Structure-Function Analyses of New SARS-CoV-2 Variants B.1.1.7, B.1.351 and B.1.1.28.1: Clinical,Diagnostic, Therapeutic and Public Health Implications

SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus 2) has accumulated multiple mutations during its global circulation. Recently, three SARS-CoV-2 lineages, B.1.1.7 (501Y.V1), B.1.351 (501Y.V2) and B.1.1.28.1 (P.1), have emerged in the United Kingdom, South Africa and Brazil, respectively. Here, we have presented global viewpoint on implications of emerging SARS-CoV-2 variants based on structural–function impact of crucial mutations occurring in its spike (S), ORF8 and nucleocapsid (N) proteins. While the N501Y mutation was observed in all three lineages, the 501Y.V1 and P.1 accumulated a different set of mutations in the S protein. The missense mutational effects were predicted through a COVID-19 dedicated resource followed by atomistic molecular dynamics simulations. Current findings indicate that some mutations in the S protein might lead to higher affinity with host receptors and resistance against antibodies, but not all are due to different antibody binding (epitope) regions. Mutations may, however, result in diagnostic tests failures and possible interference with binding of newly identified anti-viral candidates against SARS-CoV-2, likely necessitating roll out of recurring “flu-like shots” annually for tackling COVID-19. The functional relevance of these mutations has been described in terms of modulation of host tropism, antibody resistance, diagnostic sensitivity and therapeutic candidates. Besides global economic losses, post-vaccine reinfections with emerging variants can have significant clinical, therapeutic and public health impacts.     

Will SARS-CoV-2 Become Just Another Seasonal Coronavirus?

The future prevalence and virulence of SARS-CoV-2 is uncertain. Some emerging pathogens become avirulent as populations approach herd immunity. Although not all viruses follow this path, the fact that the seasonal coronaviruses are benign gives some hope. We develop a general mathematical model to predict when the interplay among three factors, correlation of severity in consecutive infections, population heterogeneity in susceptibility due to age, and reduced severity due to partial immunity, will promote avirulence as SARS-CoV-2 becomes endemic. Each of these components has the potential to limit severe, high-shedding cases over time under the right circumstances, but in combination they can rapidly reduce the frequency of more severe and infectious manifestation of disease over a wide range of conditions. As more reinfections are captured in data over the next several years, these models will help to test if COVID-19 severity is beginning to attenuate in the ways our model predicts, and to predict the disease.     

COVID-19 and the gastrointestinal tract: Source of infection or merely a target of the inflammatory process following SARS-CoV-2 infection?

Gastrointestinal (GI) symptoms have been described in a conspicuous percentage of coronavirus disease 2019 (COVID-19) patients. This clinical evidence is supported by the detection of viral RNA in stool, which also supports the hypothesis of a possible fecal-oral transmission route. The involvement of GI tract in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is corroborated by the theoretical assumption that angiotensin converting enzyme 2, which is a SARS-CoV-2 target receptor, is present along the GI tract. Studies have pointed out that gut dysbiosis may occur in COVID-19 patients, with a possible correlation with disease severity and with complications such as multisystem inflammatory syndrome in children. However, the question to be addressed is whether dysbiosis is a consequence or a contributing cause of SARS-CoV-2 infection. In such a scenario, pharmacological therapies aimed at decreasing GI permeability may be beneficial for COVID-19 patients. Considering the possibility of a fecal-oral transmission route, water and environmental sanitation play a crucial role for COVID-19 containment, especially in developing countries.     

COVID-19: Multiorgan Dissemination of SARS-CoV-2 Is Driven by Pulmonary Factors

Multi-organ failure is one of the common causes of fatal outcome in COVID-19 patients. However, the pathogenetic association of the SARS-CoV-2 viral load (VL) level with fatal dysfunctions of the lungs, liver, kidneys, heart, spleen and brain, as well as with the risk of death in COVID-19 patients remains poorly understood. SARS-CoV-2 VL in the lungs, heart, liver, kidneys, brain, spleen and lymph nodes have been measured by RT qPCR using the following formula: N^SARS-CoV−2/N^{ABL1 ×} 100. Dissemination of SARS-CoV-2 in 30.5% of cases was mono-organ, and in 63.9% of cases, it was multi-organ. The average SARS-CoV-2 VL in the exudative phase of diffuse alveolar damage (DAD) was 60 times higher than in the proliferative phase. The SARS-CoV-2 VL in the lungs ranged from 0 to 250,281 copies. The “pulmonary factors” of SARS-CoV-2 multi-organ dissemination are the high level of SARS-CoV-2 VL (≥4909) and the exudative phase of DAD. The frequency of SARS-CoV-2 dissemination to lymph nodes was 86.9%, heart–56.5%, spleen–52.2%, liver–47.8%, kidney–26%, and brain–13%. We found no link between the SARS-CoV-2 VL level in the liver, kidneys, and heart and the serum level of CPK, LDH, ALP, ALT, AST and Cr of COVID-19 patients. Isolated detection of SARS-CoV-2 RNA in the myocardium of COVID-19 patients who died from heart failure is possible. The pathogenesis of COVID-19-associated multi-organ failure requires further research in a larger cohort of patients.     

