Antiviral activity of the human endogenous retrovirus-R envelope protein against SARS-CoV-2

Coronavirus-induced disease-19 (COVID-19), caused by SARS-CoV-2, is still a major global health challenge. Human endogenous retroviruses (HERVs) represent retroviral elements that were integrated into the ancestral human genome. HERVs are important in embryonic development as well as in the manifestation of diseases, including cancer, inflammation, and viral infections. Here, we analyze the expression of several HERVs in SARS-CoV-2-infected cells and observe increased activity of HERV-E, HERV-V, HERV-FRD, HERV-MER34, HERV-W, and HERV-K-HML2. In contrast, the HERV-R envelope is downregulated in cell-based models and PBMCs of COVID-19 patients. Overexpression of HERV-R inhibits SARS-CoV-2 replication, suggesting its antiviral activity. Further analyses demonstrate the role of the extracellular signal-regulated kinase (ERK) in regulating HERV-R antiviral activity. Lastly, our data indicate that the crosstalk between ERK and p38 MAPK controls the synthesis of the HERV-R envelope protein, which in turn modulates SARS-CoV-2 replication. These findings suggest the role of the HERV-R envelope as a prosurvival host factor against SARS-CoV-2 and illustrate a possible advantage of integration and evolutionary maintenance of retroviral elements in the human genome.Copyright © 2023 The Authors.

Exploring the intersection of Aspergillus fumigatus biofilms, infections, immune response and antifungal resistance.

Aspergillus fumigatus is an opportunistic pathogen that primarily affects the lungs and frequently elicits an allergic immune response in human hosts via inhalation of its airborne asexual spores (conidia). In immunocompromised individuals, the conidia of this fungus can germinate in the lung and result in severe systemic infections characterised by widespread tissue and organ damage. Conversely, in healthy hosts, the innate immune system is instrumental in eliminating the conidia and preventing disease progression. As with numerous other pathogenic fungi, A. fumigatus possesses a set of virulence factors that facilitate its infective mechanism and the circumvention of immune defences in susceptible hosts. The intrinsic capacity of A. fumigatus to form complex 3D-structured biofilms, both on biotic and abiotic surfaces, represents a key determinant of its evasion of the host immune system and resistance to antifungal drugs. This review delineates the pivotal role of A. fumigatus biofilm structure and function as a significant virulence factor in pathogenic infections, such as aspergilloma and invasive pulmonary aspergillosis (IPA). Additionally, we discuss the importance for the development of novel antifungal drugs as drug-resistant strains continue to evolve. Furthermore, co-infections of A. fumigatus with other nosocomial pathogens have a substantial impact on patient's health outcomes. In this context, we provide a brief overview of COVID-19-associated pulmonary aspergillosis (CAPA), a recently documented condition that has gained attention due to its associated high degree of severity.

Exploring the role of secretory proteins in the human infectious diseases diagnosis and therapeutics.

Secretory proteins are playing important role during the host-pathogen interaction to develop the infection or protection into the cell. Pathogens developing infectious disease to human being are taken up by host macrophages or number of immune cells, play an important role in physiological, developmental and immunological function. At the same time, infectious agents are also secreting various proteins to neutralize the resistance caused by host cells and also helping the pathogens to develop the infection. Secretory proteins (secretome) are only developed at the time of host-pathogen interaction, therefore they become very important to develop the targeted and potential therapeutic strategies. Pathogen specific secretory proteins released during interaction with host cell provide opportunity to develop point of care and rapid diagnostic kits. Proteins secreted by pathogens at the time of interaction with host cell have also been found as immunogenic in nature and numbers of vaccines have been developed to control the spread of human infectious diseases. This chapter highlights the importance of secretory proteins in the development of diagnostic and therapeutic strategies to fight against human infectious diseases.

A new framework for host-pathogen interaction research.

