers in Ecology and Evolution 2019; 7www.front iersin.org].

Fig. (1)
The figure represents groups of cells and molecules (Blood and tissue host cells, viral enzymes, snake venom enzymes) that could have close enzymatic and pharmacological interactions. The red ellipse represents blood components, clotting/fibrinolysis factors, and inflammatory mediators that are the resulting output of cells and enzymatic activations in the host body under physiological conditions or during pathological situations. Viral proteins and enzymes have close interaction with the host cells, starting from the priming of the S spike protein by host serine proteases. Blood coagulation/fibrinolysis enzymatic system involves many protease activities. Snake venom proteases, phospholipases and toxins interact with many host cells and blood components that lead to hemostasis dysfunction. The ellipse forms do not imply separate physical compartments in the host body. It is meant that foreign enzymes and molecules of invading organisms can pharmacologically interact with host enzymatic and molecular machinery, which leads to physiopathological events. * TMPRSS2: Transmembrane protease serine2. ACE2: Angiotensin converting enzyme 2. TF: Tissue factor. vWF: von Willebrand factor. tPA: Tissue plasminogen activator. PAI-1: Plasminogen activator inhibitor. PAF: platelet activating factor. NO: Nitric oxide.


2.3. Serine Protease-dependent Entry of the Virus in Host Cells

Entry of the SARS-Cov-2 in host cells was shown to involve the priming of the S spike protein of the virus by a host cell serine protease (Fig. 1). Thus, surface proteases of the host cell play a key role in the infectivity of viruses (Fig. 2). In the case of SARS-Cov-2, TMPRSS2 (Transmembrane protease serine2), a human serine protease, primes the S virus protein [32Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181(2): 271-280.e8.
[http://dx.doi.org/10.1016/j.cell.2020.02.052] [PMID: 32142651]
], and leads to the subsequent binding of the virus to its receptor; Angiotensin Converting Enzyme 2. Other host proteases could play a role in priming the S spike protein as well [33Dahms SO, Arciniega M, Steinmetzer T, Huber R, Than ME. Structure of the unliganded form of the proprotein convertase furin suggests activation by a substrate-induced mechanism. Proc Natl Acad Sci USA 2016; 113(40): 11196-201.
[http://dx.doi.org/10.1073/pnas.1613630113] [PMID: 27647913]
]. Research on the molecular sequence of SARS-Cov-2 RNA and its spike glycoprotein sequence have shed light on other host cell serine protease enzymes that could participate in priming the S protein on host cells [34Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res 2020; 176: 104742.
[http://dx.doi.org/10.1016/j.antiviral.2020.104742] [PMID: 32057769]
, 35Shang J, Wan Y, Luo C, et al. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci USA 2020; 117(21): 11727-34.
[http://dx.doi.org/10.1073/pnas.2003138117] [PMID: 32376634]
]. The above studies have shown that SARS-Cov-2 RNA, unlike its coronavirus predecessors, has a genomic sequence of 12 bases, which encodes a peptide sequence of a few amino acids that represents a cleavage site for several serine proteases found in the entire human organism. The sequence of the SARS-Cov-2 S glycoprotein would explain why the virus can infect most of the organs, and this would explain the actual higher virulence of SARS-Cov-2 and its widespread effects on the bloodstream, lungs and other organs. Interestingly, plasmin was also described as a possible priming enzyme of the S viral protein during SARS-Cov-2 infection [25Ji HL, Zhao R, Matalon S, Matthay MA. Elevated plasmin(ogen) as a common risk factor for COVID-19 susceptibility. Physiol Rev 2020; 100(3): 1065-75.
[http://dx.doi.org/10.1152/physrev.00013.2020] [PMID: 32216698]
], and its possible inhibition was suggested to be one of the therapeutic targets against SARS-Cov-2.

2.4. Perspectives in Therapeutic Targeting of SARS-Cov-2 - Associated Pathology

Due to recent clinical and biological findings on COVID-19 cited above, the physiopathology and clinical aspects of COVID-19 were much better understood, which allowed better therapeutic management of the disease, especially in severe cases. In the absence of a specific antiviral drug against SARS-Cov-2, anti-bacterials, blood thinners and corticoids were the main drugs that gave some hope, mainly in COVID-19 severe cases.

Fig. (2)
A host cell bearing receptors of SARS-Cov-2; ACE-2. Cell infection by the virus involves priming of the S spike glycoprotein of the virus by cellular serine proteases and possibly by other extracellular serine proteases. Priming of the S spike protein allows the virus to pursue its entry into the host cell, and proceed to the rest of the biochemical steps for its RNA and protein synthesis, followed by virion assembly.


