CYP19A1 mediates severe SARS-CoV-2 disease outcome in males.

Male sex represents one of the major risk factors for severe COVID-19 outcome. However, underlying mechanisms that mediate sex-dependent disease outcome are as yet unknown. Here, we identify the CYP19A1 gene encoding for the testosterone-to-estradiol metabolizing enzyme CYP19A1 (also known as aromatase) as a host factor that contributes to worsened disease outcome in SARS-CoV-2-infected males. We analyzed exome sequencing data obtained from a human COVID-19 cohort (n = 2,866) using a machine-learning approach and identify a CYP19A1-activity-increasing mutation to be associated with the development of severe disease in men but not women. We further analyzed human autopsy-derived lungs (n = 86) and detect increased pulmonary CYP19A1 expression at the time point of death in men compared with women. In the golden hamster model, we show that SARS-CoV-2 infection causes increased CYP19A1 expression in the lung that is associated with dysregulated plasma sex hormone levels and reduced long-term pulmonary function in males but not females. Treatment of SARS-CoV-2-infected hamsters with a clinically approved CYP19A1 inhibitor (letrozole) improves impaired lung function and supports recovery of imbalanced sex hormones specifically in males. Our study identifies CYP19A1 as a contributor to sex-specific SARS-CoV-2 disease outcome in males. Furthermore, inhibition of CYP19A1 by the clinically approved drug letrozole may furnish a new therapeutic strategy for individualized patient management and treatment.

The proprotein convertase SKI-1/S1P is a critical host factor for Nairobi sheep disease virus infectivity.

Nairobi sheep disease virus (NSDV) belongs to the Orthonairovirus genus in the Bunyavirales order and is genetically related to human-pathogenic Crimean-Congo hemorrhagic fever virus (CCHFV). NSDV is a zoonotic pathogen transmitted by ticks and primarily affects naïve small ruminants in which infection leads to severe and often fatal hemorrhagic gastroenteritis. Despite its veterinary importance and the striking similarities in the clinical picture between NSDV-infected ruminants and CCHFV patients, the molecular pathogenesis of NSDV and its interactions with the host cell are largely unknown. Here, we identify the membrane-bound proprotein convertase site-1 protease (S1P), also known as subtilisin/kexin-isozyme-1 (SKI-1), as a host factor affecting NSDV infectivity. Absence of S1P in SRD-12B cells, a clonal CHO-K1 cell variant with a genetic defect in the S1P gene (MBTPS1), results in significantly decreased NSDV infectivity while transient complementation of SKI-1/S1P rescues NSDV infection. SKI-1/S1P is dispensable for virus uptake but critically required for production of infectious virus progeny. Moreover, we provide evidence that SKI-1/S1P is involved in the posttranslational processing of the NSDV glycoprotein precursor. Our results demonstrate the role of SKI-1/S1P in the virus life cycle of NSDV and suggest that this protease is a common host factor for orthonairoviruses and may thus represent a promising broadly-effective, indirect antiviral target.

ANP32B Deficiency Protects Mice From Lethal Influenza A Virus Challenge by Dampening the Host Immune Response.

Deciphering complex virus-host interactions is crucial for pandemic preparedness. In this study, we assessed the impact of recently postulated cellular factors ANP32A and ANP32B of influenza A virus (IAV) species specificity on viral pathogenesis in a genetically modified mouse model. Infection of ANP32A-/- and ANP32A+/+ mice with a seasonal H3N2 IAV or a highly pathogenic H5N1 human isolate did not result in any significant differences in virus tropism, innate immune response or disease outcome. However, infection of ANP32B-/- mice with H3N2 or H5N1 IAV revealed significantly reduced virus loads, inflammatory cytokine response and reduced pathogenicity compared to ANP32B+/+ mice. Genome-wide transcriptome analyses in ANP32B+/+ and ANP32B-/- mice further uncovered novel immune-regulatory pathways that correlate with reduced pathogenicity in the absence of ANP32B. These data show that ANP32B but not ANP32A promotes IAV pathogenesis in mice. Moreover, ANP32B might possess a yet unknown immune-modulatory function during IAV infection. Targeting ANP32B or its regulated pathways might therefore pose a new strategy to combat severe influenza.

Indirect ELISA based on Hendra and Nipah virus proteins for the detection of henipavirus specific antibodies in pigs.

Hendra virus (HeV) and Nipah virus (NiV) belong to the genus Henipavirus in the family Paramyxoviridae. Henipavirus infections were first reported in the 1990's causing severe and often fatal outbreaks in domestic animals and humans in Southeast Asia and Australia. NiV infections were observed in humans in Bangladesh, India and in the first outbreak in Malaysia, where pigs were also infected. HeV infections occurred in horses in the North-Eastern regions of Australia, with singular transmission events to humans. Bats of the genus Pteropus have been identified as the reservoir hosts for henipaviruses. Molecular and serological indications for the presence of henipa-like viruses in African fruit bats, pigs and humans have been published recently. In our study, truncated forms of HeV and NiV attachment (G) proteins as well as the full-length NiV nucleocapsid (N) protein were expressed using different expression systems. Based on these recombinant proteins, Enzyme-linked Immunosorbent Assays (ELISA) were developed for the detection of HeV or NiV specific antibodies in porcine serum samples. We used the NiV N ELISA for initial serum screening considering the general reactivity against henipaviruses. The G protein based ELISAs enabled the differentiation between HeV and NiV infections, since as expected, the sera displayed higher reactivity with the respective homologous antigens. In the future, these assays will present valuable tools for serosurveillance of swine and possibly other livestock or wildlife species in affected areas. Such studies will help assessing the potential risk for human and animal health worldwide by elucidating the distribution of henipaviruses.

Bat Astroviruses: Towards Understanding the Transmission Dynamics of a Neglected Virus Family.

Bats belong to the order Chiroptera that represents the second largest order of mammals with more than 1200 species and an almost global distribution. Environmental changes and deforestation have severely influenced many ecosystems, intensifying the contact between wildlife and humans. In recent years, bats have been found to harbor a number of different viruses with zoonotic potential, as well as a great diversity of astroviruses, for which the question of zoonotic potential remains unanswered to date. Human astroviruses have been identified as the causative agent for diarrhea in children and immunocompromised patients. For a long time, astroviruses have been considered to be strictly species-specific. However, a great genetic diversity has recently been discovered among animal and human astroviruses that might indicate the potential of these viruses to cross species barriers. Furthermore, our knowledge about the tissue tropism of astroviruses has been expanded to some neurotropic strains that have recently been shown to be responsible for encephalitis in humans and livestock. This review gives an overview on what is known about astroviruses in bats, humans and livestock, especially bovines and pigs. Future research activities are suggested to unravel astrovirus infection dynamics in bat populations to further assess the zoonotic potential of these viruses.