Unravelling Antigenic Cross-Reactions toward the World of Coronaviruses: Extent of the Stability of Shared Epitopes and SARS-CoV-2 Anti-Spike Cross-Neutralizing Antibodies.

The human immune repertoire retains the molecular memory of a very great diversity of target antigens (epitopes) and can recall this upon a second encounter with epitopes against which it has previously been primed. Although genetically diverse, proteins of coronaviruses exhibit sufficient conservation to lead to antigenic cross-reactions. In this review, our goal is to question whether pre-existing immunity against seasonal human coronaviruses (HCoVs) or exposure to animal CoVs has influenced the susceptibility of human populations to SARS-CoV-2 and/or had an impact upon the physiopathological outcome of COVID-19. With the hindsight that we now have regarding COVID-19, we conclude that although antigenic cross-reactions between different coronaviruses exist, cross-reactive antibody levels (titers) do not necessarily reflect on memory B cell frequencies and are not always directed against epitopes which confer cross-protection against SARS-CoV-2. Moreover, the immunological memory of these infections is short-term and occurs in only a small percentage of the population. Thus, in contrast to what might be observed in terms of cross-protection at the level of a single individual recently exposed to circulating coronaviruses, a pre-existing immunity against HCoVs or other CoVs can only have a very minor impact on SARS-CoV-2 circulation at the level of human populations.

Molecular Mimicry of the Viral Spike in the SARS-CoV-2 Vaccine Possibly Triggers Transient Dysregulation of ACE2, Leading to Vascular and Coagulation Dysfunction Similar to SARS-CoV-2 Infection.

The benefits of SARS-CoV-2 spike mRNA vaccines are well known, including a significant decline in COVID-19 morbidity and a decrease in the mortality rate of SARS-CoV-2 infected persons. However, pharmacovigilance studies have revealed the existence of rare cases of cardiovascular complications after mass vaccination using such formulations. Cases of high blood pressure have also been reported but were rarely documented under perfectly controlled medical supervision. The press release of these warning signals triggered a huge debate over COVID-19 vaccines' safety. Thereby, our attention was quickly focused on issues involving the risk of myocarditis, acute coronary syndrome, hypertension and thrombosis. Rare cases of undesirable post-vaccine pathophysiological phenomena should question us, especially when they occur in young subjects. They are more likely to occur with inappropriate use of mRNA vaccine (e.g., at the time when the immune response is already very active during a low-noise infection in the process of healing), leading to angiotensin II (Ang II) induced inflammation triggering tissue damage. Such harmful effects observed after the COVID-19 vaccine evoke a possible molecular mimicry of the viral spike transiently dysregulating angiotensin converting enzyme 2 (ACE2) function. Although the benefit/risk ratio of SARS-CoV-2 spike mRNA vaccine is very favorable, it seems reasonable to suggest medical surveillance to patients with a history of cardiovascular diseases who receive the COVID-19 vaccine.

Unraveling the Underlying Molecular Mechanism of 'Silent Hypoxia' in COVID-19 Patients Suggests a Central Role for Angiotensin II Modulation of the AT1R-Hypoxia-Inducible Factor Signaling Pathway.

A few days after being infected with SARS-CoV-2, a fraction of people remain asymptomatic but suffer from a decrease in arterial oxygen saturation in the absence of apparent dyspnea. In light of our clinical investigation on the modulation of molecules belonging to the renin angiotensin system (RAS) in COVID-19 patients, we propose a model that explains 'silent hypoxia'. The RAS imbalance caused by SARS-CoV-2 results in an accumulation of angiotensin 2 (Ang II), which activates the angiotensin 2 type 1 receptor (AT1R) and triggers a harmful cascade of intracellular signals leading to the nuclear translocation of the hypoxia-inducible factor (HIF)-1α. HIF-1α transactivates many genes including the angiotensin-converting enzyme 1 (ACE1), while at the same time, ACE2 is downregulated. A growing number of cells is maintained in a hypoxic condition that is self-sustained by the presence of the virus and the ACE1/ACE2 ratio imbalance. This is associated with a progressive worsening of the patient's biological parameters including decreased oxygen saturation, without further clinical manifestations. When too many cells activate the Ang II-AT1R-HIF-1α axis, there is a 'hypoxic spillover', which marks the tipping point between 'silent' and symptomatic hypoxia in the patient. Immediate ventilation is required to prevent the 'hypoxic spillover'.

