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.     

SARS-CoV-2 Infection and Possible Neonatal Neurological Outcomes: A Literature Review

The virus responsible for COVID-19 is designated “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2), a highly transmissible and pathogenic coronavirus. Although people of all ages are susceptible to SARS-CoV-2 infection, clinical manifestations may vary with age. The response of neonates to SARS-CoV-2 infection or exposure differs from that of children and adults. Encephalitis due to viral infections in the central nervous system (CNS) and childhood multisystem inflammatory syndrome (MIS-C) are some of the possible neonatal consequences of SARS-CoV-2 infection. This review aims to verify possible neonatal neurological outcomes after SARS-CoV-2 infection. Overall, the cellular and molecular basis of the neurological sequelae of SARS-CoV-2 in neonates remains unclear, and attempts to elucidate the pathophysiology of COVID-19 involve a comparison with the mechanism of other viral diseases. There are a considerable number of case reports in the literature exploring neurological outcomes in the neonatal period. In this review, we present possible effects of SARS-CoV-2 in neonates, emphasizing the importance of monitoring this group. The mechanisms of SARS-CoV-2 entry into the CNS have not yet been fully elucidated, and the potential severity of SARS-CoV-2 infection in neonates, as well as the possible short- and long-term neurological sequelae, remain unclear.     

COVID-19 in normal,diseased and transplanted liver

Starting from December 2019 the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has extended in the entire world giving origin to a pandemic. Although the respiratory system is the main apparatus involved by the infection, several other organs may suffer coronavirus disease 2019 (COVID-19)-related injuries. The human tissues expressing angiotensin-converting enzyme 2 (ACE2) are all possible targets of viral damage. In fact myocarditis, meningo-encephalitis, acute kidney injury and other complications have been described with regard to SARS-CoV-2 infection. The liver has a central role in the body homeostasis contributing to detoxification, catabolism and also synthesis of important factor such as plasma proteins. ACE2 is significantly expressed just by cholangiocytes within the liver, however transaminases are increased in more than one third of COVID-19 patients, at hospital admission. The reasons for liver impairment in the course of this infection are not completely clear at present and multiple factors such as: Direct viral effect, release of cytokines, ischemic damage, use of hepatotoxic drugs, sepsis, and others, may contribute to damage. While COVID-19 seems to elicit just a transient alteration of liver function tests in subjects with normal hepatic function, of concern, more severe sequelae are frequently observed in patients with a reduced hepatic reserve. In this review we report data regarding SARS-CoV-2 infection in subjects with normal or diseased liver. In addition the risks of COVID-19 in immunosuppressed patients (either transplanted or suffering for autoimmune liver diseases) are also described.     

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.     

Antibody-Dependent Enhancement of SARS-CoV-2 Infection of Human Immune Cells: In Vitro Assessment Provides Insight in COVID-19 Pathogenesis

Patients with COVID-19 generally raise antibodies against SARS-CoV-2 following infection, and the antibody level is positively correlated to the severity of disease. Whether the viral antibodies exacerbate COVID-19 through antibody-dependent enhancement (ADE) is still not fully understood. Here, we conducted in vitro assessment of whether convalescent serum enhanced SARS-CoV-2 infection or induced excessive immune responses in immune cells. Our data revealed that SARS-CoV-2 infection of primary B cells, macrophages and monocytes, which express variable levels of FcγR, could be enhanced by convalescent serum from COVID-19 patients. We also determined the factors associated with ADE, and found which showed a time-dependent but not viral-dose dependent manner. Furthermore, the ADE effect is not associated with the neutralizing titer or RBD antibody level when testing serum samples collected from different patients. However, it is higher in a medium level than low or high dilutions in a given sample that showed ADE effect, which is similar to dengue. Finally, we demonstrated more viral genes or dysregulated host immune gene expression under ADE conditions compared to the no-serum infection group. Collectively, our study provides insight into the understanding of an association of high viral antibody titer and severe lung pathology in severe patients with COVID-19.     

Inflammatory effect on the gastrointestinal system associated with COVID-19

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) that causes coronavirus disease-2019 (COVID-19) has provoked a global pandemic, mainly affecting the respiratory tract; however, a percentage of infected individuals can develop gastrointestinal (GI) symptoms. Some studies describe the development of GI symptoms and how they affect the progression of COVID-19. In this review, we summarize the main mechanisms associated with gut damage during infection by SARS-CoV-2 as well as other organs such as the liver and pancreas. Not only are host factors associated with severe COVID-19 but intestinal microbiota dysbiosis is also observed in patients with severe disease.     

