Showing papers in "Reviews in Medical Virology in 2020"

Interleukin-6 in Covid-19: A systematic review and meta-analysis.

Abstract: Coronaviruses may activate dysregulated host immune responses. As exploratory studies have suggested that interleukin-6 (IL-6) levels are elevated in cases of complicated Covid-19, we undertook a systematic review and meta-analysis to assess the evidence in this field. We systematically searched MEDLINE and EMBASE for studies investigating the immunological response in Covid-19; additional grey literature searches were undertaken. Study selection and data abstraction was undertaken independently by two authors. Meta-analysis was undertaken using random effects models to compute ratios of means with 95% confidence intervals (95%CIs). Eight published studies and two preprints (n = 1798) were eligible for inclusion. Meta-analysis of mean IL-6 concentrations demonstrated 2.9-fold higher levels in patients with complicated Covid-19 compared with patients with noncomplicated disease (six studies; n = 1302; 95%CI, 1.17-7.19; I2 = 100%). Consistent results were found in sensitivity analyses exclusively restricted to studies comparing patients requiring ICU admission vs no ICU admission (two studies; n = 540; ratio of means = 3.24; 95%CI, 2.54-4.14; P < .001; I2 = 87%). Nine of ten studies were assessed to have at least moderate risk of bias. In patients with Covid-19, IL-6 levels are significantly elevated and associated with adverse clinical outcomes. Inhibition of IL-6 may be a novel target for therapeutics for the management of dysregulated host responses in patients with Covid-19 and high-quality studies of intervention in this field are urgently required.

Laboratory testing of SARS-CoV, MERS-CoV, and SARS-CoV-2 (2019-nCoV): Current status, challenges, and countermeasures.

Abstract: Emerging and reemerging infectious diseases are global public concerns. With the outbreak of unknown pneumonia in Wuhan, China in December 2019, a new coronavirus, SARS-CoV-2 has been attracting tremendous attention. Rapid and accurate laboratory testing of SARS-CoV-2 is essential for early discovery, early reporting, early quarantine, early treatment, and cutting off epidemic transmission. The genome structure, transmission, and pathogenesis of SARS-CoV-2 are basically similar to SARS-CoV and MERS-CoV, the other two beta-CoVs of medical importance. During the SARS-CoV and MERS-CoV epidemics, a variety of molecular and serological diagnostic assays were established and should be referred to for SARS-CoV-2. In this review, by summarizing the articles and guidelines about specimen collection, nucleic acid tests (NAT) and serological tests for SARS-CoV, MERS-CoV, and SARS-CoV-2, several suggestions are put forward to improve the laboratory testing of SARS-CoV-2. In summary, for NAT: collecting stool and blood samples at later periods of illness to improve the positive rate if lower respiratory tract specimens are unavailable; increasing template volume to raise the sensitivity of detection; putting samples in reagents containing guanidine salt to inactivate virus as well as protect RNA; setting proper positive, negative and inhibition controls to ensure high-quality results; simultaneously amplifying human RNase P gene to avoid false-negative results. For antibody test, diverse assays targeting different antigens, and collecting paired samples are needed.

Immune responses and pathogenesis of SARS-CoV-2 during an outbreak in Iran: Comparison with SARS and MERS.

Abstract: The beginning of 2020 has seen the emergence of COVID-19, an outbreak caused by a novel coronavirus, SARS-CoV-2, an important pathogen for humans. There is an urgent need to better understand this new virus and to develop ways to control its spread. In Iran, the first case of the COVID-19 was reported after spread from China and other countries. Fever, cough, and fatigue were the most common symptoms of this virus. In worldwide, the incubation period of COVID-19 was 3 to 7 days and approximately 80% of infections are mild or asymptomatic, 15% are severe, requiring oxygen, and 5% are critical infections, requiring ventilation. To mount an antiviral response, the innate immune system recognizes molecular structures that are produced by the invasion of the virus. COVID-19 infection induces IgG antibodies against N protein that can be detected by serum as early as day 4 after the onset of disease and with most patients seroconverting by day 14. Laboratory evidence of clinical patients showed that a specific T-cell response against SARS-CoV-2 is important for the recognition and killing of infected cells, particularly in the lungs of infected individuals. At present, there is no specific antiviral therapy for COVID-19 and the main treatments are supportive. In this review, we investigated the innate and acquired immune responses in patients who recovered from COVID-19, which could inform the design of prophylactic vaccines and immunotherapy for the future.

Melatonin: Roles in influenza, Covid-19, and other viral infections.