An update on angiotensin-converting enzyme 2 structure/functions, polymorphism, and duplicitous nature in the pathophysiology of coronavirus disease 2019: Implications for vascular and coagulation disease associated with severe acute respiratory syndrome coronavirus infection.

It has been known for many years that the angiotensin-converting enzyme 2 (ACE2) is a cell surface enzyme involved in the regulation of blood pressure. More recently, it was proven that the severe acute respiratory syndrome coronavirus (SARS-CoV-2) interacts with ACE2 to enter susceptible human cells. This functional duality of ACE2 tends to explain why this molecule plays such an important role in the clinical manifestations of coronavirus disease 2019 (COVID-19). At the very start of the pandemic, a publication from our Institute (entitled "ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome"), was one of the first reviews linking COVID-19 to the duplicitous nature of ACE2. However, even given that COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin system (RAS), we were still far from understanding the complexity of the mechanisms which are controlled by ACE2 in different cell types. To gain insight into the physiopathology of SARS-CoV-2 infection, it is essential to consider the polymorphism and expression levels of the ACE2 gene (including its alternative isoforms). Over the past 2 years, an impressive amount of new results have come to shed light on the role of ACE2 in the pathophysiology of COVID-19, requiring us to update our analysis. Genetic linkage studies have been reported that highlight a relationship between ACE2 genetic variants and the risk of developing hypertension. Currently, many research efforts are being undertaken to understand the links between ACE2 polymorphism and the severity of COVID-19. In this review, we update the state of knowledge on the polymorphism of ACE2 and its consequences on the susceptibility of individuals to SARS-CoV-2. We also discuss the link between the increase of angiotensin II levels among SARS-CoV-2-infected patients and the development of a cytokine storm associated microvascular injury and obstructive thrombo-inflammatory syndrome, which represent the primary causes of severe forms of COVID-19 and lethality. Finally, we summarize the therapeutic strategies aimed at preventing the severe forms of COVID-19 that target ACE2. Changing paradigms may help improve patients' therapy.

Choosing a cellular model to study SARS-CoV-2.

As new pathogens emerge, new challenges must be faced. This is no different in infectious disease research, where identifying the best tools available in laboratories to conduct an investigation can, at least initially, be particularly complicated. However, in the context of an emerging virus, such as SARS-CoV-2, which was recently detected in China and has become a global threat to healthcare systems, developing models of infection and pathogenesis is urgently required. Cell-based approaches are crucial to understanding coronavirus infection biology, growth kinetics, and tropism. Usually, laboratory cell lines are the first line in experimental models to study viral pathogenicity and perform assays aimed at screening antiviral compounds which are efficient at blocking the replication of emerging viruses, saving time and resources, reducing the use of experimental animals. However, determining the ideal cell type can be challenging, especially when several researchers have to adapt their studies to specific requirements. This review strives to guide scientists who are venturing into studying SARS-CoV-2 and help them choose the right cellular models. It revisits basic concepts of virology and presents the currently available in vitro models, their advantages and disadvantages, and the known consequences of each choice.

The impact of COVID-19 on populations living at high altitude: Role of hypoxia-inducible factors (HIFs) signaling pathway in SARS-CoV-2 infection and replication.