Coronaviral Infection and Interferon Response: The Virus-Host Arms Race and COVID-19

The recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in unprecedented morbidity and mortality worldwide. The host cells use a number of pattern recognition receptors (PRRs) for early detection of coronavirus infection, and timely interferon secretion is highly effective against SARS-CoV-2 infection. However, the virus has developed many strategies to delay interferon secretion and disarm cellular defense by intervening in interferon-associated signaling pathways on multiple levels. As a result, some COVID-19 patients suffered dramatic susceptibility to SARS-CoV-2 infection, while another part of the population showed only mild or no symptoms. One hypothesis suggests that functional differences in innate immune integrity could be the key to such variability. This review tries to decipher possible interactions between SARS-CoV-2 proteins and human antiviral interferon sensors. We found that SARS-CoV-2 actively interacts with PRR sensors and antiviral pathways by avoiding interferon suppression, which could result in severe COVID-19 pathogenesis. Finally, we summarize data on available antiviral pharmaceutical options that have shown potential to reduce COVID-19 morbidity and mortality in recent clinical trials.     

Coronavirus disease–2019 and the intestinal tract: An overview

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can progress to a severe respiratory and systemic disease named coronavirus disease–2019 (COVID-19). The most common symptoms are fever and respiratory discomfort. Nevertheless, gastrointestinal infections have been reported, with symptoms such as diarrhea, nausea, vomiting, abdominal pain, and lack of appetite. Importantly, SARS-CoV-2 can remain positive in fecal samples after nasopharyngeal clearance. After gastrointestinal SARS-CoV-2 infection and other viral gastrointestinal infections, some patients may develop alterations in the gastrointestinal microbiota. In addition, some COVID-19 patients may receive antibiotics, which may also disturb gastrointestinal homeostasis. In summary, the gastrointestinal system, gut microbiome, and gut-lung axis may represent an important role in the development, severity, and treatment of COVID-19. Therefore, in this review, we explore the current pieces of evidence of COVID-19 gastrointestinal manifestations, possible implications, and interventions.     

Inflammasomes and SARS-CoV-2 Infection

SARS-CoV-2 is a new type of coronavirus that has caused worldwide pandemic. The disease induced by SARS-CoV-2 is called COVID-19. A majority of people with COVID-19 have relatively mild respiratory symptoms. However, a small percentage of COVID-19 patients develop a severe disease where multiple organs are affected. These severe forms of SARS-CoV-2 infections are associated with excessive production of pro-inflammatory cytokines, so called “cytokine storm”. Inflammasomes, which are protein complexes of the innate immune system orchestrate development of local and systemic inflammation during virus infection. Recent data suggest involvement of inflammasomes in severe COVID-19. Activation of inflammasome exerts two major effects: it activates caspase-1-mediated processing and secretion of pro-inflammatory cytokines IL-1β and IL-18, and induces inflammatory cell death, pyroptosis, via protein called gasdermin D. Here, we provide comprehensive review of current understanding of the activation and possible functions of different inflammasome structures during SARS-CoV-2 infection and compare that to response caused by influenza A virus. We also discuss how novel SARS-CoV-2 mRNA vaccines activate innate immune response, which is a prerequisite for the activation of protective adaptive immune response.     