Characterization of SARS-CoV-2 Evasion: Interferon Pathway and Therapeutic Options

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic. SARS-CoV-2 is characterized by an important capacity to circumvent the innate immune response. The early interferon (IFN) response is necessary to establish a robust antiviral state. However, this response is weak and delayed in COVID-19 patients, along with massive pro-inflammatory cytokine production. This dysregulated innate immune response contributes to pathogenicity and in some individuals leads to a critical state. Characterizing the interplay between viral factors and host innate immunity is crucial to better understand how to manage the disease. Moreover, the constant emergence of new SARS-CoV-2 variants challenges the efficacy of existing vaccines. Thus, to control this virus and readjust the antiviral therapy currently used to treat COVID-19, studies should constantly be re-evaluated to further decipher the mechanisms leading to SARS-CoV-2 pathogenesis. Regarding the role of the IFN response in SARS-CoV-2 infection, in this review we summarize the mechanisms by which SARS-CoV-2 evades innate immune recognition. More specifically, we explain how this virus inhibits IFN signaling pathways (IFN-I/IFN-III) and controls interferon-stimulated gene (ISG) expression. We also discuss the development and use of IFNs and potential drugs controlling the innate immune response to SARS-CoV-2, helping to clear the infection.     

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.     

Use of Antiandrogens as Therapeutic Agents in COVID-19 Patients

COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), is estimated to have caused over 6.5 million deaths worldwide. The emergence of fast-evolving SARS-CoV-2 variants of concern alongside increased transmissibility and/or virulence, as well as immune and vaccine escape capabilities, highlight the urgent need for more effective antivirals to combat the disease in the long run along with regularly updated vaccine boosters. One of the early risk factors identified during the COVID-19 pandemic was that men are more likely to become infected by the virus, more likely to develop severe disease and exhibit a higher likelihood of hospitalisation and mortality rates compared to women. An association exists between SARS-CoV-2 infectiveness and disease severity with sex steroid hormones and, in particular, androgens. Several studies underlined the importance of the androgen-mediated regulation of the host protease TMPRSS2 and the cell entry protein ACE2, as well as the key role of these factors in the entry of the virus into target cells. In this context, modulating androgen signalling is a promising strategy to block viral infection, and antiandrogens could be used as a preventative measure at the pre- or early hospitalisation stage of COVID-19 disease. Different antiandrogens, including commercial drugs used to treat metastatic castration-sensitive prostate cancer and other conditions, have been tested as antivirals with varying success. In this review, we summarise the most recent updates concerning the use of antiandrogens as prophylactic and therapeutic options for COVID-19.     

Antiviral Drug Discovery for the Treatment of COVID-19 Infections

The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recently emerged human coronavirus. COVID-19 vaccines have proven to be successful in protecting the vaccinated from infection, reducing the severity of disease, and deterring the transmission of infection. However, COVID-19 vaccination faces many challenges, such as the decline in vaccine-induced immunity over time, and the decrease in potency against some SARS-CoV-2 variants including the recently emerged Omicron variant, resulting in breakthrough infections. The challenges that COVID-19 vaccination is facing highlight the importance of the discovery of antivirals to serve as another means to tackle the pandemic. To date, neutralizing antibodies that block viral entry by targeting the viral spike protein make up the largest class of antivirals that has received US FDA emergency use authorization (EUA) for COVID-19 treatment. In addition to the spike protein, other key targets for the discovery of direct-acting antivirals include viral enzymes that are essential for SARS-CoV-2 replication, such as RNA-dependent RNA polymerase and proteases, as judged by US FDA approval for remdesivir, and EUA for Paxlovid (nirmatrelvir + ritonavir) for treating COVID-19 infections. This review presents an overview of the current status and future direction of antiviral drug discovery for treating SARS-CoV-2 infections, covering important antiviral targets such as the viral spike protein, non-structural protein (nsp) 3 papain-like protease, nsp5 main protease, and the nsp12/nsp7/nsp8 RNA-dependent RNA polymerase complex.     

COVID-19 and hepatic injury: cellular and molecular mechanisms in diverse liver cells

The coronavirus disease 2019(COVID-19) represents a global health and economic challenge. Hepatic injuries have been approved to be associated with severe acute respiratory syndrome coronavirus(SARS-CoV-2) infection. The viral tropism pattern of SARS-CoV-2 can induce hepatic injuries either by itself or by worsening the conditions of patients with hepatic diseases. Besides, other factors have been reported to play a crucial role in the pathological forms of hepatic injuries induced by SARS-CoV-2...     