Cases of coronavirus disease 2019 (COVID-19) have been reported worldwide. However, one epidemiological report has claimed a lower incidence of the disease in people living at high altitude (>2,500 m), proposing the hypothesis that adaptation to hypoxia may prove to be advantageous with respect to SARS-CoV-2 infection. This publication was initially greeted with skepticism, because social, genetic, or environmental parametric variables could underlie a difference in susceptibility to the virus for people living in chronic hypobaric hypoxia atmospheres. Moreover, in some patients positive for SARS-CoV-2, early post-infection 'happy hypoxia" requires immediate ventilation, since it is associated with poor clinical outcome. If, however, we accept to consider the hypothesis according to which the adaptation to hypoxia may prove to be advantageous with respect to SARS-CoV-2 infection, identification of the molecular rational behind it is needed. Among several possibilities, HIF-1 regulation appears to be a molecular hub from which different signaling pathways linking hypoxia and COVID-19 are controlled. Interestingly, HIF-1α was reported to inhibit the infection of lung cells by SARS-CoV-2 by reducing ACE2 viral receptor expression. Moreover, an association of the rs11549465 variant of HIF-1α with COVID-19 susceptibility was recently discovered. Here, we review the evidence for a link between HIF-1α, ACE2 and AT1R expression, and the incidence/severity of COVID-19. We highlight the central role played by the HIF-1α signaling pathway in the pathophysiology of COVID-19.

Role of spike compensatory mutations in the interspecies transmission of SARS-CoV-2.

SARS-CoV-2, the virus responsible for COVID-19 in humans, can efficiently infect a large number of animal species. Like any virus, and particularly RNA viruses, SARS-CoV-2 undergoes mutations during its life cycle some of which bring a selective advantage, leading to the selection of a given lineage. Minks are very susceptible to SARS-CoV-2 and owing to their presence in mass rearing, they make a good model for studying the relative importance of mutations in viral adaptation to host species. Variants, such as the mink-selected SARS-CoV-2 Y453F and D614G or H69del/V70del, Y453F, I692V and M1229I were identified in humans after spreading through densely caged minks. However, not all mink-specific mutations are conserved when the virus infects human populations back. Many questions remain regarding the interspecies evolution of SARS-CoV-2 and the dynamics of transmission leading to the emergence of new variant strains. We compared the human and mink ACE2 receptor structures and their interactions with SARS-CVoV-2 variants. In minks, ACE2 presents a Y34 amino acid instead of the H34 amino acid found in the human ACE2. H34 is essential for the interaction with the Y453 residue of the SARS-CoV-2 Spike protein. The Y453F mink mutation abolishes this conflict. A series of 18 mutations not involved in the direct ACE2 interaction was observed in addition to the Y453F and D614G in 16 different SARS-CoV-2 strains following bidirectional infections between humans and minks. These mutations were not random and were distributed into five different functional groups having an effect on the kinetics of ACE2-RD interaction. The interspecies transmission of SARS-CoV-2 from humans to minks and back to humans, generated specific mutations in each species which improved the affinity for the ACE2 receptor either by direct mutation of the core 453 residue or by associated compensatory mutations.

Screening and Whole Genome Sequencing of SARS-CoV-2 Circulating During the First Three Waves of the COVID-19 Pandemic in Libreville and the Haut-Ogooué Province in Gabon.