For virus targeting, and according to the above mentioned possible physiopathological processes that could be associated with SARS-Cov-2 infection (Fig. 1), as most of the molecular mechanisms of the viral infection involve catalytic activities of proteases, starting from the first beginning of viral S Spike protein priming, until virus replication and assembly, it should be obvious to target several protease activities on both host cells and viral enzymatic machinery. Viral protease inhibition was used as a therapeutic strategy for many viral infections, such as the HIV ones [36Patick AK, Potts KE. Protease inhibitors as antiviral agents. Clin Microbiol Rev 1998; 11(4): 614-27.
[http://dx.doi.org/10.1128/CMR.11.4.614] [PMID: 9767059]
]. Recently, molecular modeling studies have suggested some old protease inhibitors for COVID-19 therapy [37Chen YW, Bennu Yiu CP, Wong KY. Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL) structure: Virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates. F1000Research 2020; 9: 129.]. Therapeutic strategies that use nucleotide and nucleoside drugs that interfere with viral replication are presented elsewhere [38Jordheim LP, Durantel D, Zoulim F, Dumontet C. Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat Rev Drug Discove 2013; 12: 447-64.
[http://dx.doi.org/10.1038/nrd4010]
], and will not be discussed in this paper.

Promising therapeutic strategies for COVID-19 are being suggested, such as lactoferrin milk enzyme [39El-Fakharany EM, Sánchez L, Al-Mehdar HA, Redwan EM. Effectiveness of human, camel, bovine and sheep lactoferrin on the hepatitis C virus cellular infectivity: Comparison study. Virol J 2013; 10: 199.
[http://dx.doi.org/10.1186/1743-422X-10-199] [PMID: 23782993]
-43Campione E, Lanna C, Cosio T, et al. Pleiotropic effect of Lactoferrin in the prevention and treatment of COVID-19 infection randomized clinical trial, in vitro and in silico preliminary evidences https://www.biorxiv.org/content/10.1101/2020.08.11.244996v3] and oligosaccharides [44Tandon D, Haque MM, Gote M, et al. A prospective randomized, double-blind, placebo-controlled, dose-response relationship study to investigate efficacy of fructo-oligosaccharides (FOS) on human gut microflora. Sci Rep 2019; 9(1): 5473.
[http://dx.doi.org/10.1038/s41598-019-41837-3] [PMID: 30940833]
-48Morrow AL, Ruiz-Palacios GM, Jiang X, Newburg DS. Human-milk glycans that inhibit pathogen binding protect breast-feeding infants against infectious diarrhea. J Nutr 2005; 135(5): 1304-7.
[http://dx.doi.org/10.1093/jn/135.5.1304] [PMID: 15867329]
] as next antivirals in human infectious diseases, as these substances have exhibited antiviral activities in laboratory experiments. Interestingly, in a recent clinical study on COVID-19 patients in Italy [43Campione E, Lanna C, Cosio T, et al. Pleiotropic effect of Lactoferrin in the prevention and treatment of COVID-19 infection randomized clinical trial, in vitro and in silico preliminary evidences https://www.biorxiv.org/content/10.1101/2020.08.11.244996v3], lactoferrin has been used to treat mild-to-moderate and asymptomatic COVID-19 patients to prevent disease evolution. The study concluded that lactoferrin induced an early viral clearance and a fast clinical symptoms recovery, in addition to a statistically significant reduction of D-Dimer, Interleukin-6 and ferritin blood levels. Hence, lactoferrin might be a real promising therapeutic molecule either as a purified active ingredient or as part of a whole natural product.

