Periodontal disease and clinical association with COVID-19 infection

SARS-CoV-2 infection can cause long-standing damage to the immune system characterized by increased inflammatory cytokine activation. Maintaining periodontal health may reduce host susceptibility to COVID-19 and prevent COVID-19 aggravation in infected patients. There is sufficient evidence in the literature to warrant an association between the presence of PDs and the development and course of respiratory illnesses. Optimum oral health, maintaining good systemic health, and elimination of smoking habits may be beneficial for the prevention and management of COVID-19 infections. Future studies on the periodontal status of patients with COVID-19, including from mild to severe forms, could allow the opportune identification of people at risk of severe illness and generate relevant recommendations. The connection, if any, between the oral microbiome and COVID-19 complications is urgently required to establish the importance of oral hygiene and pre-existing oral disease in the severity and mortality risk of COVID-19.

RAPALOGS DOWNMODULATE INTRINSIC IMMUNITY and PROMOTE CELL ENTRY of SARS-CoV-2

Background: SARS-CoV-2 infection in immunocompromised individuals has been associated with prolonged virus shedding and the development of novel viral variants. Rapamycin and rapamycin analogs (rapalogs, including everolimus, temsirolimus, and ridaforolimus) are FDA-approved for use as mTOR inhibitors in multiple clinical settings, including cancer and autoimmunity, but a common side effect of these drugs is immunosuppression and increased susceptibility to infection. Immune impairment caused by rapalog use is traditionally attributed to their impacts on T cell signaling and cytokine production. Methods: We used replication-competent SARS-CoV-2 and HIV pseudotyped with betacoronavirus Spike proteins to assess how rapalog pretreatment of cells ex vivo and rodent animals in vivo impacts susceptibility to Spike-mediated infection. Results: We show that exposure to rapalogs increases cellular susceptibility to SARS-CoV-2 infection by antagonizing components of the constitutive and interferon-induced cell-intrinsic immune response. Pre-treatment of cells (including human lung epithelial cells and primary human small airway epithelial cells) with rapalogs promoted the early stages of SARS-CoV-2 infection by facilitating Spike-mediated virus entry. Rapalogs also boosted infection mediated by Spike from SARS-CoV and MERS-CoV in addition to hemagglutinin of influenza A virus and glycoprotein from vesicular stomatitis virus, suggesting that rapalogs downmodulate antiviral defenses that pose a common barrier to these viral fusion proteins. By identifying one rapalog (ridaforolimus) that lacks this function, we demonstrate that the extent to which rapalogs promote virus entry is linked to their capacity to trigger the lysosomal degradation of IFITM2 and IFITM3, intrinsic inhibitors of virus-cell membrane fusion. Mechanistically, rapalogs that promote virus entry inhibit the mTOR-mediated phosphorylation of TFEB, a transcription factor controlling lysosome biogenesis and lysosomal degradation pathways such as autophagy. In contrast, TFEB phosphorylation by mTOR was not inhibited by ridaforolimus. In the hamster model of SARS-CoV-2 infection, injection of rapamycin four hours prior to virus exposure resulted in elevated virus titers in lungs, accelerated weight loss, and decreased survival. Conclusion: Our findings indicate that preexisting use of certain rapalogs may elevate host susceptibility to SARS-CoV-2 infection and disease by activating a lysosome-mediated suppression of intrinsic immunity.

Animal models for studying COVID-19, prevention, and therapy: Pathology and disease phenotypes.

Translational models have played an important role in the rapid development of safe and effective vaccines and therapeutic agents for the ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Animal models recapitulating the clinical and underlying pathological manifestations of COVID-19 have been vital for identification and rational design of safe and effective vaccines and therapies. This manuscript provides an overview of commonly used COVID-19 animal models and the pathologic features of SARS-CoV-2 infection in these models in relation to their clinical presentation in humans. Also discussed are considerations for selecting appropriate animal models for infectious diseases such as COVID-19, the host determinants that can influence species-specific susceptibility to SARS-CoV-2, and the pathogenesis of COVID-19. Finally, the limitations of currently available COVID-19 animal models are highlighted.

Age-Specific Transmissibility Change of COVID-19 and Associations With Breathing Air Volume, Preexisting Immunity, and Government Response.