Since the onset of the COVID-19 pandemic, the SARS-CoV-2 viral dynamics in Africa have been less documented than on other continents. In Gabon, a Central African country, a total number of 37,511 cases of COVID-19 and 281 deaths have been reported as of December 8, 2021. After the first COVID-19 case was reported on March 12, 2020, in the capital Libreville, the country experienced two successive waves. The first one, occurred in March 2020 to August 2020, and the second one in January 2021 to May 2021. The third wave began in September 2021 and ended in November 2021. In order to reduce the data gap regarding the dynamics of SARS-CoV-2 in Central Africa, we performed a retrospective genotyping study using 1,006 samples collected from COVID-19 patients in Gabon from 2020 to 2021. Using SARS-CoV-2 variant screening by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) and whole genome sequencing (WGS), we genotyped 809 SARS-CoV-2 samples through qRT-PCR and identified to generated 291 new genomes. It allowed us to describe specific mutations and changes in the SARS-CoV-2 variants in Gabon. The qRT-PCR screening of 809 positive samples from March 2020 to September 2021 showed that 119 SARS-CoV-2 samples (14.7%) were classified as VOC Alpha (Pangolin lineage B.1.1.7), one (0.1%) was a VOC Beta (B.1.351), and 198 (24.5 %) were VOC Delta (B.1.617.2), while 491 samples (60.7%) remained negative for the variants sought. The B1.1 variant was predominant during the first wave while the VOC Alpha dominated the second wave. The B1.617.2 Delta variant is currently the dominant variant of the third wave. Similarly, the analysis of the 291 genome sequences indicated that the dominant variant during the first wave was lineage B.1.1, while the dominant variants of the second wave were lineages B.1.1.7 (50.6%) and B.1.1.318 (36.4%). The third wave started with the circulation of the Delta variant (B.1.617). Finally, we compared these results to the SARS-CoV-2 sequences reported in other African, European, American and Asian countries. Sequences of Gabonese SARS-CoV-2 strains presented the highest similarities with those of France, Belgium and neighboring countries of Central Africa, as well as West Africa.

[SARS-CoV-2 has no origin]. / Le virus SARS-CoV-2 n'a pas « d'origine ¼.

Since the beginning of the COVID-19 pandemic, the question of the origin of this virus has been the subject of a vivid controversy. It is the question of the "origin" itself which is biased. Darwin showed that there is no determined origin to any animal or plant species, simply an evolutionary and selective process. The same is true for viruses, there is no origin, but an evolutionary process. Viruses circulate from host to host, animals or humans. Pandemic viruses are already circulating in humans and evolving before the onset of disease. This evolutionary process then continues and gives rise to successive variants. The solution is not to target the disease or the putative causative agent but rather to address the process of disease emergence.

Title: Le virus SARS-CoV-2 n'a pas « d'origine ¼. Abstract: Depuis le début de la pandémie de COVID-19, la question de l'origine de ce virus fait l'objet d'une vive polémique. C'est la question de « l'origine ¼ qui est biaisée. Darwin a montré qu'il n'y a pas d'origine déterminée à aucune espèce animale ou végétale, simplement un processus évolutif et sélectif. Il en est de même pour les virus, il n'y a pas d'origine, mais un processus évolutif. Les virus circulent d'hôte à hôte, animaux ou humains. Les virus pandémiques circulent déjà chez l'homme et évoluent avant l'apparition d'une maladie. Ce processus évolutif se poursuit et donne naissance à des variants successifs. La solution n'est pas de cibler la maladie ou le possible agent causal, mais plutôt de cibler le processus d'émergence de la maladie lui-même.

Control of CDH1/E-Cadherin Gene Expression and Release of a Soluble Form of E-Cadherin in SARS-CoV-2 Infected Caco-2 Intestinal Cells: Physiopathological Consequences for the Intestinal Forms of COVID-19.

