The viral tricks that make bats resilient & humans vulnerable: IISc scientists uncover key insights

Bengaluru: A new study from the Indian Institute of Science (IISc) sheds light on how viruses like SARS-CoV-2 regulate host cell death and why bats and humans respond differently to these viral manipulations.

Zoonotic viruses, often carried by bats and birds, pose significant threats to human health. These pathogens can cause mild to severe diseases when transmitted to humans. Host cell death is a natural defence mechanism to limit viral spread and activate immune responses, but excessive or uncontrolled cell death can lead to severe tissue damage and worsen disease outcomes.

The research, led by Kesavardana Sannula, Assistant Professor at IISc's Department of Biochemistry, explores how zoonotic viruses mimic the host’s cell death mechanisms. The team focused on RIP homotypic interaction motifs (RHIMs) — key protein components involved in regulating cell death and inflammation.

The study revealed that SARS-CoV-2’s Nsp13 protein, critical for viral replication, contains an RHIM similar to those found in humans. Nsp13 was shown to activate robust cell death in human cells, particularly when working with host RHIM proteins ZBP1 and RIPK3, potentially contributing to the respiratory damage observed in severe Covid-19 cases.

Interestingly, altering the RHIM in Nsp13 enhanced cell survival, suggesting its pivotal role in triggering cell death.

The researchers also identified that Z-RNA segments in the virus’ genome drives this Nsp13-mediated activation.

While bats also express RHIM proteins, they exhibit milder symptoms and less tissue damage despite hosting viruses with RHIM mimics.

To investigate, the researchers examined how Nsp13-RHIM regulates cell death in bat cells. “We initially found that Nsp13 could activate cell death in bat cells, similar to humans,” explained Sanchita Mishra, first author and PhD student in Sannula’s lab. “However, bat cell death was non-inflammatory and Nsp13-RHIM independent — likely sufficient to clear the viral replication niche without causing severe inflammation.”

These findings offer critical insights into the evolutionary interplay between zoonotic viruses and their hosts, providing potential avenues for developing targeted antiviral therapies.