Abstract: There is a growing appreciation that the regulation of the melatonergic pathways, both pineal and systemic, may be an important aspect in how viruses drive the cellular changes that underpin their control of cellular function. We review the melatonergic pathway role in viral infections, emphasizing influenza and covid-19 infections. Viral, or preexistent, suppression of pineal melatonin disinhibits neutrophil attraction, thereby contributing to an initial "cytokine storm", as well as the regulation of other immune cells. Melatonin induces the circadian gene, Bmal1, which disinhibits the pyruvate dehydrogenase complex (PDC), countering viral inhibition of Bmal1/PDC. PDC drives mitochondrial conversion of pyruvate to acetyl-coenzyme A (acetyl-CoA), thereby increasing the tricarboxylic acid cycle, oxidative phosphorylation, and ATP production. Pineal melatonin suppression attenuates this, preventing the circadian "resetting" of mitochondrial metabolism. This is especially relevant in immune cells, where shifting metabolism from glycolytic to oxidative phosphorylation, switches cells from reactive to quiescent phenotypes. Acetyl-CoA is a necessary cosubstrate for arylalkylamine N-acetyltransferase, providing an acetyl group to serotonin, and thereby initiating the melatonergic pathway. Consequently, pineal melatonin regulates mitochondrial melatonin and immune cell phenotype. Virus- and cytokine-storm-driven control of the pineal and mitochondrial melatonergic pathway therefore regulates immune responses. Virus-and cytokine storm-driven changes also increase gut permeability and dysbiosis, thereby suppressing levels of the short-chain fatty acid, butyrate, and increasing circulating lipopolysaccharide (LPS). The alterations in butyrate and LPS can promote viral replication and host symptom severity via impacts on the melatonergic pathway. Focussing on immune regulators has treatment implications for covid-19 and other viral infections.

Clinical features of deaths in the novel coronavirus epidemic in China.

Abstract: In response to the recent novel coronavirus outbreak originating in Wuhan, Hubei province, China, observations concerning novel coronavirus mortality are of urgent public health importance. The present work presents the first review of the fatal novel coronavirus cases in China. Clinical data of fatal cases published by the Chinese Government were studied. As of 2 February 2020, the clinical data of 46 fatal cases were identified. The case fatality rate was significantly higher in Hubei province than the rest of China. While 67% of all deceased patients were male, gender was unlikely to be associated with mortality. Diabetes was likely to be associated with mortality. There is, however, not yet sufficient evidence to support the association between hypertension and mortality as similar prevalence of hypertension was also observed in the Hubei population.

Using heat to kill SARS-CoV-2.

Abstract: The current coronavirus pandemic has reached global proportions and requires unparalleled collective and individual efforts to slow its spread. One critically important issue is the proper sterilization of physical objects that have been contaminated by the virus. Here, we review the currently existing literature on thermal inactivation of coronavirus (SARS-CoV-2) and present preliminary guideless on temperatures and exposure durations required to sterilize. We also compare these temperatures/exposure durations with potential household appliances that may be thought capable of performing sterilization.

Why the elderly appear to be more severely affected by COVID-19: The potential role of immunosenescence and CMV.

Abstract: The significantly higher mortality rates seen in the elderly compared with young children during the coronavirus disease 2019 (Covid-19) pandemic is likely to be driven in part by an impaired immune response in older individuals. Cytomegalovirus (CMV) seroprevalence approaches 80% in the elderly. CMV has been shown to accelerate immune ageing by affecting peripheral blood T cell phenotypes and increasing inflammatory mediated cytokines such as IL-6. The elderly with pre-existing but clinically silent CMV infection may therefore be particularly susceptible to severe Covid-19 disease and succumb to a cytokine storm which may have been promoted by CMV. Here, we evaluate the potential role of CMV in those with severe Covid-19 disease and consider how this relationship can be investigated in current research studies.

A brief review of interplay between vitamin D and angiotensin-converting enzyme 2: Implications for a potential treatment for COVID-19.

Abstract: The novel coronavirus disease 2019 (COVID-19) is rapidly expanding and causing many deaths all over the world with the World Health Organization (WHO) declaring a pandemic in March 2020 Current therapeutic options are limited and there is no registered and/or definite treatment or vaccine for this disease or the causative infection, severe acute respiratory coronavirus 2 syndrome (SARS-CoV-2) Angiotensin-converting enzyme 2 (ACE2), a part of the renin-angiotensin system (RAS), serves as the major entry point into cells for SARS-CoV-2 which attaches to human ACE2, thereby reducing the expression of ACE2 and causing lung injury and pneumonia Vitamin D, a fat-soluble-vitamin, is a negative endocrine RAS modulator and inhibits renin expression and generation It can induce ACE2/Ang-(1-7)/MasR axis activity and inhibits renin and the ACE/Ang II/AT1R axis, thereby increasing expression and concentration of ACE2, MasR and Ang-(1-7) and having a potential protective role against acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) Therefore, targeting the unbalanced RAS and ACE2 down-regulation with vitamin D in SARS-CoV-2 infection is a potential therapeutic approach to combat COVID-19 and induced ARDS

Immunopathology and immunotherapeutic strategies in severe acute respiratory syndrome coronavirus 2 infection.