COVID-19 is the biggest pandemic the world has seen this century. Alongside the respiratory damage observed in patients with severe forms of the disease, gastrointestinal symptoms have been frequently reported. These symptoms (e.g., diarrhoea), sometimes precede the development of respiratory tract illnesses, as if the digestive tract was a major target during early SARS-CoV-2 dissemination. We hypothesize that in patients carrying intestinal SARS-CoV-2, the virus may trigger epithelial barrier damage through the disruption of E-cadherin (E-cad) adherens junctions, thereby contributing to the overall gastrointestinal symptoms of COVID-19. Here, we use an intestinal Caco-2 cell line of human origin which expresses the viral receptor/co-receptor as well as the membrane anchored cell surface adhesion protein E-cad to investigate the expression of E-cad after exposure to SARS-CoV-2. We found that the expression of CDH1/E-cad mRNA was significantly lower in cells infected with SARS-CoV-2 at 24 hours post-infection, compared to virus-free Caco-2 cells. The viral receptor ACE2 mRNA expression was specifically down-regulated in SARS-CoV-2-infected Caco-2 cells, while it remained stable in HCoV-OC43-infected Caco-2 cells, a virus which uses HLA class I instead of ACE2 to enter cells. It is worth noting that SARS-CoV-2 induces lower transcription of TMPRSS2 (involved in viral entry) and higher expression of B0AT1 mRNA (that encodes a protein known to co-express with ACE2 on intestinal cells). At 48 hours post-exposure to the virus, we also detected a small but significant increase of soluble E-cad protein (sE-cad) in the culture supernatant of SARS-CoV-2-infected Caco-2 cells. The increase of sE-cad release was also found in the intestinal HT29 cell line when infected by SARS-CoV-2. Beside the dysregulation of E-cad, SARS-CoV-2 infection of Caco-2 cells also leads to the dysregulation of other cell adhesion proteins (occludin, JAMA-A, zonulin, connexin-43 and PECAM-1). Taken together, these results shed light on the fact that infection of Caco-2 cells with SARS-CoV-2 affects tight-, adherens-, and gap-junctions. Moreover, intestinal tissues damage was associated to the intranasal SARS-CoV-2 infection in human ACE2 transgenic mice.

Control of common viral epidemics but not of SARS-CoV-2 through the application of hygiene and distancing measures.

BACKGROUND: We systematically survey respiratory and gastrointestinal infections of viral origin in samples sent to our university hospital institute in Marseille, southern France. Here, we evaluated whether the measures implemented to fight COVID-19 had an effect on the dynamics of viral respiratory or gastrointestinal infections. METHODS: We analysed PCR performed and positive for the diagnoses of viral respiratory and gastrointestinal infections over five years (January 2017-February 2021). Data were collected from our epidemiological surveillance system (MIDaS). Dates and contents of French measures against SARS-CoV-2 were collected from: https://www.gouvernement.fr/info-coronavirus/les-actions-du-gouvernement. RESULTS: Over the 2017-2021 period, 990,364 analyses were carried out for respiratory infections not including SARS-CoV-2, 510,671 for SARS-CoV-2 and 27,719 for gastrointestinal infections. During winter 2020-2021, when the most restrictive lockdown measures were in place in France, a marked decrease of infections with influenza viruses (one case versus 1,839-1,850 cases during 2017-2020 cold seasons) and with the RSV (56 cases versus 988-1,196 cases during 2017-2020 cold seasons) was observed, demonstrating the relative effectiveness of these measures on their occurrence. SARS-CoV-2 incidence seemed far less affected. Rhinoviruses, parainfluenza 3 virus, and the coronavirus NL63 remained at comparable levels. Also, the norovirus winter season positivity rates decreased continuously and significantly over time from 9.3% in 2017-2018 to 2.0% in 2020-2021. CONCLUSION: The measures taken to control COVID-19 were effective against lower respiratory tract infections viruses and gastroenteritis agents, but not on the agents of the common winter cold and SARS-CoV-2. This suggests that more specific measures to prevent COVID-19 and upper respiratory tract infections need to be discovered to limit the spread of this epidemic.

There is no "origin" to SARS-CoV-2.

Since the beginning of the COVID-19 pandemic in 2020 caused by SARS-CoV-2, the question of the origin of this virus has been a highly debated issue. Debates have been, and are still, very disputed and often violent between the two main hypotheses: a natural origin through the "spillover" model or a laboratory-leak origin. Tenants of these two options are building arguments often based on the discrepancies of the other theory. The main problem is that it is the initial question of the origin itself which is biased. Charles Darwin demonstrated in 1859 that all species are appearing through a process of evolution, adaptation and selection. There is no determined origin to any animal or plant species, simply an evolutionary and selective process in which chance and environment play a key role. The very same is true for viruses. There is no determined origin to viruses, simply also an evolutionary and selective process in which chance and environment play a key role. However, in the case of viruses the process is slightly more complex because the "environment" is another living organism. Pandemic viruses already circulate in humans prior to the emergence of a disease. They are simply not capable of triggering an epidemic yet. They must evolve in-host, i.e. in-humans, for that. The evolutionary process which gave rise to SARS-CoV-2 is still ongoing with regular emergence of novel variants more adapted than the previous ones. The real relevant question is how these viruses can emerge as pandemic viruses and what the society can do to prevent the future emergence of pandemic viruses.

