Healthcare (Commonwealth Union) – A recent study by researchers at the Indian Institute of Science (IISc) sheds light on how viruses like SARS-CoV-2 regulate cell death and highlights the contrasting ways bats and humans respond to the strategies these viruses use to subvert the host’s immune defenses.
Zoonotic viruses, which jump from animals to humans, are a major public health concern. Bats and birds serve as key reservoirs for many viruses with zoonotic potential. When these pathogens infect humans, they can lead to a range of outcomes, from mild illness to severe disease. One way the body defends against viral infections is through programmed cell death, a mechanism that limits viral spread and activates protective immune responses. However, when this process becomes uncontrolled, it can cause significant tissue damage, exacerbating disease severity. Researchers have long sought to understand how bat-derived zoonotic viruses manipulate human cells to drive excessive cell death and tissue destruction.
The Nature of Zoonotic Viruses Zoonotic viruses are a diverse group of pathogens that can be transmitted from animals to humans. They can be classified into several categories, including RNA and DNA viruses, as well as positive-sense and negative-sense RNA viruses. Examples of zoonotic viruses include the West Nile virus, Nipah virus, Ebola virus, and the recently emerged SARS-CoV-2 virus responsible for the COVID-19 pandemic. These viruses often originate in animals and can be transmitted to humans through various routes, such as direct contact, consumption of contaminated food, vector-borne transmission, or airborne transmission.
Led by Kesavardana Sannula, an Assistant Professor in the Department of Biochemistry, the study revealed that certain viruses’ mimic elements of the host’s cell death pathways. Specifically, the team focused on RIP homotypic interaction motifs (RHIMs), protein segments that play a key role in regulating cell death and inflammation.
The researchers discovered that many bat-origin viruses possess RHIM mimics. For instance, SARS-CoV-2 contains a replication enzyme called Nsp13, which includes an RHIM resembling those found in human proteins. Nsp13 was shown to strongly activate cell death in human cells, while mutations in its RHIM improved cell survival. The study further demonstrated that Nsp13 works in conjunction with human RHIM proteins, such as ZBP1 and RIPK3, to trigger cell death. This process may contribute to the respiratory damage and disease progression observed in COVID-19 cases. Additionally, the team identified Z-RNA segments within the viral genome that amplify the Nsp13-driven activation of cell death.
The study highlights that bats express RHIM proteins similar to those found in humans, making them a potential source for RHIM mimics to mutate and evolve. Interestingly, despite harboring viruses with RHIM mimics, bats exhibit only mild clinical symptoms and limited tissue damage compared to humans. To explore this intriguing difference, the researchers investigated whether and how Nsp13-RHIM influences 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,” explained Sanchita Mishra, who is the first author and PhD student in the Kesavardana lab.
Researchers of the study indicated that these findings on the differences in cell death regulation between bats and humans offer valuable clues as to why bats can tolerate certain pathogenic viruses that cause 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,” added Kesavardana, the 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.”
