A framework for predicting potential host ranges of pathogenic viruses based on receptor ortholog analysis (preprint)

Viral zoonoses are a serious threat to public health and global security, as reflected by the current scenario of the growing number of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases. However, as pathogenic viruses are highly diverse, identification of their host ranges remains a major challenge. Here, we present a combined computational and experimental framework, called REceptor ortholog-based POtential virus hoST prediction (REPOST), for the prediction of potential virus hosts. REPOST first selects orthologs from a diverse species by identity and phylogenetic analyses. Secondly, these orthologs is classified preliminarily as permissive or non-permissive type by infection experiments. Then, key residues are identified by comparing permissive and non-permissive orthologs. Finally, potential virus hosts are predicted by a key residue-specific weighted module. We performed REPOST on SARS-CoV-2 by studying angiotensin-converting enzyme 2 orthologs from 287 vertebrate animals. REPOST efficiently narrowed the range of potential virus host species (with 95.74% accuracy).

The accessible promoter–mediated supplementary effect of ACE2 provides new insight into the tissue tropism of SARS-CoV-2 (preprint)

Background：Angiotensin-converting enzyme 2 (ACE2) has been confirmed to be a receptor for the newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, cell surface ACE2 expression is reported to be inconsistent with clinical tissue tropism of SARS-CoV-2, which complicates understanding of the pathogenesis of 2019 novel coronavirus disease (COVID-19). The consumption of ACE2 by internalization and shedding processes may explain this discordance. Results：To understand the discordance between ACE2 expression and the tissue tropism of SARS-CoV-2, we examined the chromatin accessibility of ACE2 promoter in hundreds of tissues and cell lines using public DNase-seq and assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq) data. We find that ACE2 promoter is only accessible in three tissues including lung, large intestine and placenta. Also, we examined tumors tissues and ACE2 promoter is observed accessible in five tumors with reported SARS-CoV-2 susceptibility. We confirmed the susceptibility by performing SARS-CoV-2 pseudovirus infection in several cell lines. Conclusions：We propose that open chromatin at the promoter mediates the ACE2 supplementary effect and ensures the entry of SARS-CoV-2. This hypothesis provides a new view and potential clues for further investigation of COVID-19 pathogenesis.

SARS-CoV-2 manipulates the SR-B1-mediated HDL uptake pathway for its entry (preprint)

The recently emerged pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly, leading to a global COVID-19 pandemic. Binding of the viral spike protein (SARS-2-S) to cell surface receptor angiotensin-converting enzyme 2 (ACE2) mediates host cell infection. In the present study, we demonstrate that in addition to ACE2, the S1 subunit of SARS-2-S binds to HDL and that SARS-CoV-2 hijacks the SR-B1-mediated HDL uptake pathway to facilitate its entry. SR-B1 facilitates SARS-CoV-2 entry into permissive cells by augmenting virus attachment. MAb (monoclonal antibody)-mediated blocking of SARS-2-S-HDL binding and SR-B1 antagonists strongly inhibit HDL-enhanced SARS-CoV-2 infection. Notably, SR-B1 is co-expressed with ACE2 in human pulmonary and extrapulmonary tissues. These findings revealed a novel mechanism for SARS-CoV-2 entry and could provide a new target to treat SARS-CoV-2 infection.