Abstract: The outbreak of coronavirus disease 2019 (COVID-19) and pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a major concern globally. As of 14 April 2020, more than 1.9 million COVID-19 cases have been reported in 185 countries. Some patients with COVID-19 develop severe clinical manifestations, while others show mild symptoms, suggesting that dysregulation of the host immune response contributes to disease progression and severity. In this review, we have summarized and discussed recent immunological studies focusing on the response of the host immune system and the immunopathology of SARS-CoV-2 infection as well as immunotherapeutic strategies for COVID-19. Immune evasion by SARS-CoV-2, functional exhaustion of lymphocytes, and cytokine storm have been discussed as part of immunopathology mechanisms in SARS-CoV-2 infection. Some potential immunotherapeutic strategies to control the progression of COVID-19, such as passive antibody therapy and use of interferon αβ and IL-6 receptor (IL-6R) inhibitor, have also been discussed. This may help us to understand the immune status of patients with COVID-19, particularly those with severe clinical presentation, and form a basis for further immunotherapeutic investigations.

The basic reproduction number of SARS-CoV-2 in Wuhan is about to die out, how about the rest of the World?

Abstract: The virologically confirmed cases of a new coronavirus disease (COVID-19) in the world are rapidly increasing, leading epidemiologists and mathematicians to construct transmission models that aim to predict the future course of the current pandemic. The transmissibility of a virus is measured by the basic reproduction number ( R0 ), which measures the average number of new cases generated per typical infectious case. This review highlights the articles reporting rigorous estimates and determinants of COVID-19 R0 for the most affected areas. Moreover, the mean of all estimated R0 with median and interquartile range is calculated. According to these articles, the basic reproduction number of the virus epicentre Wuhan has now declined below the important threshold value of 1.0 since the disease emerged. Ongoing modelling will inform the transmission rates seen in the new epicentres outside of China, including Italy, Iran and South Korea.

Comparison of confirmed COVID-19 with SARS and MERS cases - Clinical characteristics, laboratory findings, radiographic signs and outcomes: A systematic review and meta-analysis.

Abstract: Introduction: In the current time where we face a COVID-19 pandemic, prevention, and rapid diagnosis of infected patients is crucial Within this large-scale st

YouTube as a source of patient information for Coronavirus Disease (COVID-19): A content-quality and audience engagement analysis.

Abstract: YouTube is the second most popular website in the world and is increasingly being used as a platform for disseminating health information. Our aim was to evaluate the content-quality and audience engagement of YouTube videos pertaining to the SARS (severe acute respiratory syndrome)-CoV-2 virus which causes the Coronavirus Disease 2019 (COVID-19), during the early phase of the pandemic. We chose the first 30 videos for seven different search phrases: "2019 nCoV," "SARS CoV-2," "COVID-19 virus," "coronavirus treatment," "coronavirus explained," "what is the coronavirus" and "coronavirus information." Video contents were evaluated by two independent medical students with more than 5 years of experience using the DISCERN instrument. Qualitative data, quantitative data and upload source for each video was noted for a quality and audience engagement analysis. Out of the total 210 videos, 137 met our inclusion criteria and were evaluated. The mean DISCERN score was 31.33 out of 75 possible points, which indicates that the quality of YouTube videos on COVID-19 is currently poor. There was excellent reliability between the two raters (intraclass correlation coefficient = 0.96). 55% of the videos discussed prevention, 49% discussed symptoms and 46% discussed the spread of the virus. Most of the videos were uploaded by news channels (50%) and education channels (40%). The quality of YouTube videos on SARS-CoV-2 and COVID-19 is poor, however, we have listed the top-quality videos in our article as they may be effective tools for patient education during the pandemic.

Innate immune evasion by SARS-CoV-2: Comparison with SARS-CoV.

Abstract: SARS-CoV-2 virus, a member of the Coronaviridae family, causes Covid-19 pandemic disease with severe respiratory illness. Multiple strategies enable SARS-CoV-2 to eventually overcome antiviral innate immune mechanisms which are important components of viral pathogenesis. This review considers several mechanisms of SARS-CoV-2 innate immune evasion including suppression of IFN-α/β production at the earliest stage of infection, mechanisms that exhaust natural killer cell-mediated cytotoxicity, overstimulation of NLRP3 inflammasome and induction of a cytokine storm. A comparison with SARS-CoV is made. Greater knowledge of these and other immune evasion tactics may provide us with improved possibilities for research into this novel deadly virus.