COVID-19 often manifests with different outcomes in different patients, highlighting the complexity of the host-pathogen interactions involved in manifestations of the disease at the molecular and cellular levels. In this paper, we propose a set of postulates and a framework for systematically understanding complex molecular host-pathogen interaction networks. Specifically, we first propose four host-pathogen interaction (HPI) postulates as the basis for understanding molecular and cellular host-pathogen interactions and their relations to disease outcomes. These four postulates cover the evolutionary dispositions involved in HPIs, the dynamic nature of HPI outcomes, roles that HPI components may occupy leading to such outcomes, and HPI checkpoints that are critical for specific disease outcomes. Based on these postulates, an HPI Postulate and Ontology (HPIPO) framework is proposed to apply interoperable ontologies to systematically model and represent various granular details and knowledge within the scope of the HPI postulates, in a way that will support AI-ready data standardization, sharing, integration, and analysis. As a demonstration, the HPI postulates and the HPIPO framework were applied to study COVID-19 with the Coronavirus Infectious Disease Ontology (CIDO), leading to a novel approach to rational design of drug/vaccine cocktails aimed at interrupting processes occurring at critical host-coronavirus interaction checkpoints. Furthermore, the host-coronavirus protein-protein interactions (PPIs) relevant to COVID-19 were predicted and evaluated based on prior knowledge of curated PPIs and domain-domain interactions, and how such studies can be further explored with the HPI postulates and the HPIPO framework is discussed.

Association between Microorganisms and Microplastics: How Does It Change the Host-Pathogen Interaction and Subsequent Immune Response?

Plastic pollution is a significant problem worldwide because of the risks it poses to the equilibrium and health of the environment as well as to human beings. Discarded plastic released into the environment can degrade into microplastics (MPs) due to various factors, such as sunlight, seawater flow, and temperature. MP surfaces can act as solid scaffolds for microorganisms, viruses, and various biomolecules (such as LPS, allergens, and antibiotics), depending on the MP characteristics of size/surface area, chemical composition, and surface charge. The immune system has efficient recognition and elimination mechanisms for pathogens, foreign agents, and anomalous molecules, including pattern recognition receptors and phagocytosis. However, associations with MPs can modify the physical, structural, and functional characteristics of microbes and biomolecules, thereby changing their interactions with the host immune system (in particular with innate immune cells) and, most likely, the features of the subsequent innate/inflammatory response. Thus, exploring differences in the immune response to microbial agents that have been modified by interactions with MPs is meaningful in terms of identifying new possible risks to human health posed by anomalous stimulation of immune reactivities.

Promoting self-healing power and balancing immune response: a holistic, effective strategy of traditional Chinese medicine in treating COVID-19

Background The COVID-19 pandemic is a serious challenge to human medicines. Modern medicine (MM) has been excellent in identifying the virus, sequencing its mutants, and monitoring the pandemic progress. However, due to lack of effective antivirals in the first two years of the pandemic, MM treated COVID-19 mainly by conventional supportive care with limited efficacy. In China, traditional Chinese medicine (TCM) has been actively participating the control of COVID-19, and the combination of TCM and conventional supportive care has shown better efficacies than the conventional care alone. Purpose: Clinical studies have shown that TCM treats COVID-19 through a holistic action, such as repairing organ injuries, anti-inflammation, immunoregulation and antiviral activities, etc. However, it is not clear how TCM is able to achieve these effects, and the scientific interpretation of TCM theories is lacking. This review aims to elucidate the scientific basis underlying TCM theories in the context of host-pathogen interaction and provide a working model for TCM in treating infectious diseases. Procedure: This review focuses on the essential components of host-pathogen interaction and performs an in-depth analysis of current literatures, including TCM theories and clinical studies as well as the most recent findings of tolerance (self-healing) mechanism in biomedical sciences. Conclusion: TCM treats COVID-19 through a holistic regulation of host responses, particularly by promoting patients’ self-healing power and balancing immune responses. Compared to the pathogen-centered MM, the host-centered TCM doesn't require specific antivirals and has less side-effects and drug resistance. This review provides a scientific insight into the mechanism of TCM and sheds a light on the prospective integration of TCM and MM for future challenges.