Emerging SARS-CoV-2 Genotypes Show Different Replication Patterns in Human Pulmonary and Intestinal Epithelial Cells.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) quickly spread worldwide following its emergence in Wuhan, China, and hit pandemic levels. Its tremendous incidence favoured the emergence of viral variants. The current genome diversity of SARS-CoV-2 has a clear impact on epidemiology and clinical practice, especially regarding transmission rates and the effectiveness of vaccines. In this study, we evaluated the replication of different SARS-CoV-2 isolates representing different virus genotypes which have been isolated throughout the pandemic. We used three distinct cell lines, including Vero E6 cells originating from monkeys; Caco-2 cells, an intestinal epithelium cell line originating from humans; and Calu-3 cells, a pulmonary epithelium cell line also originating from humans. We used RT-qPCR to replicate different SARS-CoV-2 genotypes by quantifying the virus released in the culture supernatant of infected cells. We found that the different viral isolates replicate similarly in Caco-2 cells, but show very different replicative capacities in Calu-3 cells. This was especially highlighted for the lineages B.1.1.7, B.1.351 and P.1, which are considered to be variants of concern. These results underscore the importance of the evaluation and characterisation of each SARS-CoV-2 isolate in order to establish the replication patterns before performing tests, and of the consideration of the ideal SARS-CoV-2 genotype-cell type pair for each assay.

Drug repurposing against SARS-CoV-1, SARS-CoV-2 and MERS-CoV.

Since the beginning of the COVID-19 pandemic, large in silico screening studies and numerous in vitro studies have assessed the antiviral activity of various drugs on SARS-CoV-2. In the context of health emergency, drug repurposing represents the most relevant strategy because of the reduced time for approval by international medicines agencies, the low cost of development and the well-known toxicity profile of such drugs. Herein, we aim to review drugs with in vitro antiviral activity against SARS-CoV-2, combined with molecular docking data and results from preliminary clinical studies. Finally, when considering all these previous findings, as well as the possibility of oral administration, 11 molecules consisting of nelfinavir, favipiravir, azithromycin, clofoctol, clofazimine, ivermectin, nitazoxanide, amodiaquine, heparin, chloroquine and hydroxychloroquine, show an interesting antiviral activity that could be exploited as possible drug candidates for COVID-19 treatment.

Understanding the origin of COVID-19 requires to change the paradigm on zoonotic emergence from the spillover to the circulation model.

While the COVID-19 pandemic continues to spread with currently more than 117 million cumulated cases and 2.6 million deaths worldwide as per March 2021, its origin is still debated. Although several hypotheses have been proposed, there is still no clear explanation about how its causative agent, SARS-CoV-2, emerged in human populations. Today, scientifically-valid facts that deserve to be debated still coexist with unverified statements blurring thus the knowledge on the origin of COVID-19. Our retrospective analysis of scientific data supports the hypothesis that SARS-CoV-2 is indeed a naturally occurring virus. However, the spillover model considered today as the main explanation to zoonotic emergence does not match the virus dynamics and somehow misguided the way researches were conducted. We conclude this review by proposing a change of paradigm and model and introduce the circulation model for explaining the various aspects of the dynamic of SARS-CoV-2 emergence in humans.

Spread of Mink SARS-CoV-2 Variants in Humans: A Model of Sarbecovirus Interspecies Evolution.