Pandemic potential of highly pathogenic avian influenza clade 2.3.4.4 A(H5) viruses

Abstract: The panzootic caused by A/goose/Guangdong/1/96-lineage highly pathogenic avian influenza (HPAI) A(H5) viruses has occurred in multiple waves since 1996. From 2013 onwards, clade 2.3.4.4 viruses of subtypes A(H5N2), A(H5N6), and A(H5N8) emerged to cause panzootic waves of unprecedented magnitude among avian species accompanied by severe losses to the poultry industry around the world. Clade 2.3.4.4 A(H5) viruses have expanded in distinct geographical and evolutionary pathways likely via long distance migratory bird dispersal onto several continents and by poultry trade among neighboring countries. Coupled with regional circulation, the viruses have evolved further by reassorting with local viruses. As of February 2019, there have been 23 cases of humans infected with clade 2.3.4.4 H5N6 viruses, 16 (70%) of which had fatal outcomes. To date, no HPAI A(H5) virus has caused sustainable human-to-human transmission. However, due to the lack of population immunity in humans and ongoing evolution of the virus, there is a continuing risk that clade 2.3.4.4 A(H5) viruses could cause an influenza pandemic if the ability to transmit efficiently among humans was gained. Therefore, multisectoral collaborations among the animal, environmental, and public health sectors are essential to conduct risk assessments and develop countermeasures to prevent disease and to control spread. In this article, we describe an assessment of the likelihood of clade 2.3.4.4 A(H5) viruses gaining human-to-human transmissibility and impact on human health should such human-to-human transmission occur. This structured analysis assessed properties of the virus, attributes of the human population, and ecology and epidemiology of these viruses in animal hosts.

An overview of the immune mechanisms of viral myocarditis.

Abstract: Viral myocarditis has been identified as a major cause of dilated cardiomyopathy (DCM) that can lead to heart failure. Historically, Coxsackieviruses and adenoviruses have been commonly suspected in myocarditis/DCM patients in North America and Europe. However, this notion is changing as other viruses such as Parvovirus B19 and human herpesvirus-6 are increasingly reported as causes of myocarditis in the United States, with the most recent example being the severe acute respiratory syndrome coronavirus 2, causing the Coronavirus Disease-19. The mouse model of Coxsackievirus B3 (CVB3)-induced myocarditis, which may involve mediation of autoimmunity, is routinely used in the study of immune pathogenesis of viral infections as triggers of DCM. In this review, we discuss the immune mechanisms underlying the development of viral myocarditis with an emphasis on autoimmunity in the development of post-infectious myocarditis induced with CVB3.

Alpha-1-antitrypsin: A possible host protective factor against Covid-19.

Abstract: Understanding Covid-19 pathophysiology is crucial for a better understanding of the disease and development of more effective treatments. Alpha-1-antitrypsin (A1AT) is a constitutive tissue protector with antiviral and anti-inflammatory properties. A1AT inhibits SARS-CoV-2 infection and two of the most important proteases in the pathophysiology of Covid-19: the transmembrane serine protease 2 (TMPRSS2) and the disintegrin and metalloproteinase 17 (ADAM17). It also inhibits the activity of inflammatory molecules, such as IL-8, TNF-α, and neutrophil elastase (NE). TMPRSS2 is essential for SARS-CoV-2-S protein priming and viral infection. ADAM17 mediates ACE2, IL-6R, and TNF-α shedding. ACE2 is the SARS-CoV-2 entry receptor and a key component for the balance of the renin-angiotensin system, inflammation, vascular permeability, and pulmonary homeostasis. In addition, clinical findings indicate that A1AT levels might be important in defining Covid-19 outcomes, potentially partially explaining associations with air pollution and with diabetes. In this review, we focused on the interplay between A1AT with TMPRSS2, ADAM17 and immune molecules, and the role of A1AT in the pathophysiology of Covid-19, opening new avenues for investigating effective treatments.

Covid-19: Time for a paradigm change.