Current Understanding of the Innate Control of Toll-like Receptors in Response to SARS-CoV-2 Infection

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, threatens the entire world. It has affected every aspect of life and increased the burden on both healthcare and socioeconomic systems. Current studies have revealed that excessive inflammatory immune responses are responsible for the severity of COVID-19, which suggests that anti-inflammatory drugs may be promising therapeutic treatments. However, there are currently a limited number of approved therapeutics for COVID-19. Toll-like receptors (TLRs), which recognize microbial components derived from invading pathogens, are involved in both the initiation of innate responses against SARS-CoV-2 infection and the hyperinflammatory phenotype of COVID-19. In this review, we provide current knowledge on the pivotal role of TLRs in immune responses against SARS-CoV-2 infection and demonstrate the potential effectiveness of TLR-targeting drugs on the control of hyperinflammation in patients with COVID-19.     

Human ACE2 Polymorphisms from Different Human Populations Modulate SARS-CoV-2 Infection

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 6 million deaths worldwide. The high variability in COVID-19 symptoms remains one of the most interesting mysteries of the pandemic. Genetic and environmental factors are likely to be key determinants of COVID-19 symptomatology. Here, we explored ACE2 as a genetic determinant for SARS-CoV-2 infection and COVID-19 symptomatology. Each human genome encodes two alleles of ACE2, which encodes the cell entry receptor for SARS-CoV-2. Here, we determined whether naturally occurring human ACE2 (hACE2) polymorphisms in the human population affect SARS-CoV-2 infection and the severity of COVID-19 symptoms. ACE2 variants S19P, I21V, E23K, K26R, K31R, N33I, H34R, E35K, and T92I showed increased virus infection compared to wild-type ACE2; thus, these variants could increase the risk for COVID-19. In contrast, variants D38V, Y83H, I468V, and N638S showed reduced infection, indicating a potential protective effect. hACE2 variants K26R and T92I increased infection by three-fold without changing the levels of ACE2 on the surface of the cells, suggesting that these variants may increase the risk of severe COVID-19. On the contrary, hACE2 variants D38V and Y83H decreased SARS-CoV-2 infection by four- and ten-fold, respectively, without changing surface expression, suggesting that these variants may protect against severe COVID-19. Remarkably, all protective hACE2 Polymorphisms were found almost exclusively in Asian populations, which may provide a partial explanation for the low COVID-19 mortality rates in Asian countries. Thus, hACE2 polymorphisms may modulate susceptibility to SARS-CoV-2 in the host and partially account for the differences in severity of COVID-19 among different ethnic groups.     

Symptomatic SARS-CoV-2 Reinfection in a Healthy Healthcare Worker in Italy Confirmed by Whole-Genome Sequencing

This study describes a case of SARS-CoV-2 reinfection confirmed by whole-genome sequencing in a healthy physician who had been working in a COVID-19 hospital in Italy since the beginning of the pandemic. Nasopharyngeal swabs were obtained from the patient at each presentation as part of routine surveillance. Nucleic acid amplification testing was performed on the two samples to confirm SARS-CoV-2 infection, and serological tests were used to detect SARS-CoV-2 IgG antibodies. Comparative genome analysis with whole-genome sequencing was performed on nasopharyngeal swabs collected during the two episodes of COVID-19. The first COVID-19 episode was in March 2020, and the second was in January 2021. Both SARS-CoV-2 infections presented with mild symptoms, and seroconversion for SARS-CoV-2 IgG was documented. Genomic analysis showed that the viral genome from the first infection belonged to the lineage B.1.1.74, while that from the second infection to the lineage B.1.177. Epidemiological, clinical, serological, and genomic analyses confirmed that the second episode of SARS-CoV-2 infection in the healthcare worker met the qualifications for “best evidence” for reinfection. Further studies are urgently needed to assess the frequency of such a worrisome occurrence, particularly in the light of the recent diffusion of SARS-CoV-2 variants of concern.     

SARS-CoV-2 Seroconversion in an Adult Horse with Direct Contact to a COVID-19 Individual

The authors report on a possible direct exposure to SARS-CoV-2 from a COVID-19-positive individual to an adult horse. The individual, diagnosed with COVID-19 (Delta B.1.617.2), had daily contact to her two horses prior to and during the development of clinical disease. None of the two horses developed abnormal clinical signs or had detectable SARS-CoV-2 in blood, nasal secretion, or feces via RT-qPCR. However, one of the two horses showed close temporal seroconversion to SARS-CoV-2 using a protein-based ELISA and the plaque reduction neutralization test. The results suggest that horses can become silently infected with SARS-CoV-2 following close contact with humans infected with SARS-CoV-2. As a precautionary measure, humans infected with SARS-CoV-2 should avoid close contact with equids and other companion animals during the time of their illness to prevent viral transmission.     