Background: The comprehensive impacts of diverse breathing air volumes and preexisting immunity on the host susceptibility to and transmission of COVID-19 at various pandemic stages have not been investigated. Methods: We classified the US weekly COVID-19 data into 0-4, 5-11, 12-17, 18-64, and 65+ age groups and applied the odds ratio (OR) of incidence between one age group and the 18-64 age group to delineate the transmissibility change. Results: The changes of incidence ORs between May, 2020 and November, 2021 were 0.22-0.66 (0-4 years), 0.20-1.34 (5-11 years), 0.39-1.04 (12-17 years), and 0.82-0.73 (65+ years). The changes could be explained by age-specific preexisting immunity including previous infection and vaccination, as well as volumes of breathing air. At the early pandemic, the ratio that 0-4-year children exhaled one-fifth of air and discharge a similar ratio of viruses was closely associated with incidence OR between two age groups. While, after a rollout of pandemic and vaccination, the much less increased preexisting immunity in children resulted in rapidly increased OR of incidence. The ARIMA model predicted the largest increase of relative transmissibility in 6 coming months in 5-11-year children. Conclusions: The volume of breathing air may be a notable factor contributing to the infectivity of COVID-19 among different age groups of patients. This factor and the varied preexisting greatly shape the transmission of COVID-19 at different periods of pandemic among different age groups of people.

Exogenous Chemical Exposure Increased Transcription Levels of the Host Virus Receptor Involving Coronavirus Infection.

Virus receptors are highly involved in mediating the entrance of infectious viruses into host cells. Here, we found that typical chemical exposure caused the upregulation of virus receptor mRNA levels. Chemicals with the same structural characteristics can affect the transcription of angiotensin-converting enzyme 2 (ACE2), a dominant receptor of SARS-CoV-2. Some chemicals can also regulate the transcription of ACE2 by similar regulatory mechanisms, such as multilayer biological responses and the crucial role of TATA-box binding protein associated factor 6. The abovementioned finding suggested that chemical mixtures may have a joint effect on the ACE2 mRNA level in the real scenario, where humans are exposed to numerous chemicals simultaneously in daily life. Chemically regulated virus receptor transcription was in a tissue-dependent manner, with the highest sensitivity in pulmonary epithelial cells. Therefore, in addition to genetic factors, exogenous chemical exposure can be an emerging nongenetic factor that stimulates the transcription of virus receptor abundance and may elevate the protein expression. These alterations could ultimately give rise to the susceptibility to virus infection and disease severity. This finding highlights new requirements for sufficient epidemiological data about exposomes on pathogen receptors in the host.

Extracting and evaluating features from rna virus sequences to predict host species susceptibility using deep learning

Identifying and monitoring hosts of zoonotic RNA viruses, that is, RNA viruses which can be transmitted from one species to another, including the recent SARS-CoV-2 causing the COVID-19 pandemic, is paramount to control their spread. However, efforts to control such spread may be affected if there are unmonitored or unknown hosts. To help identify potential hosts that may harbour such zoonotic viruses, we propose a pipeline that extracts features from sequences of RNA viruses, then uses the extracted features with deep learning to predict host species susceptibility. In addition to using sequence-related features, our method also extracts and uses features derived from the RNA secondary structures that can be formed by the viral sequences, since RNA secondary structures are known to take part in virus-host interaction. We evaluated the performance of our method and the different extracted features with a dataset containing RNA virus sequences and the host they infect, regardless of the viral species, from the NCBI Virus database. Using 10-fold cross validation, we found that a combination of the extracted features yielded the highest overall prediction accuracy of 86.89%. © 2021 Owner/Author.