Abstract: As of May 11, 2020, coronavirus disease 2019 (Covid-19) has been confirmed in 4 152 670 people worldwide, carrying a mortality of approximately 6.8%, compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals as well as vaccines to provide primary protection. Accumulating evidence suggests that a subgroup of patients with severe Covid-19 might have a cytokine storm syndrome. We recommend identification and treatment of such hyper inflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. In order to change the approach to patients with severe general conditions by physicians (including anesthesiologists, emergency room resuscitators, infectious disease doctors, cardiologists), a few concepts must be elaborated. The conventional treatment of patients with viral infection has been antipyretic and analgesics to treat the flu-like symptoms and the use of antivirals, in those specific infections where specific antivirals have been identified. Virologists and pharmacologists succeeded in the development of antivirals mainly for herpesviruses and HIV-1, and more recently for HBV and HCV. Acute viral infections, including seasonal influenza and measles, commonly resolve without treatment, although 1% to 2% of the cases may progress to severe respiratory and cardiac distress. So far, intubation and mechanical respiratory support have been available for acute respiratory distress syndrome (ARDS) patients waiting for a spontaneous recovery. Only for those with severe deterioration with no signs of improvement and often in the septic shock phase, were corticosteroids used as a last resort. But steroid efficacy is not consistent, ranging from highly effective to a negative treatment, contributing to patient mortality, so steroids are not recommended routinely for Covid-19 cases. A new era is emerging: patient treatment with drugs specifically targeted to precise biomolecular pathways. The cytokine storm-related pneumonia observed in cancer patients treated with novel biotherapies (including CAR-T cells) has opened the field to anti-IL6R monoclonal antibodies (mAb) and other molecules that act on the IL-6/IL-6R axis. Cytokine storms have been reported also for acute syndrome associated to DNA viruses, in particular HHV-8 or EBV virus-associated hemophagocytic syndrome (VAHS). In particular, the lung injury present in Covid-19 represents a cytokine-storm reaction akin to anaphylaxis that progresses to ARDS. We propose that clinicians in the front line coping with Covid-19 should focus on this reaction and give it the urgency they would afford to traditional cases of anaphylaxis. Physicians are more familiar with IgE-mediated anaphylaxis, which represents the major mechanism underlying allergic anaphylaxis and is primarily mediated by histamine release (Figure 1). The cytokine-release reaction, mainly related to IL6 (besides TNF-α and IL-1β), represents a hypersensitivity reaction (HSR), triggered by chimeric, humanized, and human mAbs and chemotherapeutic agents, including oxaliplatin. HSR mediators (ie, IL-6) activate monocytes, macrophages, mast cells, and other immune cells with the Fc gamma receptor (FcgR)—an essential player of many immune system effector functions, including the release of inflammatory mediators and antibodydependent cellular cytotoxicity. Cytokine storm reactions are further characterized by activation of direct and indirect activation of the coagulation pathway. In particular the complement cascade generates anaphylatoxins, such as C3a and C5a, which bind to complement receptors resulting in the release of histamine, leukotrienes, and prostaglandins. All such molecules contribute to the main symptoms such as flushing, hives, hypoxia, vasodilation, and hypotension. In patients infected with influenza A virus (eg, H5N1), the inflammatory cytokines such as IL-1β, IL-8, and IL-6 play a major role in mediating and amplifying acute lung injury (ALI) and ARDS by stimulating C5a chemotaxis. The C5a induces innate immune cells including mast cells, neutrophils, and monocytes/macrophages to release proinflammatory cytokines such as IL-12, TNF-α, and macrophage inflammatory proteins-1α. In addition, C5a also stimulates adaptive immune cells such as T and B cells to release cytokines such as TNF-α, IL-1β, IL-6, and IL-8. The clinical condition caused by many cytokines triggered by highly pathogenic viruses like H5N1, has been called a “cytokine storm”. Cytokines were rapidly induced at 24 hours post-infection with H5N1. The proinflammatory cytokines including IL-1β and TNF-α might contribute to the severity of disease by promoting maximal lung inflammation caused by H5N1 viral infection. Cytokines have been also blamed for enhancing or modifying virus receptor exposure on endothelial cells lining the myocardial tissue, increasing susceptibility to H1N1 virus infection. Compared to healthy volunteers, H7N9-infected patients have significantly higher levels of cytokines such as IL-6, IFN-γ-inducible protein 10 (IP-10), IL-10, IFN-γ, and TNF-α. A dangerous cytokine storm also occurs in SARS. The representative SARS-CoV ssRNAs had powerful immunostimulatory activities inducing releasing proinflammatory cytokines TNF-α, IL-6, and IL-12. Elevated levels of some pro-inflammatory cytokines including monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-beta1 (TGFβ1), TNF-α, IL-1, and IL-6, produced by cells infected by SARS-CoV, might cause ALI. In addition, one cytokine could induce other cytokines to further enhance the pro-inflammatory response as was noted when elevated levels of TNF-α induced other cytokines like IL-6. Thus, the cytokine storm reaction plays an important role in ALI. Limited data are available on the interaction between IL-6 and C5a. In a DOI: 10.1002/rmv.2134

Dengue: Status of current and under-development vaccines.

Abstract: Dengue is an emerging mosquito-borne viral infection with increasing reports of outbreaks. The clinical picture ranges from a benign febrile illness through to severe and potentially fatal manifestations. No specific anti-viral treatment exists, and therapy only consists of supportive care. During the last three decades, several attempts to develop an effective vaccine have been made. The first dengue vaccine to obtain licensure was Dengvaxia, which was authorized in 2015 and is currently available in over 20 countries. Its use has been approved with strict limitations regarding age and serostatus of the recipients, highlighting the necessity for a more safe and efficacious vaccine. At present several vaccine, candidates are undergoing clinical and pre-clinical trials. The most advanced candidates are TDV and TDV 003/005, two live-attenuated vaccines, but another 15 vaccines are under development, introducing novel immunization strategies to the traditional dengue vaccine scenario. This work reviews the current research status on dengue vaccines.

Three months of COVID-19: A systematic review and meta-analysis.

Abstract: The pandemic of 2019 novel coronavirus (SARS-CoV-2019), reminiscent of the 2002-SARS-CoV outbreak, has completely isolated countries, disrupted health systems and partially paralyzed international trade and travel. In order to be better equipped to anticipate transmission of this virus to new regions, it is imperative to track the progress of the virus over time. This review analyses information on progression of the pandemic in the past 3 months and systematically discusses the characteristics of SARS-CoV-2019 virus including its epidemiologic, pathophysiologic, and clinical manifestations. Furthermore, the review also encompasses some recently proposed conceptual models that estimate the spread of this disease based on the basic reproductive number for better prevention and control procedures. Finally, we shed light on how the virus has endangered the global economy, impacting it both from the supply and demand side.