慢性基础肝病对新型冠状病毒肺炎患者结局的影响

目的 目前,由严重急性呼吸综合征冠状病毒-2(SARS-Co V-2)感染导致的新型冠状病毒肺炎(COVID-19)仍在全球肆虐,成为国际关注的卫生公共事件。报道显示约2%～11%SARS-Co V-2感染患者患有慢性肝病基础,可出现不同程度的肝脏生化学异常。然而,SARS-Co V-2感染是否加重慢性肝病人群肝功能恶化导致慢加急性肝衰竭或急性肝功能失代偿等事件,仍有待于深入研究。本综述讨论了不同慢性肝病人群感染COVID-19的临床病程和预后情况,为临床治疗提供参考。     

SARS-CoV-2 and the pancreas: What do we know about acute pancreatitis in COVID-19 positive patients?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause pancreatic damage, both directly to the pancreas via angiotensin-converting enzyme 2 receptors (the transmembrane proteins required for SARS-CoV-2 entry, which are highly expressed by pancreatic cells) and indirectly through locoregional vasculitis and thrombosis. Despite that, there is no clear evidence that SARS-CoV-2 is an etiological agent of acute pancreatitis. Acute pancreatitis in coronavirus disease 2019 (COVID-19) positive patients often recognizes biliary or alcoholic etiology. The prevalence of acute pancreatitis in COVID-19 positive patients is not exactly known. However, COVID-19 positive patients with acute pancreatitis have a higher mortality and an increased risk of intensive care unit admission and necrosis compared to COVID-19 negative patients. Acute respiratory distress syndrome is the most frequent cause of death in COVID-19 positive patients and concomitant acute pancreatitis. In this article, we reported recent evidence on the correlation between COVID-19 infection and acute pancreatitis.     

Implications of the Immune Polymorphisms of the Host and the Genetic Variability of SARS-CoV-2 in the Development of COVID-19

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current pandemic affecting almost all countries in the world. SARS-CoV-2 is the agent responsible for coronavirus disease 19 (COVID-19), which has claimed millions of lives around the world. In most patients, SARS-CoV-2 infection does not cause clinical signs. However, some infected people develop symptoms, which include loss of smell or taste, fever, dry cough, headache, severe pneumonia, as well as coagulation disorders. The aim of this work is to report genetic factors of SARS-CoV-2 and host-associated to severe COVID-19, placing special emphasis on the viral entry and molecules of the immune system involved with viral infection. Besides this, we analyze SARS-CoV-2 variants and their structural characteristics related to the binding to polymorphic angiotensin-converting enzyme type 2 (ACE2). Additionally, we also review other polymorphisms as well as some epigenetic factors involved in the immunopathogenesis of COVID-19. These factors and viral variability could explain the increment of infection rate and/or in the development of severe COVID-19.     

Gastrointestinal and hepatic manifestations of COVID-19:A comprehensive review

The severe acute respiratory syndrome-coronavirus-2(SARS-CoV-2) that causes coronavirus disease-2019(COVID-19) is a global pandemic, manifested by an infectious pneumonia. Although patients primarily present with fever, cough and dyspnea, some patients also develop gastrointestinal(GI) and hepatic manifestations. The most common GI symptoms reported are diarrhea, nausea,vomiting, and abdominal discomfort. Liver chemistry abnormalities are common and include elevation of aspartate transferase, alanine transferase, and total bilirubin. Studies have shown that SARS-CoV-2 infects the GI tract via its viral receptor angiotensin converting enzyme Ⅱ, which is expressed on enterocytes of the ileum and colon. Viral RNA has also been isolated from stool specimens of COVID-19 patients, which raised the concern for fecal-oral transmission in addition to droplet transmission. Although indirect evidence has suggested possible fecal-oral transmission of SARS-CoV-2, more effort is needed to establish the role of the fecal-oral transmission route. Further research will help elucidate the association between patients with underlying GI diseases, such as chronic liver disease and inflammatory bowel disease, and severity of COVID-19. In this review, we summarize the data on GI involvement to date, as well as the impact of COVID-19 on underlying GI diseases.     

