ABSTRACT
SARS-CoV-2 causes the ongoing COVID-19 pandemic. Natural SARS-COV-2 infection has been detected in dogs, cats and tigers. However, the symptoms in canines and felines were mild. The underlying mechanisms are unknown. Excessive activation of inflammasome pathways can trigger cytokine storm and severe damage to host. In current study, we performed a comparative genomics study of key components of inflammasome and pyroptosis pathways in dogs, cats and tigers. Cats and tigers do not have AIM2 and NLRP1. Dogs do not contain AIM2, and encode a short form of NLRC4. The activation sites in GSDMB were absent in dogs, cats and tigers, while GSDME activation sites in cats and tigers were abolished. We propose that deficiencies of inflammasome and pyroptosis pathways might provide an evolutionary advantage against SARS-CoV-2 by reducing cytokine storm-induced host damage. Our findings will shed important lights on the mild symptoms in canines and felines infected with SARS-CoV-2.
Subject(s)
COVID-19/immunology , COVID-19/veterinary , Cat Diseases , Dog Diseases , Inflammasomes/immunology , Pyroptosis/immunology , Animals , Cat Diseases/immunology , Cat Diseases/virology , Cats , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/immunology , Dog Diseases/immunology , Dog Diseases/virology , Dogs , Genomics , Humans , Inflammasomes/genetics , Pyroptosis/genetics , SARS-CoV-2 , TigersABSTRACT
The global coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is one of seven human coronaviruses. G-quadruplexes are intrinsic obstacles to genome replication. Whether G-quadruplexes are present in human coronaviruses is unknown. In the current study, we have predicted that all seven human coronaviruses harbor G-quadruplex sequences. Conserved G-quadruplex sequences in SARS-CoV and SARS-CoV-2 were analyzed and verified by circular dichroism (CD) spectroscopy and Thioflavin T fluorescence assay. Similar to SARS-CoV, SARS-CoV-2 encodes an nsP3 protein, which is predicted to associate with G-quadruplexes. Targeting G-quadruplex sequences in the SARS-CoV-2 genome by G-quadruplex ligands could be a new way to conquer COVID-19.
ABSTRACT
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.