Factors Associated with Severe COVID-19 and Post-Acute COVID-19 Syndrome in a Cohort of People Living with HIV on Antiretroviral Treatment and with Undetectable HIV RNA

SARS-CoV-2 can produce both severe clinical conditions and long-term sequelae, but data describing post-acute COVID-19 syndrome (PACS) are lacking for people living with HIV (PLWH). We aimed at assessing the prevalence and factors associated with severe COVID-19 and PACS in our cohort. We included all unvaccinated adult PLWH on antiretroviral treatment and plasma HIV-RNA < 40 cp/mL since at least six months before SARS-CoV-2 infection at the Infectious and Tropical Diseases Unit of Padua (Italy), from 20 February 2020 to 31 March 2021. COVID-19 severity was defined by WHO criteria; PACS was defined as the persistence of symptoms or development of sequelae beyond four weeks from SARS-CoV-2 infection. Demographic and clinical variables were collected, and data were analyzed by non-parametric tests. 123 subjects meeting the inclusion criteria among 1800 (6.8%) PLWH in care at the Infectious and Tropical diseases Unit in Padua were diagnosed with SARS-CoV-2 infection/COVID-19 during the study period. The median age was 51 years (40–58), 79.7% were males, and 77.2% of Caucasian ethnicity. The median CD4+ T-cell count and length of HIV infection were 560 cells/mmc (444–780) and 11 years, respectively. Of the patients, 35.0% had asymptomatic SARS-CoV-2 infection, 48% developed mild COVID-19, 17.1% presented moderate or severe COVID-19 requiring hospitalization and 4.1% died. Polypharmacy was the single independent factor associated with severe COVID-19. As for PACS, among 75 patients who survived SARS-CoV-2 symptomatic infection, 20 (26.7%) reported PACS at a median follow-up of six months: asthenia (80.0%), shortness of breath (50.0%) and recurrent headache (25.0%) were the three most common complaints. Only the severity of the COVID-19 episode predicted PACS after adjusting for relevant demographic and clinical variables. In our study, PLWH with sustained viral suppression and good immunological response showed that the risk of hospital admission for COVID-19 was low, even though the severity of the disease was associated with high mortality. In addition, the likelihood of developing severe COVID-19 and PACS was mainly driven by similar risk factors to those faced by the general population, such as polypharmacy and the severity of SARS-CoV-2 infection.     

Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) poses a persistent threat to global public health. Although primarily a respiratory illness, extrapulmonary manifestations of COVID-19 include gastrointestinal, cardiovascular, renal and neurological diseases. Recent studies suggest that dysfunction of the endothelium during COVID-19 may exacerbate these deleterious events by inciting inflammatory and microvascular thrombotic processes. Although controversial, there is evidence that SARS-CoV-2 may infect endothelial cells by binding to the angiotensin-converting enzyme 2 (ACE2) cellular receptor using the viral Spike protein. In this review, we explore current insights into the relationship between SARS-CoV-2 infection, endothelial dysfunction due to ACE2 downregulation, and deleterious pulmonary and extra-pulmonary immunothrombotic complications in severe COVID-19. We also discuss preclinical and clinical development of therapeutic agents targeting SARS-CoV-2-mediated endothelial dysfunction. Finally, we present evidence of SARS-CoV-2 replication in primary human lung and cardiac microvascular endothelial cells. Accordingly, in striving to understand the parameters that lead to severe disease in COVID-19 patients, it is important to consider how direct infection of endothelial cells by SARS-CoV-2 may contribute to this process.     

Persistent COVID-19 Symptoms Minimally Impact the Development of SARS-CoV-2-Specific T Cell Immunity

SARS-CoV-2 represents an unprecedented public health challenge. While the majority of SARS-CoV-2-infected individuals with mild-to-moderate COVID-19 resolve their infection with few complications, some individuals experience prolonged symptoms lasting for weeks after initial diagnosis. Persistent viral infections are commonly accompanied by immunologic dysregulation, but it is unclear if persistent COVID-19 impacts the development of virus-specific cellular immunity. To this end, we analyzed SARS-CoV-2-specific cellular immunity in convalescent COVID-19 patients who experienced eight days or fewer of COVID-19 symptoms or symptoms persisting for 18 days or more. We observed that persistent COVID-19 symptoms were not associated with the development of an overtly dysregulated cellular immune response. Furthermore, we observed that reactivity against the N protein from SARS-CoV-2 correlates with the amount of reactivity against the seasonal human coronaviruses 229E and NL63. These results provide insight into the processes that regulate the development of cellular immunity against SARS-CoV-2 and related human coronaviruses.     