In relationship to traditional medicine, some natural food and plant extracts, known for their antiviral, anti-oxidant, anti-inflammatory and anti-cancer properties, were recently proposed as therapeutic candidates for the management of COVID-19. These potential therapeutic candidates include camel milk, a known traditional food of many countries in Asia and Africa, where people use it for both nutrition and healing purposes. The health benefits and therapeutic properties of camel milk are well documented in many reviews [49Singh R, Mal G, Kumar D, Patil NV, Pathak KML. Camel milk: An important natural adjuvant. Agric Res 2017; 6(4): 327-40.
[http://dx.doi.org/10.1007/s40003-017-0284-4]
-51Abrhaley A, Leta S. Medicinal value of camel milk and meat. J Appl Anim Res 2018; 46: 552-8.
[http://dx.doi.org/10.1080/09712119.2017.1357562]
]. Among camel milk active components, lactoferrin was extensively studied for its anti-viral and antibacterial properties [39El-Fakharany EM, Sánchez L, Al-Mehdar HA, Redwan EM. Effectiveness of human, camel, bovine and sheep lactoferrin on the hepatitis C virus cellular infectivity: Comparison study. Virol J 2013; 10: 199.
[http://dx.doi.org/10.1186/1743-422X-10-199] [PMID: 23782993]
, 52El-Fakharany EM, El-Baky NA, Linjawi MH, et al. Influence of camel milk on the hepatitis C virus burden of infected patients. Exp Ther Med 2017; 13(4): 1313-20.
[http://dx.doi.org/10.3892/etm.2017.4159] [PMID: 28413471]
, 53el Agamy EI, Ruppanner R, Ismail A, Champagne CP, Assaf R. Antibacterial and antiviral activity of camel milk protective proteins. J Dairy Res 1992; 59(2): 169-75.
[http://dx.doi.org/10.1017/S0022029900030417] [PMID: 1319434]
], and gut bacteria and immune modulatory properties [54Giansanti F, Panella G, Leboffe L, Antonini G. Lactoferrin from milk: Nutraceutical and pharmacological properties. Pharmaceuticals (Basel) 2016; 9(4): E61.
[http://dx.doi.org/10.3390/ph9040061] [PMID: 27690059]
]. Lactoferrin was shown to have a serine protease activity that could have some biochemical relevance in its anti-viral properties [40Zwirzitz A, Reiter M, Skrabana R, et al. Lactoferrin is a natural inhibitor of plasminogen activation. J Biol Chem 2018; 293(22): 8600-13.
[http://dx.doi.org/10.1074/jbc.RA118.003145] [PMID: 29669808]
]. Lactoferrin was also described to possess anti plasminogen activity, which could play a role in the control of blood clot and fibrinolysis [41Hendrixson DR, Qiu J, Shewry SC, et al. Human milk lactoferrin is a serine protease that cleaves Haemophilus surface proteins at arginine-rich sites. Mol Microbiol 2003; 47(3): 607-17.
[http://dx.doi.org/10.1046/j.1365-2958.2003.03327.x] [PMID: 12535064]
].

Milk oligosaccharides have anti-viral properties [45Morozov V, Hansman G, Hanisch FG, Schroten H, Kunz C. Human milk oligosaccharides as promising antivirals. Mol Nutr Food Res 2018; 62(6): e1700679.
[http://dx.doi.org/10.1002/mnfr.201700679] [PMID: 29336526]
-48Morrow AL, Ruiz-Palacios GM, Jiang X, Newburg DS. Human-milk glycans that inhibit pathogen binding protect breast-feeding infants against infectious diarrhea. J Nutr 2005; 135(5): 1304-7.
[http://dx.doi.org/10.1093/jn/135.5.1304] [PMID: 15867329]
, 55Ramani S, Stewart CJ, Laucirica DR, et al. Human milk oligosaccharides, milk microbiome and infant gut microbiome modulate neonatal rotavirus infection. Nat Commun 2018; 9(1): 5010.
[http://dx.doi.org/10.1038/s41467-018-07476-4] [PMID: 30479342]
, 56Weichert S, Koromyslova A, Singh BK, et al. Structural basis for norovirus inhibition by human milk oligosaccharides. J Virol 2016; 90(9): 4843-8.
[http://dx.doi.org/10.1128/JVI.03223-15] [PMID: 26889023]
], in part, due to their carbohydrate binding on viral glycoproteins. Oligosaccharides and lactoferrin are both present in camel milk, and the latter was suggested as a functional diet for COVID-19 management [57Errasfa M. Milk oligosaccharides and lectins as candidates for clinical trials against COVID-19. Curr Nutr Food Sci 2020; 16: 1.
[http://dx.doi.org/10.2174/1573401316999200819125355]
]. However, the effect of whole camel milk ingestion intended for antiviral and antibacterial effects could involve other molecules than oligosaccharides and lactoferrin.