The rapid spread of SARS-CoV-2 variants has quickly spanned doubts and the fear about their ability escape vaccine protection. Some of these variants initially identified in caged were also found in humans. The claim that these variants exhibited lower susceptibility to antibody neutralization led to the slaughter of 17 million minks in Denmark. SARS-CoV-2 prevalence tests led to the discovery of infected farmed minks worldwide. In this study, we revisit the issue of the circulation of SARS-CoV-2 variants in minks as a model of sarbecovirus interspecies evolution by: (1) comparing human and mink angiotensin I converting enzyme 2 (ACE2) and neuropilin 1 (NRP-1) receptors; (2) comparing SARS-CoV-2 sequences from humans and minks; (3) analyzing the impact of mutations on the 3D structure of the spike protein; and (4) predicting linear epitope targets for immune response. Mink-selected SARS-CoV-2 variants carrying the Y453F/D614G mutations display an increased affinity for human ACE2 and can escape neutralization by one monoclonal antibody. However, they are unlikely to lose most of the major epitopes predicted to be targets for neutralizing antibodies. We discuss the consequences of these results for the rational use of SARS-CoV-2 vaccines.

Origin of COVID-19: Dismissing the Mojiang mine theory and the laboratory accident narrative.

The origin of SARS-CoV-2 is still the subject of a controversial debate. The natural origin theory is confronted to the laboratory leak theory. The latter is composite and comprises contradictory theories, one being the leak of a naturally occurring virus and the other the leak of a genetically engineered virus. The laboratory leak theory is essentially based on a publication by Rahalkar and Bahulikar in 2020 linking SARS-CoV-2 to the Mojiang mine incident in 2012 during which six miners fell sick and three died. We analyzed the clinical reports. The diagnosis is not that of COVID-19 or SARS. SARS-CoV-2 was not present in the Mojiang mine. We also bring arguments against the laboratory leak narrative.

Cyclosporin A: A Repurposable Drug in the Treatment of COVID-19?

Coronavirus disease 2019 (COVID-19) is now at the forefront of major health challenge faced globally, creating an urgent need for safe and efficient therapeutic strategies. Given the high attrition rates, high costs, and quite slow development of drug discovery, repurposing of known FDA-approved molecules is increasingly becoming an attractive issue in order to quickly find molecules capable of preventing and/or curing COVID-19 patients. Cyclosporin A (CsA), a common anti-rejection drug widely used in transplantation, has recently been shown to exhibit substantial anti-SARS-CoV-2 antiviral activity and anti-COVID-19 effect. Here, we review the molecular mechanisms of action of CsA in order to highlight why this molecule seems to be an interesting candidate for the therapeutic management of COVID-19 patients. We conclude that CsA could have at least three major targets in COVID-19 patients: (i) an anti-inflammatory effect reducing the production of proinflammatory cytokines, (ii) an antiviral effect preventing the formation of the viral RNA synthesis complex, and (iii) an effect on tissue damage and thrombosis by acting against the deleterious action of angiotensin II. Several preliminary CsA clinical trials performed on COVID-19 patients report lower incidence of death and suggest that this strategy should be investigated further in order to assess in which context the benefit/risk ratio of repurposing CsA as first-line therapy in COVID-19 is the most favorable.

Whole Genome Sequencing of SARS-CoV-2 Strains in COVID-19 Patients From Djibouti Shows Novel Mutations and Clades Replacing Over Time.

Since the start of COVID-19 pandemic the Republic of Djibouti, in the horn of Africa, has experienced two epidemic waves of the virus between April and August 2020 and between February and May 2021. By May 2021, COVID-19 had affected 1.18% of the Djiboutian population and caused 152 deaths. Djibouti hosts several foreign military bases which makes it a potential hot-spot for the introduction of different SARS-CoV-2 strains. We genotyped fifty three viruses that have spread during the two epidemic waves. Next, using spike sequencing of twenty-eight strains and whole genome sequencing of thirteen strains, we found that Nexstrain clades 20A and 20B with a typically European D614G substitution in the spike and a frequent P2633L substitution in nsp16 were the dominant viruses during the first epidemic wave, while the clade 20H South African variants spread during the second wave characterized by an increase in the number of severe forms of COVID-19.