Angiotensin-converting enzyme 2: The old door for new severe acute respiratory syndrome coronavirus 2 infection.

Abstract: Coronavirus (CoV) disease 2019 (COVID-19) is an ongoing pandemic caused by severe acute respiratory syndrome CoV 2 (SARS-CoV-2). The highly contagious SARS-CoV-2 belongs to the genus Betacoronavirus, and it is phylogenetically closely related to SARS-CoV, a human CoV that caused an outbreak back in 2002 to 2003. Both SARS-CoV-2 and SARS-CoV enter human cells via the interactions between viral crown-like spike protein and human angiotensin-converting enzyme 2 (ACE2) receptor. Here, we aim to review the involvement of ACE2 in human CoV infections by discussing the roles of ACE2 in CoV evolution, cross-species transmissibility, and COVID-19 susceptibility. We also provide our perspectives on COVID-19 treatment and prevention.

Drugs against SARS-CoV-2: What do we know about their mode of action?

Abstract: The health emergency caused by the recent Covid-19 pandemic highlights the need to identify effective treatments against the virus causing this disease (SARS-CoV-2). The first clinical trials have been testing repurposed drugs that show promising anti-SARS-CoV-2 effects in cultured cells. Although more than 2400 clinical trials are already under way, the actual number of tested compounds is still limited to approximately 20, alone or in combination. In addition, knowledge on their mode of action (MoA) is currently insufficient. Their first results reveal some inconsistencies and contradictory results and suggest that cohort size and quality of the control arm are two key issues for obtaining rigorous and conclusive results. Moreover, the observed discrepancies might also result from differences in the clinical inclusion criteria, including the possibility of early treatment that may be essential for therapy efficacy in patients with Covid-19. Importantly, efforts should also be made to test new compounds with a documented MoA against SARS-CoV-2 in clinical trials. Successful treatment will probably be based on multitherapies with antiviral compounds that target different steps of the virus life cycle. Moreover, a multidisciplinary approach that combines artificial intelligence, compound docking, and robust in vitro and in vivo assays will accelerate the development of new antiviral molecules. Finally, large retrospective studies on hospitalized patients are needed to evaluate the different treatments with robust statistical tools and to identify the best treatment for each Covid-19 stage. This review describes different candidate antiviral strategies for Covid-19, by focusing on their mechanism of action.

The role of endogenous retroviruses‐K in human cancer

Abstract: It is known that human endogenous retroviruses (HERVs) constitute almost 8% of the human genome. Although the expression of HERVs from the human genome is tightly regulated, different exogenous and endogenous factors could trigger HERV activation. Aberrant expression of different HERVs may potentially cause a variety of diseases such as neurological and autoimmune diseases as well as cancer. It is suggested that HERV-K can induce cancer through different mechanisms that are discussed. The interplay between some tumor viruses and HERV-K seems to be a key player in progression of viral-associated cancers because elevated levels of Rec and Np9 proteins are observed in several cancers. The frequent over expression of HERV proteins and some specific antibodies in cancer cells could be considered as suitable prognostic and therapeutic biomarkers in diagnosis and treatment of cancers. The expression of HERV proteins in cancers and development of immune responses against them may also be used as targets for cancer immunotherapy. Further studies are warranted to evaluate the role of HERVs in cancer formation and use of different HERV proteins in developing new diagnostic and therapeutic approaches for cancer treatments.

Lessons from dermatology about inflammatory responses in Covid-19.

Abstract: The SARS-Cov-2 is a single-stranded RNA virus composed of 16 non-structural proteins (NSP 1-16) with specific roles in the replication of coronaviruses. NSP3 has the property to block host innate immune response and to promote cytokine expression. NSP5 can inhibit interferon (IFN) signalling and NSP16 prevents MAD5 recognition, depressing the innate immunity. Dendritic cells, monocytes, and macrophages are the first cell lineage against viruses' infections. The IFN type I is the danger signal for the human body during this clinical setting. Protective immune responses to viral infection are initiated by innate immune sensors that survey extracellular and intracellular space for foreign nucleic acids. In Covid-19 the pathogenesis is not yet fully understood, but viral and host factors seem to play a key role. Important points in severe Covid-19 are characterized by an upregulated innate immune response, hypercoagulopathy state, pulmonary tissue damage, neurological and/or gastrointestinal tract involvement, and fatal outcome in severe cases of macrophage activation syndrome, which produce a 'cytokine storm'. These systemic conditions share polymorphous cutaneous lesions where innate immune system is involved in the histopathological findings with acute respiratory distress syndrome, hypercoagulability, hyperferritinemia, increased serum levels of D-dimer, lactic dehydrogenase, reactive-C-protein and serum A amyloid. It is described that several polymorphous cutaneous lesions similar to erythema pernio, urticarial rashes, diffuse or disseminated erythema, livedo racemosa, blue toe syndrome, retiform purpura, vesicles lesions, and purpuric exanthema or exanthema with clinical aspects of symmetrical drug-related intertriginous and flexural exanthema. This review describes the complexity of Covid-19, its pathophysiological and clinical aspects.

