LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike protein

The interactions between severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) and human host factors enable the virus to propagate infections that lead to COVID-19. The spike protein is the largest structural component of the virus and mediates interactions essential for infection, including with the primary ACE2 receptor. We performed two independent cell-based systematic screens to determine whether there are additional proteins by which the spike protein of SARS-CoV-2 can interact with human cells. We discovered that in addition to ACE2, expression of LRRC15 also causes spike protein binding. This interaction is distinct from other known spike attachment mechanisms such as heparan sulfates or lectin receptors. Measurements of orthologous coronavirus spike proteins implied the interaction was restricted to SARS-CoV-2, suggesting LRRC15 represents a novel class of spike binding interaction. We localized the interaction to the C-terminus of the S1 domain, and showed that LRRC15 shares recognition of the ACE2 receptor binding domain. From analyzing proteomics and single-cell transcriptomics, we identify LRRC15 expression as being common in human lung vasculature cells and fibroblasts. Although infection assays demonstrated that LRRC15 alone is not sufficient to permit viral entry, we present evidence it can modulate infection of human cells. This unexpected interaction merits further investigation to determine how SARS-CoV-2 exploits host LRRC15 and whether it could account for any of the distinctive features of COVID-19.

Preliminary Study on Human Host Factors Perpetuating the Transmission of Schistosomiasis in Endemic Community of Wudil, Kano State, Nigeria

Objective: A cross-sectional study was conducted to determine the human host factors that contribute to the perpetuation of schistosomiasis transmission in endemic communities of Wudil, Kano State, Nigeria. Methods: Information was derived from structured questionnaires supplemented with oral interviews, on perception of the community on the cause of urogenital schistosomiasis, using self-reported macrohaematuria, as the disease proxy, water-use practices, riverside urination and defaecation, and the choice for treatment of schistosome infection. Results: Out of 139 study participants, the perceived causes of gross haematuria by the respondents were Excessive Salt Intake (41.73%); Scorching Sun (20.86%); Unknown (17.27%); Infection (10.07%); Supernatural Force (5.86%) and Water Contact (4.32%). The respondents with self-reported terminal haematuria were 49.64%; riverine water contact 75.54% and riverside contamination 65.41%. Of the 72.46% of the respondents with gross haematuria who attempted for medication only 8.0% visited health facilities, while majority relied on traditional herbalists (39.13%) and roadside medicine stores (20.29%) for treatment. There was a strong association between riverine water contact and terminal haematuria (Odds Ratio: 6.09, 95% CI, 2.825-13.131, P<0.0001; Relative Risk: 2.737, 95% CI, 1.664-4.502, P<0.0001). Conclusion: Exposure to contaminated water as a result of socioeconomic activities, riverside, poor perception on the cause of the disease and lack of adherence to orthodox treatment of positive cases are the key promoters of schistosomiasis transmission in the study area. Excessive salt intake and scorching sun are the major perceived causes of haematuria among the study participants. This underpins the need for health education and other efficacious interventions for community awareness on the disease etiology which is central to effective elimination campaign.

In Vivo Models of HDV Infection: Is Humanizing NTCP Enough?

The discovery of sodium taurocholate co-transporting polypeptide (NTCP) as a hepatitis B (HBV) and delta virus (HDV) entry receptor has encouraged the development of new animal models of infection. This review provides an overview of the different in vivo models that are currently available to study HDV either in the absence or presence of HBV. By presenting new advances and remaining drawbacks, we will discuss human host factors which, in addition to NTCP, need to be investigated or identified to enable a persistent HDV infection in murine hepatocytes. Detailed knowledge on species-specific factors involved in HDV persistence also shall contribute to the development of therapeutic strategies.

Conserved Genomic Terminals of SARS-CoV-2 as Coevolving Functional Elements and Potential Therapeutic Targets

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 40 million people worldwide, with over 1 million deaths as of October 2020 and with multiple efforts in the development and testing of antiviral drugs and vaccines under way. In order to gain insights into SARS-CoV-2 evolution and drug targets, we investigated how and to what extent the SARS-CoV-2 genome sequence differs from those of other well-characterized human and animal coronavirus genomes, as well as how polymorphic SARS-CoV-2 genomes are generally. We ultimately sought to identify features in the SARS-CoV-2 genome that may contribute to its viral replication, host pathogenicity, and vulnerabilities. Our analyses suggest the presence of unique sequence signatures in the 3′ untranslated region (3′-UTR) of betacoronavirus lineage B, which phylogenetically encompasses SARS-CoV-2 and SARS-CoV as well as multiple groups of bat and animal coronaviruses. In addition, we identified genome-wide patterns of variation across different SARS-CoV-2 strains that likely reflect the effects of selection. Finally, we provide evidence for a possible host-microRNA-mediated interaction between the 3′-UTR and human microRNA hsa-miR-1307-3p based on the results of multiple computational target prediction analyses and an assessment of similar interactions involving the influenza A H1N1 virus. This interaction also suggests a possible survival mechanism, whereby a mutation in the SARS-CoV-2 3′-UTR leads to a weakened host immune response. The potential roles of host microRNAs in SARS-CoV-2 replication and infection and the exploitation of conserved features in the 3′-UTR as therapeutic targets warrant further investigation. IMPORTANCE The coronavirus disease 2019 (COVID-19) outbreak is having a dramatic global effect on public health and the economy. As of October 2020, SARS-CoV-2 has been detected in over 189 countries, has infected over 40 million people, and is responsible for more than 1 million deaths. The genome of SARS-CoV-2 is small but complex, and its functions and interactions with human host factors are being studied extensively. The significance of our study is that, using extensive SARS-CoV-2 genome analysis techniques, we identified potential interacting human host microRNA targets that share similarity with those of influenza A virus H1N1. Our study results will allow the development of virus-host interaction models that will enhance our understanding of SARS-CoV-2 pathogenesis and motivate the exploitation of both the interacting viral and host factors as therapeutic targets.