Liver injury in the era of COVID-19

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has undoubtedly revolutionized the whole globe and given a new point of view on respiratory tract infections. Nevertheless, coronavirus disease 2019 (COVID-19) cannot be perceived as a disease limited only to pneumonia with diverse severity. More and more reports have demonstrated a wide range of possible systemic symptoms, including hepatic complications. Liver injury has been observed in a significant proportion of patients, especially in those with a severe or critical illness. COVID-19 might provoke a deterioration of liver function in patients with already diagnosed chronic liver diseases and without pre-existing liver disorders. The deterioration of liver function worsens the prognosis, increases the risk of a severe course of SARS-CoV-2 infection and prolongs the hospital stay. In general, patients who develop liver dysfunction in COVID-19 are mainly males, elderly people, and those with higher body mass index. The underlying mechanisms for hepatic failure in patients infected with SARS-CoV-2 are still unclear, nevertheless liver damage appears to be directly connected with virus-induced cytopathic effects. A liver injury observed during hospitalization might be simultaneously caused by the use of potentially hepatotoxic drugs, mainly antiviral agents. This minireview focuses on a possible relationship between COVID-19 and the liver, potential molecular mechanisms of liver damage, the characteristics of liver injury and suggested factors predisposing to hepatic manifestations in COVID-19 patients.     

Liver injury in COVID-19: A minireview

Coronavirus disease 2019 (COVID-19), caused by infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has escalated into a global tragedy afflicting human health, life, and social governance. Through the increasing depth of research and a better understanding of this disease, it has been ascertained that, in addition to the lungs, SARS-CoV-2 can also induce injuries to other organs including the liver. Liver injury is a common clinical manifestation of COVID-19, particularly in severe cases, and is often associated with a poorer prognosis and higher severity of COVID-19. This review focuses on the general existing information on liver injury caused by COVID-19, including risk factors and subpopulations of liver injury in COVID-19, the association between preexisting liver diseases and the severity of COVID-19, and the potential mechanisms by which SARS-CoV-2 affects the liver. This review may provide some useful information for the development of therapeutic and preventive strategies for COVID-19-associated liver injury.     

Cardiovascular Tropism and Sequelae of SARS-CoV-2 Infection

The extrapulmonary manifestation of coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), became apparent early in the ongoing pandemic. It is now recognized that cells of the cardiovascular system are targets of SARS-CoV-2 infection and associated disease pathogenesis. While some details are emerging, much remains to be understood pertaining to the mechanistic basis by which SARS-CoV-2 contributes to acute and chronic manifestations of COVID-19. This knowledge has the potential to improve clinical management for the growing populations of patients impacted by COVID-19. Here, we review the epidemiology and pathophysiology of cardiovascular sequelae of COVID-19 and outline proposed disease mechanisms, including direct SARS-CoV-2 infection of major cardiovascular cell types and pathogenic effects of non-infectious viral particles and elicited inflammatory mediators. Finally, we identify the major outstanding questions in cardiovascular COVID-19 research.     

The epidemiology,pathophysiological mechanisms,and management toward COVID-19 patients with Type 2 diabetes: A systematic review

This review comprehensively summarizes epidemiologic evidence of COVID-19 in patients with Type 2 diabetes, explores pathophysiological mechanisms, and integrates recommendations and guidelines for patient management. We found that diabetes was a risk factor for diagnosed infection and poor prognosis of COVID-19. Patients with diabetes may be more susceptible to adverse outcomes associated with SARS-CoV-2 infection due to impaired immune function and possible upregulation of enzymes that mediate viral invasion. The chronic inflammation caused by diabetes, coupled with the acute inflammatory reaction caused by SARS-CoV-2, results in a propensity for inflammatory storm. Patients with diabetes should be aware of their increased risk for COVID-19.     

COVID-19 pandemic: Its impact on liver disease and liver transplantation

Severe pulmonary disease caused by the novel coronavirus [severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)], has devastated many countries around the world.It has overwhelmed the medical system.The priorities of many institutions have changed to manage critically ill corona virus infectious disease-2019(COVID-19) patients,which affected the working style of many departments.Hepatologists and transplant surgeons look after a very sensitive patient group.Patients with liver disease need special attention and continuous follow-up.Similarly,transplant candidates also need special care.Healthcare professionals in the field of hepatology face the overwhelming task of taking care of COVID-19 patients with hepatic complications,liver disease or transplant patients who are SARS-CoV-2 positive,and the patients on routine surveillance who do not have COVID-19.This review will evaluate COVID-19 from the perspective of its effect on the liver and its possible effects on patients with liver disease.Furthermore,the level of care for liver transplant recipients during the pandemic will be discussed.