Emerging and re-emerging infectious diseases in 2022

Emerging infectious diseases are commonly defined as outbreaks of previously unknown diseases or known diseases that are rapidly increasing in incidence or geographic range in the last decades or the persistence of infectious diseases that cannot be controlled. The reappearance of a previously known infection after a period of disappearance or decline in incidence is known as re-emergence. Many factors contribute to the emergence or re-emergence of a disease. Research indicates that newly emergent infections may result from changes in or the evolution of existing organisms, the spread of known diseases to new geographic areas or new hosts (e.g. humans), or the appearance of previously unrecognized infections in persons living or working in areas undergoing ecologic changes. This increases individual exposure to insects, animals, and environmental sources which may harbor new or unusual infectious agents. Recent decades have seen several emerging and re-emerging infections like HIV, SARS-1, MERS, Zika virus and most recently SARS-CoV-2 and monkeypox. Some of them, like the Zika virus or Ebola virus diseases, have had a limited global impact. Others, however, have affected the entire world. The SARS-CoV-2 pandemic is present on all continents and has caused approximately 18 million deaths worldwide thus far. The full economic and social impact of the SARS-CoV-2 pandemic is still under investigation, but is likely to be massive. In my presentation, I will analyze how we managed the SARS-CoV-2 pandemic in Estonia, what measures were correct and which mistakes have been made. We still are learning how to live with the virus so that our lives are minimally disturbed. Another global threat is constantly increasing antibiotic resistance that could be controlled by improving antibiotic stewardship and hospital hygiene. Improved control over the spread of antibiotic-resistant encoding genes would enable stopping antibiotic resistance as well. In my presentation, I will also look at the future - it is unlikely that emerging/re-emerging infections are completely avoided, but their societal damage could be minimized by better preparedness for emerging situations. The latter requires cooperation between neighboring countries and outside, especially strengthening research on host-pathogen interactions.

Multiple functions of heterogeneous nuclear ribonucleoproteins in the positive single-stranded RNA virus life cycle.

The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a diverse family of RNA binding proteins that are implicated in RNA metabolism, such as alternative splicing, mRNA stabilization and translational regulation. According to their different cellular localization, hnRNPs display multiple functions. Most hnRNPs were predominantly located in the nucleus, but some of them could redistribute to the cytoplasm during virus infection. HnRNPs consist of different domains and motifs that enable these proteins to recognize predetermined nucleotide sequences. In the virus-host interactions, hnRNPs specifically bind to viral RNA or proteins. And some of the viral protein-hnRNP interactions require the viral RNA or other host factors as the intermediate. Through various mechanisms, hnRNPs could regulate viral translation, viral genome replication, the switch of translation to replication and virion release. This review highlights the common features and the distinguish roles of hnRNPs in the life cycle of positive single-stranded RNA viruses.

Brain Organoids as a Model to Study Zika Virus and SARS-CoV-2 Infections

In recent years, we are living through different viral pandemics that result in neurological impairments. Given the human-specific nature of brain development, physiology, and pathology, it is imperative to use human models to investigate the neurological impact of viral infections, such as Zika virus and SARS-CoV-2. Brain organoids are powerful in vitro platforms for the analysis of the effects of viral infections on brain development and function, with prospective application to new emerging viral threats. Using brain organoids, it was possible to show that Zika virus infects neural stem cells, disrupting the cell cycle and neurogenesis, leading to microcephaly, a severe reduction of the brain. On the other hand, while it is still under investigation how SARS-CoV-2 might enter and alter the brain, organoid studies are helping to characterize its neurotropism and potential mechanisms of neurovirulence. Here, we describe a method for the infection of human brain organoid cultures with Zika and Sars-CoV-2 viruses that can be used to study neurodevelopmental phenotypes, alteration in neuronal functionality, host-pathogen interactions, as well as for drug testing. Copyright © 2023, Springer Science+Business Media, LLC, part of Springer Nature.

Translesion Synthesis: From Cancer Resistance to Host-Pathogen Interactions

Genome instability mechanisms that characterize cancer initiation and subsequent therapy resistance are still less well understood. Recent evidence suggests that the REV1-dependent translesion synthesis (TLS) is the cornerstone for new mutation formation that primes genome instability, including intrinsic and acquired resistance to therapy. Remarkably, REV1 inhibition also switches the biology of cisplatin-dependent cell death response from apoptosis to senescence, suggesting that REV1 functions beyond a DNA damage polymerase. Furthermore, we discovered two unexpected phenotypes of REV1 TLS polymerase: a) REV1 inhibition triggers autophagy that associated with radioresistance. b) By means of striking preliminary data we show that REV1 inhibition limits SARS-CoV-2 RNA virus propagation, which we recently reported to cause hostcell DNA damage response and telomere instability. These new observations add to the repertoire of REV1- dependent genome instability pathways significant to understanding a wide repertoire of human diseases, including cancer pathogenesis.