Functional genomic screens identify human host factors for SARS-CoV-2 and common cold coronaviruses

The Coronaviridae are a family of viruses that causes disease in humans ranging from mild respiratory infection to potentially lethal acute respiratory distress syndrome. Finding host factors that are common to multiple coronaviruses could facilitate the development of therapies to combat current and future coronavirus pandemics. Here, we conducted parallel genome-wide CRISPR screens in cells infected by SARS-CoV-2 as well as two seasonally circulating common cold coronaviruses, OC43 and 229E. This approach correctly identified the distinct viral entry factors ACE2 (for SARS-CoV-2), aminopeptidase N (for 229E) and glycosaminoglycans (for OC43). Additionally, we discovered phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis as critical host pathways supporting infection by all three coronaviruses. By contrast, the lysosomal protein TMEM106B appeared unique to SARS-CoV-2 infection. Pharmacological inhibition of phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis reduced replication of all three coronaviruses. These findings offer important insights for the understanding of the coronavirus life cycle as well as the potential development of host-directed therapies.

Why COVID-19 Transmission Is More Efficient and Aggressive Than Viral Transmission in Previous Coronavirus Epidemics?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing a pandemic of coronavirus disease 2019 (COVID-19). The worldwide transmission of COVID-19 from human to human is spreading like wildfire, affecting almost every country in the world. In the past 100 years, the globe did not face a microbial pandemic similar in scale to COVID-19. Taken together, both previous outbreaks of other members of the coronavirus family (severe acute respiratory syndrome (SARS-CoV) and middle east respiratory syndrome (MERS-CoV)) did not produce even 1% of the global harm already inflicted by COVID-19. There are also four other CoVs capable of infecting humans (HCoVs), which circulate continuously in the human population, but their phenotypes are generally mild, and these HCoVs received relatively little attention. These dramatic differences between infection with HCoVs, SARS-CoV, MERS-CoV, and SARS-CoV-2 raise many questions, such as: Why is COVID-19 transmitted so quickly? Is it due to some specific features of the viral structure? Are there some specific human (host) factors? Are there some environmental factors? The aim of this review is to collect and concisely summarize the possible and logical answers to these questions.

Why COVID-19 Transmission is More Efficient and Aggressive than Viral Transmission in Previous Coronavirus Epidemics?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing pandemic of coronavirus disease 2019 (COVID-19). The worldwide transmission of COVID-19 from human to human is spreading like wildfire, affecting almost every country in the world. In the past 100 years, the globe did not face microbial pandemic similar in scale to COVID-19. Taken together, both previous outbreaks of other members of the coronavirus family (SARS-CoV and MERS-CoV) did not produce even 1% of the global harm already inflicted by COVID-19. There are also four other CoVs capable of infecting humans (HCoVs), which circulate continuously in the human population, but their phenotypes are generally mild, and these HCoVs received relatively little attention. These dramatic differences between infection with HCoVs, SARS-CoV, MERS-CoV, and SARS-CoV-2 raise many questions, such as: Why is COVID-19 transmitted so quickly? Is it due to the some specific features of the viral structure? Are there some specific human (host) factors? Are there some environmental factors? The aim of this review is to collect and concisely summaries the possible and logic answers to these questions.

Host ESCRT factors are recruited during chikungunya virus infection and are required for the intracellular viral replication cycle

Chikungunya fever is a re-emerging zoonotic disease caused by chikungunya virus (CHIKV), a member of the Alphavirus genus in the Togaviridae family. Only a few studies have reported on the host factors required for intracellular CHIKV trafficking. Here, we conducted an imaging-based siRNA screen to identify human host factors for intracellular trafficking that are involved in CHIKV infection, examined their interactions with CHIKV proteins, and investigated the contributions of these proteins to CHIKV infection. The results of the siRNA screen revealed that host endosomal sorting complexes required for transport (ESCRT) proteins are recruited during CHIKV infection. Co-immunoprecipitation analyses revealed that both structural and nonstructural CHIKV proteins interact with hepatocyte growth factor–regulated tyrosine kinase substrate (HGS), a component of the ESCRT-0 complex. We also observed that HGS co-localizes with the E2 protein of CHIKV and with dsRNA, a marker of the replicated CHIKV genome. Results from gene knockdown analyses indicated that, along with other ESCRT factors, HGS facilitates both genome replication and post-translational steps during CHIKV infection. Moreover, we show that ESCRT factors are also required for infections with other alphaviruses. We conclude that during CHIKV infection, several ESCRT factors are recruited via HGS and are involved in viral genome replication and post-translational processing of viral proteins.