The Renin-Angiotensin System: A Key Role in SARS-CoV-2-Induced COVID-19.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), was first identified in Eastern Asia (Wuhan, China) in December 2019. The virus then spread to Europe and across all continents where it has led to higher mortality and morbidity, and was declared as a pandemic by the World Health Organization (WHO) in March 2020. Recently, different vaccines have been produced and seem to be more or less effective in protecting from COVID-19. The renin-angiotensin system (RAS), an essential enzymatic cascade involved in maintaining blood pressure and electrolyte balance, is involved in the pathogenicity of COVID-19, since the angiotensin-converting enzyme II (ACE2) acts as the cellular receptor for SARS-CoV-2 in many human tissues and organs. In fact, the viral entrance promotes a downregulation of ACE2 followed by RAS balance dysregulation and an overactivation of the angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis, which is characterized by a strong vasoconstriction and the induction of the profibrotic, proapoptotic and proinflammatory signalizations in the lungs and other organs. This mechanism features a massive cytokine storm, hypercoagulation, an acute respiratory distress syndrome (ARDS) and subsequent multiple organ damage. While all individuals are vulnerable to SARS-CoV-2, the disease outcome and severity differ among people and countries and depend on a dual interaction between the virus and the affected host. Many studies have already pointed out the importance of host genetic polymorphisms (especially in the RAS) as well as other related factors such age, gender, lifestyle and habits and underlying pathologies or comorbidities (diabetes and cardiovascular diseases) that could render individuals at higher risk of infection and pathogenicity. In this review, we explore the correlation between all these risk factors as well as how and why they could account for severe post-COVID-19 complications.

The Rhinolophus affinis bat ACE2 and multiple animal orthologs are functional receptors for bat coronavirus RaTG13 and SARS-CoV-2.

Bat coronavirus (CoV) RaTG13 shares the highest genome sequence identity with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among all known coronaviruses, and also uses human angiotensin converting enzyme 2 (hACE2) for virus entry. Thus, SARS-CoV-2 is thought to have originated from bat. However, whether SARS-CoV-2 emerged from bats directly or through an intermediate host remains elusive. Here, we found that Rhinolophus affinis bat ACE2 (RaACE2) is an entry receptor for both SARS-CoV-2 and RaTG13, although the binding of RaACE2 to the receptor-binding domain (RBD) of SARS-CoV-2 is markedly weaker than that of hACE2. We further evaluated the receptor activities of ACE2s from additional 16 diverse animal species for RaTG13, SARS-CoV, and SARS-CoV-2 in terms of S protein binding, membrane fusion, and pseudovirus entry. We found that the RaTG13 spike (S) protein is significantly less fusogenic than SARS-CoV and SARS-CoV-2, and seven out of sixteen different ACE2s function as entry receptors for all three viruses, indicating that all three viruses might have broad host rages. Of note, RaTG13 S pseudovirions can use mouse, but not pangolin ACE2, for virus entry, whereas SARS-CoV-2 S pseudovirions can use pangolin, but not mouse, ACE2 enter cells efficiently. Mutagenesis analysis revealed that residues 484 and 498 in RaTG13 and SARS-CoV-2 S proteins play critical roles in recognition of mouse and human ACE2s. Finally, two polymorphous Rhinolophous sinicus bat ACE2s showed different susceptibilities to virus entry by RaTG13 and SARS-CoV-2 S pseudovirions, suggesting possible coevolution. Our results offer better understanding of the mechanism of coronavirus entry, host range, and virus-host coevolution.

ACE2 isoform diversity predicts the host susceptibility of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the ongoing coronavirus disease 2019 (COVID-19) pandemic. Angiotensin-converting enzyme 2 (ACE2) is the functional receptor for SARS-CoV-2. In our current study, we found that two types of deficient ACE2 isoforms from different mammals compete with full-length ACE2 for association with S protein. One type of ACE2 is a natural soluble isoform, the other type of ACE2 only associates with one loop of the receptor-binding domain (RBD) of the SARS-CoV-2 S protein. Mammals with either type of ACE2 will be deficient in support of SARS-CoV-2 entry. By combining S recognition and isoform analysis of ACE2, we predict that felids, mustelids, hamsters, and sheep are susceptible to SARS-CoV-2, while canids, swines, cattle, and goats are not permissive for SARS-CoV-2. Thus, the differential susceptibilities of mammals with SARS-CoV-2 infection could be partially explained by the ACE2 isoform diversity. Our findings will shed important light on predicting the host range of other zoonotic viruses.

SARS-CoV-2 and COVID-19: A genetic, epidemiological, and evolutionary perspective.

In less than five months, COVID-19 has spread from a small focus in Wuhan, China, to more than 5 million people in almost every country in the world, dominating the concern of most governments and public health systems. The social and political distresses caused by this epidemic will certainly impact our world for a long time to come. Here, we synthesize lessons from a range of scientific perspectives rooted in epidemiology, virology, genetics, ecology and evolutionary biology so as to provide perspective on how this pandemic started, how it is developing, and how best we can stop it.