High-resolution interaction prediction in the CAPRI covid-19 open science initiative

SARS-CoV-2 has been deregulating society for over two years. Whereas targeted interactions allow the virus to recruit signaling pathways in order to facilitate replication, fortuitous host-pathogen interactions lead to the emergence of covid-19 at various levels of severity. The CAPRI community has been mobilizing its resources and expertise to model the structures and interaction interfaces of SARS-CoV-2 to human protein complexes. A comprehensive list of putatively interacting protein pairs has been prioritized from a Y2H-determined protein-protein interaction map, out of which five targets were offered for prediction in a uniquely open initiative, sharing data, analyses and results as they were being produced. Close to 30 predictor groups produced close to 30 GB of data, representing more than 50,000 three-dimensional interaction models. These have been processed and filtered by approximately the same amount of scorer groups using a plethora of scoring functions to produce an enriched subset of some 1000 structures. We have further reduced this set through clustering and contact overlap scoring to produce a high-resolution community consensus prediction for the host-pathogen interactions offered. The results show a varying degree of reliability for the targets, with generally a better consensus for the interaction surface on the human protein than on the SARS protein. The results also show the feasibility of such large-scale approaches and the added value of using several, distinctly different, prediction methodologies to reach a consensus prediction.

Is it possible that our generation will deal a new pandemic caused by another Coronavirus?

The current COVID-19 pandemic was induced by the emergence of a coronavirus from an animal as a reservoir. Thus, it is of great importance to know how the evolution of these viral agents occurs in the nature. In this article, the main mechanisms associated with the evolution of coronaviruses were presented, indicating the animal species that act as reservoirs or evolutionary hosts, the viral genetic mechanisms involved in the generation of viral variants, the contribution of human actions to generate recombinant coronaviruses with pandemic potential. From the points discussed in the article, we conclude that the generation of new coronaviruses can be avoided with the implementation of public policies that propose health actions and thus there will only be human health if there is environmental health and animal health.

Differences between Omicron SARS-CoV-2 RBD and other variants in their ability to interact with cell receptors and monoclonal antibodies.

SARS-CoV-2 remains a health threat with the continuous emergence of new variants. This work aims to expand the knowledge about the SARS-CoV-2 receptor-binding domain (RBD) interactions with cell receptors and monoclonal antibodies (mAbs). By using constant-pH Monte Carlo simulations, the free energy of interactions between the RBD from different variants and several partners (Angiotensin-Converting Enzyme-2 (ACE2) polymorphisms and various mAbs) were predicted. Computed RBD-ACE2-binding affinities were higher for two ACE2 polymorphisms (rs142984500 and rs4646116) typically found in Europeans which indicates a genetic susceptibility. This is amplified for Omicron (BA.1) and its sublineages BA.2 and BA.3. The antibody landscape was computationally investigated with the largest set of mAbs so far in the literature. From the 32 studied binders, groups of mAbs were identified from weak to strong binding affinities (e.g. S2K146). These mAbs with strong binding capacity and especially their combination are amenable to experimentation and clinical trials because of their high predicted binding affinities and possible neutralization potential for current known virus mutations and a universal coronavirus.Communicated by Ramaswamy H. Sarma.

Insights from a computational analysis of the SARS-CoV-2 Omicron variant: Host-pathogen interaction, pathogenicity, and possible drug therapeutics.

INTRODUCTION: Prominently accountable for the upsurge of COVID-19 cases as the world attempts to recover from the previous two waves, Omicron has further threatened the conventional therapeutic approaches. The lack of extensive research regarding Omicron has raised the need to establish correlations to understand this variant by structural comparisons. Here, we evaluate, correlate, and compare its genomic sequences through an immunoinformatic approach to understand its epidemiological characteristics and responses to existing drugs. METHODS: We reconstructed the phylogenetic tree and compared the mutational spectrum. We analyzed the mutations that occurred in the Omicron variant and correlated how these mutations affect infectivity and pathogenicity. Then, we studied how mutations in the receptor-binding domain affect its interaction with host factors through molecular docking. Finally, we evaluated the drug efficacy against the main protease of the Omicron through molecular docking and validated the docking results with molecular dynamics simulation. RESULTS: Phylogenetic and mutational analysis revealed the Omicron variant is similar to the highly infectious B.1.620 variant, while mutations within the prominent proteins are hypothesized to alter its pathogenicity. Moreover, docking evaluations revealed significant differences in binding affinity with human receptors, angiotensin-converting enzyme 2 and NRP1. Surprisingly, most of the tested drugs were proven to be effective. Nirmatrelvir, 13b, and Lopinavir displayed increased effectiveness against Omicron. CONCLUSION: Omicron variant may be originated from the highly infectious B.1.620 variant, while it was less pathogenic due to the mutations in the prominent proteins. Nirmatrelvir, 13b, and Lopinavir would be the most effective, compared to other promising drugs that were proven effective.