Lectins of plant and seaweed origins are known for their interaction with carbohydrate moieties of glycoproteins and for interacting with viruses [58Carter A. Mitchell, Koreen Ramessar, and Barry R. O’Keefe. Antiviral lectins: Selective inhibitors of viral entry. Antiviral Res 2017; 142: 37-54.
[http://dx.doi.org/10.1016/j.antiviral.2017.03.007]
]. Many lectins were previously shown to bind the S glycoprotein of coronaviruses [59Keyaerts E, Vijgen L, Pannecouque C, et al. Plant lectins are potent inhibitors of coronaviruses by interfering with two targets in the viral replication cycle. Antiviral Res 2007; 75(3): 179-87.
[http://dx.doi.org/10.1016/j.antiviral.2007.03.003] [PMID: 17428553]
] and gave promising results in laboratory experiments against viral infection [60Kumaki Y, Wandersee MK, Smith AJ, et al. Inhibition of severe acute respiratory syndrome coronavirus replication in a lethal SARS-CoV BALB/c mouse model by stinging nettle lectin, Urtica dioica agglutinin. Antiviral Res 2011; 90(1): 22-32.
[http://dx.doi.org/10.1016/j.antiviral.2011.02.003] [PMID: 21338626]
]. Interestingly, in recent laboratory experiments, a lectin from edible hyacinth beans was shown to block the infections of Influenza and SARS-Cov-2 in vitro and in vivo [61Liu YM, Shahed-Al-Mahmud M, Chen X, et al. A carbohydrate-binding protein from the edible lablab beans effectively blocks the infections of influenza viruses and SARS-CoV-2. Cell Rep 2020; 32(6): 108016.
[http://dx.doi.org/10.1016/j.celrep.2020.108016] [PMID: 32755598]
]. Many laboratory experiments [62Gordts SC, Renders M, Férir G, et al. NICTABA and UDA, two GlcNAc-binding lectins with unique antiviral activity profiles. J Antimicrob Chemother 2015; 70(6): 1674-85.
[http://dx.doi.org/10.1093/jac/dkv034] [PMID: 25700718]
, 63van der Meer FJ, de Haan CA, Schuurman NM, et al. Antiviral activity of carbohydrate-binding agents against Nidovirales in cell culture. Antiviral Res 2007; 76(1): 21-9.
[http://dx.doi.org/10.1016/j.antiviral.2007.04.003] [PMID: 17560666]
] have shown binding and antiviral properties of several species of lectins, and these data have encouraged researchers to suggest lectins as a therapeutic tool against COVID-19 [57Errasfa M. Milk oligosaccharides and lectins as candidates for clinical trials against COVID-19. Curr Nutr Food Sci 2020; 16: 1.
[http://dx.doi.org/10.2174/1573401316999200819125355]
, 61Liu YM, Shahed-Al-Mahmud M, Chen X, et al. A carbohydrate-binding protein from the edible lablab beans effectively blocks the infections of influenza viruses and SARS-CoV-2. Cell Rep 2020; 32(6): 108016.
[http://dx.doi.org/10.1016/j.celrep.2020.108016] [PMID: 32755598]
]. Though, because of their high molecular weight, lectins use in clinical trials would be facing some challenging issues, such as route of administration, the bioavailability of the administered lectins, and their possible antigenic and mitogenic properties.

In relation to the physiopathology associated with COVID-19, mainly inflammatory reactions and weakness of antioxidants status of patients, other natural substances were proposed for COVID-19 management, such as thymoquinone; the main active ingredient of Nigella sativa extracts. Nigella sativa extracts and thymoquinone were widely studied for their therapeutic potentials [64Darakhshan S, Bidmeshki Pour A, Hosseinzadeh Colagar A, Sisakhtnezhad S. Thymoquinone and its therapeutic potentials. Pharmacol Res 2015; 95-96: 138-58.
[http://dx.doi.org/10.1016/j.phrs.2015.03.011] [PMID: 25829334]
]. Both thymoquinone and Nigella sativa extracts have interesting pharmacological properties [65Goyal SN, Prajapati CP, Gore PR, et al. Therapeutic potential and pharmaceutical development of thymoquinone: A multitargeted molecule of natural origin. Front Pharmacol 2017; 8: 656.
[http://dx.doi.org/10.3389/fphar.2017.00656] [PMID: 28983249]
], such as anti-inflammatory, anti-cancer and anti-oxidants. The use of thymoquinone by COVID-19 patients was suggested in a recent publication [66Ahmad A, Rehman MU, Ahmad P, Alkharfy KM. COVID-19 and thymoquinone: Connecting the dots. Phytother Res 2020; 34(11): 2786-9.
[http://dx.doi.org/10.1002/ptr.6793] [PMID: 32588453]
]. Route of administration and pharmaceutical presentations of thymoquinone were suggested [67Mohammadabadi MR, Mozafari MR. Enhanced efficacy and bioavailability of thymoquinone using nanoliposomal dosage form. J Drug Deliv Sci Technol 2018; 47: 445-53.
[http://dx.doi.org/10.1016/j.jddst.2018.08.019]
, 68Mohammadabadi MR, Mozafari MR. Development of nanoliposome-encapsulated thymoquinone:Evaluation of loading efficiency and particle characterization. J Biopharm 2019; 11: 39-46.] that could be of interest in clinical application.

