How bat-origin pathogenic viruses manipulate human cell death and inflammation

A new study by researchers at the Indian Institute of Science (IISc) offers insights into cell death regulation by viruses like SARS-CoV-2, and how bats and humans respond differently to tricks that such viruses use to manipulate the host’s defense.

Zoonotic virus infections pose a serious concern to human health. Bats and birds are among the main reservoirs for several pathogenic viruses that show zoonotic transmission potential. When they reach the human host, these viruses can cause either mild or severe disease. Host cell death after viral infections is a defense strategy to limit viral spread and mount protective immune responses. However, uncontrolled cell death response can drive excessive tissue damage, leading to disease severity. Scientists have strived to pinpoint how zoonotic viruses that originate from bats manipulate the human host to cause excessive cell death and tissue damage.

The study, led by Kesavardana Sannula, Assistant Professor at the Department of Biochemistry, has uncovered how such viruses mimic components of the host’s cell death machinery. They zeroed in on protein motifs called RIP homotypic interaction motif (RHIMs) that regulate host cell death and inflammation.

Several viruses that originate in bats show mimics of these RHIMs. SARS-CoV-2, for example, contains Nsp13 – an enzyme protein critical for virus replication – that has an RHIM similar to those found in humans. The researchers found that Nsp13 promotes robust human cell death activation; mutating the RHIM in Nsp13 therefore enhanced cell survival. Nsp13 was found to work in synergy with host RHIM proteins called ZBP1 and RIPK3 to promote cell death activation, which might possibly be contributing to the respiratory damage and disease progression seen in COVID-19. The researchers also found that RNA segments in the Z conformation (Z-RNA) in the virus’s genome were driving the Nsp13-mediated cell death activation.

Since bats express host RHIM proteins similar to humans, they can serve as the source for RHIM mimics to mutate and evolve, the study suggests. Interestingly, bats show mild clinical symptoms and tissue damage compared to humans despite harbouring viruses with RHIM mimics. To understand this conundrum, the authors tested whether and how Nsp13-RHIM regulates bat cell death.

“We were initially disappointed to see that Nsp13 could also activate cell death in bat cells like in human cells. We later found the nature of bat cell death to be preferably non-inflammatory and Nsp13-RHIM independent, possibly just enough to clear the viral replication niche but not cause severe inflammation,” says Sanchita Mishra, first author and PhD student in Kesavardana's lab.  

These insights on how cell death is regulated differently in bats and humans provide some clues to why some pathogenic viruses are tolerated in bats but cause more severe diseases in humans.  

“Nsp13 was an attractive therapeutic target for stopping SARS-CoV-2 replication, but with very little success so far. Targeting the RHIM cell death function of Nsp13 could be a better strategy to alleviate SARS-CoV-2-induced tissue damage and inflammation. This is something that we are currently exploring,” says Kesavardana, lead author of the study. “Understanding fundamental differences in cellular responses to viruses in bats and humans is critical to guide pandemic preparedness for such zoonotic virus infections.”