Impact of breast milk-acquired cytomegalovirus infection in premature infants: Pathogenesis, prevention, and clinical consequences?

Abstract: Maternal-fetal transmission of cytomegalovirus (CMV) represents the most common infectious cause of long-term neurodevelopmental disability in children. Congenital CMV (cCMV) infection is associated with microcephaly, seizure disorders, cognitive disability, developmental delay, and sensorineural hearing loss (SNHL). Of these disabilities, SNHL is the most common, affecting approximately 10% of infants with cCMV. Although the sequelae of cCMV are well recognized, it is much less clear what long-term morbidities may occur in neonates that acquire post-natal CMV infection. Post-natal CMV (pCMV) infection is most commonly transmitted by breast-feeding, and in full-term infants is of little consequence. However, in preterm, very-low birthweight (VLBW) infants (<1500 g), pCMV can result in a severe sepsis-like syndrome, with wide-ranging end-organ disease manifestations. Although such short-term complications are well recognized among clinicians caring for premature infants, the long-term risks with respect to adverse neurodevelopmental outcomes remain controversial. In this review, we provide an overview of the clinical manifestations of breast milk-acquired pCMV infection. In particular, we summarize studies that have examined-sometimes with conflicting conclusions-the risks of long-term adverse neurodevelopmental outcome in VLBW infants that acquire pCMV from breast milk. We highlight proposed preventive strategies and antiviral interventions, and offer recommendations for high-priority areas for future basic science and clinical research.

Global epidemiology of nonpolio enteroviruses causing severe neurological complications: A systematic review and meta-analysis.

Abstract: Enteroviruses are RNA viruses found as commensals in the human gut and respiratory system, which may cause a wide spectrum of disease. Enteroviruses may cause severe neurologic complications including acute flaccid paralysis (AFP) and encephalitis and are the most commonly diagnosed agents of viral meningitis. Outbreaks of more severe disease are often associated with particular genotypes, such as enterovirus-A71 causing rhombencephalitis and AFP. There are more than 300 described genotypes of human enterovirus, with overlaps in clinical phenotypes between genotypes, and uncertainty about which genotypes are more prevalent in neurological manifestations. A systematic review of observational studies was conducted to evaluate the most prevalent enterovirus genotypes causing AFP, encephalitis, and meningitis. The genotyping methods and sampling sites were compiled as secondary outcomes. Sources included MEDLINE, Embase (publications until January 2019), and references selected from included studies. Meta-analyses using a random effects model were performed to calculate the pooled proportion of enterovirus genotypes in each disease. Ninety-six publications met the eligibility criteria, comprising 3779 AFP cases, 1140 encephalitis cases, and 32 810 meningitis cases. Enterovirus-A71 was most frequently associated with AFP (pooled proportion 0.12, 95% CI, 0.05-0.20) and encephalitis (0.77, 95% CI, 0.61-0.91). Echovirus 30 (0.35, 95% CI, 0.27-0.42) was the most predominant genotype in meningitis cases. Genotypes were most commonly determined using VP1 RT- reverse transcription-polymerase chain reaction, and most samples assessed were cerebrospinal fluid. With the emergence of enteroviruses as an increasing cause of neurological diseases, surveillance and testing need to increase to identify the aetiology of the most common and most severe disorders.

Remdesivir: A beacon of hope from Ebola virus disease to COVID-19.

Abstract: Since the emergence of coronavirus disease 2019 (Covid-19), many studies have been performed to characterize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and find the optimum way to combat this virus. After suggestions and assessments of several therapeutic options, remdesivir (GS-5734), a direct-acting antiviral drug previously tested against Ebola virus disease, was found to be moderately effective and probably safe for inhibiting SARS-CoV-2 replication. Finally, on 1 May 2020, remdesivir (GS-5734) was granted emergency use authorization as an investigational drug for the treatment of Covid-19 by the Food and Drug Administration. However, without a doubt, there are challenging days ahead. Here, we provide a review of the latest findings (based on preprints, post-prints, and news releases in scientific websites) related to remdesivir efficacy and safety for the treatment of Covid-19, along with covering remdesivir history from bench-to-bedside, as well as an overview of its mechanism of action. In addition, active clinical trials, as well as challenging issues related to the future of remdesivir in Covid-19, are covered. Up to the date of writing this review (19 May 2020), there is one finished randomized clinical trial and two completed non-randomized studies, in addition to some ongoing studies, including three observational studies, two expanded access studies, and seven active clinical trials registered on the clinicaltrials.gov and isrctn.com websites. Based on these studies, it seems that remdesivir could be an effective and probably safe treatment option for Covid-19. However, more randomized controlled studies are required.

Updates in Hepatitis E virus (HEV) field; lessons learned from human liver chimeric mice.