How to manage inflammatory bowel disease during the COVID-19 pandemic: A guide for the practicing clinician

Managing inflammatory bowel disease (IBD) during the coronavirus disease 2019 (COVID-19) pandemic has been a challenge faced by clinicians and their patients, especially concerning whether to proceed with biologics and immunosuppressive agents in the background of a global outbreak of a highly contagious new coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2). The knowledge about the impact of this virus on patients with IBD, although it is still scarce, is rapidly evolving. In particular, concerns surrounding medications’ impact for IBD on the risk of acquiring SARS-CoV-2 infection or developing COVID-19, and potentially exacerbate viral replication and the COVID-19 course, are a current thinking of both practicing clinicians and providers caring for patients with IBD. Managing patients with IBD infected with SARS-CoV-2 depends on both the clinical activity of the IBD and the occasional development and severity of COVID-19. In this review, we summarize the current data regarding gastrointestinal involvement by SARS-CoV-2 and pharmacologic and surgical management for IBD concerning this infection, and the COVID-19 impact on both the patient's psychological functioning and endoscopy services, and we concisely summarize the telemedicine roles during the COVID-19 pandemic.     

Severe SARS-CoV-2 Infection in a Cat with Hypertrophic Cardiomyopathy

Coronavirus disease 19 (COVID-19), has claimed millions of human lives worldwide since the emergence of the zoonotic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China in December 2019. Notably, most severe and fatal SARS-CoV-2 infections in humans have been associated with underlying clinical conditions, including diabetes, hypertension and heart diseases. Here, we describe a case of severe SARS-CoV-2 infection in a domestic cat (Felis catus) that presented with hypertrophic cardiomyopathy (HCM), a chronic heart condition that has been described as a comorbidity of COVID-19 in humans and that is prevalent in domestic cats. The lung and heart of the affected cat presented clear evidence of SARS-CoV-2 replication, with histological lesions similar to those observed in humans with COVID-19 with high infectious viral loads being recovered from these organs. The study highlights the potential impact of comorbidities on the outcome of SARS-CoV-2 infection in animals and provides important information that may contribute to the development of a feline model with the potential to recapitulate the clinical outcomes of severe COVID-19 in humans.     

SARS-CoV-2 Non-Structural Proteins and Their Roles in Host Immune Evasion

Coronavirus disease 2019 (COVID-19) has caused an unprecedented global crisis and continues to threaten public health. The etiological agent of this devastating pandemic outbreak is the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). COVID-19 is characterized by delayed immune responses, followed by exaggerated inflammatory responses. It is well-established that the interferon (IFN) and JAK/STAT signaling pathways constitute the first line of defense against viral and bacterial infections. To achieve viral replication, numerous viruses are able to antagonize or hijack these signaling pathways to attain productive infection, including SARS-CoV-2. Multiple studies document the roles of several non-structural proteins (NSPs) of SARS-CoV-2 that facilitate the establishment of viral replication in host cells via immune escape. In this review, we summarize and highlight the functions and characteristics of SARS-CoV-2 NSPs that confer host immune evasion. The molecular mechanisms mediating immune evasion and the related potential therapeutic strategies for controlling the COVID-19 pandemic are also discussed.     

Liver dysfunction during COVID-19 pandemic: Contributing role of associated factors in disease progression and severity

In December 2019, a new strain of coronavirus was discovered in China, and the World Health Organization declared it a pandemic in March 2020. The majority of people with coronavirus disease 19 (COVID-19) exhibit no or only mild symptoms such as fever, cough, anosmia, and headache. Meanwhile, approximately 15% develop a severe lung infection over the course of 10 d, resulting in respiratory failure, which can lead to multi-organ failure, coagulopathy, and death. Since the beginning of the pandemic, it appears that there has been consideration that pre-existing chronic liver disease may predispose to deprived consequences in conjunction with COVID-19. Furthermore, extensive liver damage has been linked to immune dysfunction and coagulopathy, which leads to a more severe COVID-19 outcome. Besides that, people with COVID-19 frequently have abnormal liver function, with more significant elevations in alanine aminotransferase and aspartate aminotransferase in patients with severe COVID-19 compared to those with mild/moderate disease. This review focuses on the pathogenesis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in the liver, as well as the use of liver chemistry as a prognostic tool during COVID-19. We also evaluate the findings for viral infection of hepatocytes, and look into the potential mechanisms behind SARS-CoV-2-related liver damage.     

COVID-19 pneumonia in an HIV-positive woman on antiretroviral therapy and undetectable viral load in Porto Alegre,Brazil

COVID-19 pandemic has been a problem worldwide. It is important to identify people at risk of progressing to severe complications and to investigate if some existing antivirals could have any action against SARS-CoV-2. In this context, HIV-infected individuals and antiretroviral drugs might be included, respectively. Herein we present the case of a 63-year-old HIV-infected woman with undetectable viral load, on dolutegravir, tenofovir and lamivudine, who was hospitalized due to COVID-19 pneumonia. In spite of having some clinical markers of severity on admission, the patient improved and was discharged after a week. To our knowledge, this is the first report of severe SARS-CoV-2 infection in an HIV-infected individual in Brazil.