Post COVID 19 autoimmune complications: Two cases

Background: Autoimmune disease in adults, among spectrum of complications of COVID 19 is rare. Case Study: Both the cases were never smokers and had type 2 diabetes mellitus, hypertension and hypothyroidism with history of severe COVID 19 eleven months back in case I and seven months back in case II. Case I is 36 year old female, had off and on cough and fever (with spikes of 102o F) for one month along with loss of appetite and weight. CECT thorax showed multifocal GGOs and nodules and CT guided biopsy showed epitheliod granulomas. Fever had not responded to course of ATT. Monteux test showed no induration and BAL was negative for CBNAAT, fungal smear and culture and malignant cytology for both patients. PET CT showed metabolically active bilateral lung nodules. NCCT PNS was suggestive of pansinusitis. cANCA was positive. Case II is a 63 year male, had off and on dry cough and dyspnea off and on (grade 2 mMRC) for 2 months associated with loss of appetite and weight. Hb was 6 gm/ dl and indirect Coombs test was positive. USG whole abdomen showed coarse echotexture with multiple small nodular hypoechoic lesions in liver and spleen and splenomegaly. Serum ACE level was 95 mcg/ L. CECT thorax showed discrete areas of consolidation and ground glass opacity with perifissural and peribronchovascular nodules. TBLB showed non necrotizing granulomatous inflammation. Diagnosis of post COVID ANCA associated vasculitis was made in case I and post COVID sarcoidosis in case II. Both patients responded to immunosuppression. Discussion: Literature shows evidence for similar pathogenesis and clinical-radiological aspects between the hyper-inflammatory diseases and Covid-19 which might explain SARS-CoV-2 for the development of a rapid autoimmune and/or autoinflammatory dysregulation. Host-pathogen interactions at different points of the viral life cycle seem to be important for explaining in part the heterogeneity of clinical pictures that characterize COVID-19. Conclusion: In this progressively increasing global COVID-19 pandemic, it remains necessary to investigate early to find the effects and interactions of various immunological and autoimmune diseases in patients with recent history of COVID-19 and further intervene.

Human Nasal Epithelial Cells (hNECs ) Generated by Air-Liquid Interface (ALI) Culture as a Model System for Studying the Pathogenesis of SARS-CoV-2.

The nasal epithelium lining the human upper airway is the primary portal of entry for several respiratory pathogens, including the recently emerged SARS-CoV-2 virus responsible for the ongoing COVID-19 pandemic. Here, we describe in detail methods for in vitro ALI differentiation of primary cells collected from human donors, to obtain differentiated hNECs. This can serve as a physiologically relevant model to investigate various aspects of host-pathogen responses to SARS-CoV-2 and other emerging respiratory viruses.

A high-throughput, online tool for investigating host-pathogen macromolecular interactions buried in scientific literature

This work introduces a low-latency, searchable web tool for biologist and healthcare researchers to quickly explore a large number of host-pathogen interactions (HPI) reported in scientific publication. Our database contains 23,581 generic HPI and 257 COVID-19 related HPI extracted from 32 million PubMed s. The data was automatically collected by running our high-precision biomedical text mining system, which consumes much less effort than manual curation while still provides reliable output. Web URL: philm2web.live © 2021 IEEE.

A determination of pan-pathogen antimicrobials?

While antimicrobial drug development has historically mitigated infectious diseases that are known, COVID-19 revealed a dearth of 'in-advance' therapeutics suitable for infections by pathogens that have not yet emerged. Such drugs must exhibit a property that is antithetical to the classical paradigm of antimicrobial development: the ability to treat infections by any pathogen. Characterisation of such 'pan-pathogen' antimicrobials requires consolidation of drug repositioning studies, a new and growing field of drug discovery. In this review, a previously-established system for evaluating repositioning studies is used to highlight 4 therapeutics which exhibit pan-pathogen properties, namely azithromycin, ivermectin, niclosamide, and nitazoxanide. Recognition of the pan-pathogen nature of these antimicrobials is the cornerstone of a novel paradigm of antimicrobial development that is not only anticipatory of pandemics and bioterrorist attacks, but cognisant of conserved anti-infective mechanisms within the host-pathogen interactome which are only now beginning to emerge. Ultimately, the discovery of pan-pathogen antimicrobials is concomitantly the discovery of a new class of antivirals, and begets significant implications for pandemic preparedness research in a world after COVID-19.