Abstract: Hepatitis E virus (HEV) is the most common cause of viral hepatitis globally, and it is an emerging pathogen in developed countries. In vivo studies of HEV have long been hindered due to the lack of an efficient small animal model. Recently, human liver chimeric mice were described as an elegant model to study chronic HEV infection. HEV infection was established in mice with humanized liver that were challenged with stool preparations containing HEV genotype (gt)1 and/or gt3. An increase in viral load and the level of HEV Ag in mouse samples were markers of active infection. Plasma-derived HEV preparations were less infectious. The kinetics of HEV ORF2 Ag during HEV infection and its impact on HEV diagnosis were described in this model. In addition, the nature of HEV particles and HEV ORF2 Ag were characterized. Moreover, humanized mice were used to study the impact of HEV infection on the hepatic innate transcriptome and evaluation of anti-HEV therapies. This review highlights recent advances in the HEV field gathered from well-established experimental mouse models, with an emphasis on this model as a tool for elucidating the course of HEV infection, the study of the HEV life cycle, the interaction of the virus with the host, and the evaluation of new anti-HEV therapies.

The role of anti‐flavivirus humoral immune response in protection and pathogenesis

Abstract: Flavivirus infections are a public health threat in the world that requires the development of safe and effective vaccines. Therefore, the understanding of the anti-flavivirus humoral immune response is fundamental to future studies on flavivirus pathogenesis and the design of anti-flavivirus therapeutics. This review aims to provide an overview of the current understanding of the function and involvement of flavivirus proteins in the humoral immune response as well as the ability of the anti-envelope (anti-E) antibodies to interfere (neutralizing antibodies) or not (non-neutralizing antibodies) with viral infection, and how they can, in some circumstances enhance dengue virus infection on Fc gamma receptor (FcγR) bearing cells through a mechanism known as antibody-dependent enhancement (ADE). Thus, the dual role of the antibodies against E protein poses a formidable challenge for vaccine development. Also, we discuss the roles of antibody binding stoichiometry (the concentration, affinity, or epitope recognition) in the neutralization of flaviviruses and the "breathing" of flavivirus virions in the humoral immune response. Finally, the relevance of some specific antibodies in the design and improvement of effective vaccines is addressed.

A review and meta-analysis of the epidemiology and clinical presentation of coxsackievirus A6 causing hand-foot-mouth disease in China and global implications.

Abstract: Coxsackievirus A6 (CV-A6) has been associated with increasingly occurred sporadic hand-foot-mouth disease (HFMD) cases and outbreak events in many countries. In order to understand epidemiological characteristics of CV-A6, we collected the information describing HFMD caused by CV-A6 to describe the detection rate, severe rate and onychomadesis rate, which is defined as one or more nails defluvium, caused by CV-A6 from 2007 to 2017. The results showed that there was an outbreak of CV-A6 every other year, and overall trend of the epidemic of CA6-associated HFMD was increasing in China. The detection rate of CV-A6 in other countries was 32.0% (95% CI: 25.0%~40.0%) before 2013 and 28.0% (95% CI: 20.0%~36.0%) after 2013, respectively. Although the severe rate of HFMD caused by CV-A6 was low (0.10%, 95% CI: 0.01%~0.20%), CV-A6 can cause a high incidence of onychomadesis (28.0%, 95%CI: 21.9%-34.3%). Thus, it would be worthwhile to research and develop an effective multivalent vaccine for CV-A6 to achieve a more powerful prevention of HMFD.

A review on epidemiology and impact of human metapneumovirus infections in children using TIAB search strategy on PubMed and PubMed Central articles.

Abstract: Acute respiratory tract infections (ARTI) contribute to morbidity and mortality in children globally. Viruses including human metapneumovirus (hMPV) account for most ARTIs. The virus causes upper and lower respiratory tract infections mostly in young children and contributes to hospitalization of individuals with asthma,chronic obstructive pulmonary diseases and cancer. Moreover, hMPV pauses a considerable socio-economic impact creating a substantial disease burden wherever it has been studied, although hMPV testing is relatively new in many countries. We aimed to comprehensively analyze the epidemiological aspects including prevalence, disease burden and seasonality of hMPV infections in children in the world. We acquired published data extracted from PubMed and PubMed Central articles using the title and abstract (TIAB)search strategy for the major key words on hMPV infections from 9/54 African, 11/35 American, 20/50 Asian, 2/14 Australian/Oceanian and 20/51 European countries. According to the findings of this review, the prevalence of hMPV infection ranges from 1.1 to 86% in children of less than 5 years of age globally. Presence of many hMPV genotypes (A1, A2, B1, B2) and sub-genotypes (A2a, A2b, A2c, B2a, B2b) suggests a rapid evolution of the virus with limited influence by time and geography. hMPV infection mostly affects children between 2 to 5 years of age. The virus is active throughout the year in the tropics and epidemics occur during the winter and spring in temperate climates, contributing to a substantial disease burden globally.