Magnesium has hundreds of biochemical properties in human physiology. Its deficiency can cause cardiovascular, neurologic and metabolic health issues, with some physiopathology aspects that are identical to some of those encountered in COVID-19 patients, such as blood hemostasis and endothelium dysfunction, inflammation and oxidative stress [69Wolf FI, Cittadini A. Chemistry and biochemistry of magnesium. Mol Aspects Med 2003; 24(1-3): 3-9.
[http://dx.doi.org/10.1016/S0098-2997(02)00087-0] [PMID: 12537985]
]. Those magnesium supplementation, as suggested by others [70Tang CF, Ding H, Jiao RQ, Wu XX, Kong LD. Possibility of magnesium supplementation for supportive treatment in patients with COVID-19. Eur J Pharmacol 2020; 886: 173546.
[http://dx.doi.org/10.1016/j.ejphar.2020.173546] [PMID: 32931782]
-72Iotti S, Wolf F, Mazur A, Maier JA. The COVID-19 pandemic: Is there a role for magnesium? Hypotheses and perspectives. Magnes Res 2020; 33(2): 21-7.
[http://dx.doi.org/10.1684/mrh.2020.0465] [PMID: 32554340]
], could help COVID-19 patients to overcome some of the physiopathology events of the disease.

CONCLUSION

So far, in the absence of an effective vaccine against SARS-Cov-2, drug management of critical cases of COVID-19 relies on several therapeutic protocols, including antibiotics, blood clotting/fibrinolysis drugs, glucocorticoids, antimalarial and some antivirals [73Tobaiqy M, Qashqary M, Al-Dahery S, et al. Therapeutic management of patients with COVID-19: A systematic review. Infect Preventi in Pract 2020; 2(3): 100061.
[http://dx.doi.org/10.1016/j.infpip.2020.100061]
]. Antimalarial chloroquine and hydroxychloroquine were used in many therapeutic protocols in various countries, though their efficacy is still under debate by the scientific community despite their many effective anti-viral and other biological properties shown in laboratory experiments and their long history as antimalarial drugs [74Quiros Roldan E, Biasiotto G, Magro P, Zanella I. The possible mechanisms of action of 4-aminoquinolines (chloroquine/ hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): A role for iron homeostasis? Pharmacol Res 2020; 158: 104904.
[http://dx.doi.org/10.1016/j.phrs.2020.104904] [PMID: 32430286]
]. Meanwhile, vitamins (such as vitamin C and B1), prebiotics and probiotics, as well as magnesium are suggested as adjunct treatments for COVID-19, while some health promoting foods such as olive oil [75Foscolou A, Critselis E, Panagiotakos D. Olive oil consumption and human health: A narrative review. Maturitas 2018; 118: 60-6.
[http://dx.doi.org/10.1016/j.maturitas.2018.10.013] [PMID: 30415757]
] and argan oil [76Essouiri J, Abourazzak FE, Lazrak F, et al. Efficacy of argane oil on metabolic syndrome in a moroccan knee osteoarthritis population. Curr Rheumatol Rev 2018; 14(1): 84-8.
[http://dx.doi.org/10.2174/1573397112666161205103009] [PMID: 27917705]
, 77Eljaoudi R, Elkabbaj D, Bahadi A, Ibrahimi A, Benyahia M, Errasfa M. Consumption of argan oil improves anti-oxidant and lipid status in hemodialysis patients. Phytother Res 2015; 29(10): 1595-9.
[http://dx.doi.org/10.1002/ptr.5405] [PMID: 26101142]
] could also be of high relevance for nutritional interventions for COVID-19 patients, due to their unique vitamins and antioxidants composition (polyphenols, phytosterols, vitamin E, carotenoids, oleic acid and other essential fatty acids).

ADDENDUM

Following submission of the present paper, a clinical trial was approved by the University Hospital Ethics Committee of Fez (Morocco) to investigate the effect of camel milk consumption as an adjunct treatment in parallel to the official drug protocol approved by the Ministry of Health of Morocco to treat COVID-19 patients. The clinical trial coordinator is Pr Mourad Errasfa.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The author declares no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

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"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)


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