How viruses hijack mitochondria to evade the immune system

In a discovery poised to reshape our understanding of viral survival strategies, scientists at The Wistar Institute have uncovered a viral trick that transforms the cell’s mitochondria - its energy and signalling hubs - into accomplices. Using advanced molecular and imaging techniques, the team revealed how Kaposi’s sarcoma-associated herpesvirus (KSHV) hijacks the host’s mitochondrial architecture to silence immune alarms and ensure its own replication.
The research [1], published in Nature Microbiology, centres on a small but powerful viral protein called vBcl-2, long associated with blocking cell death. But the Wistar team found it does far more - it reprograms the cell's mitochondria to disable the immune response machinery at its root.
“This reveals how viruses can rewire mitochondria to evade immunity,” said Dr Chengyu Liang, Professor and co-leader of the Molecular & Cellular Oncogenesis Program at The Wistar Institute Ellen and Ronald Caplan Cancer Center and senior author of the study. “It broadens our understanding of Bcl-2 proteins and points to new therapeutic targets.”
Using high-resolution microscopy and structural biology tools, the team showed how vBcl-2 recruits a host enzyme, NM23-H2, and redirects it to the mitochondria. Once there, NM23-H2 powers a fragmentation process - essentially slicing up the normally connected mitochondrial network. This physical disruption dismantles a key antiviral signal hub known as MAVS before it can alert the rest of the cell to the infection.
“Instead of blocking one immune protein, the virus disrupts the whole immune signalling hub,” said Liang. “It’s like FEMA failing after a disaster—MAVS is that hub, so the cell can’t coordinate its response to the virus.”
By stopping MAVS from assembling, the virus blocks activation of Type I interferon responses - our cells’ first line of defence against viral invaders. Without these signals, the cell fails to deploy crucial antiviral proteins such as TRIM22 and MxB, which normally trap virus particles in the nucleus and prevent their release.
What makes this discovery even more compelling is its broader implication: similar Bcl-2-like proteins are encoded by other herpesviruses, including the Epstein-Barr virus. This suggests that mitochondrial sabotage may be a common tactic across the herpesvirus family.
The team also identified a small-molecule inhibitor, VBNI-1, that can disrupt the vBcl-2/NM23-H2 interaction. In lab tests, this compound restored mitochondrial structure, revived immune signalling, and halted viral escape - without harming healthy cells.
“This is one of the first candidate drugs that targets the virus-mitochondria interface,” said Liang. “It gives us a potential therapeutic pathway where none existed before for KSHV - and possibly other latent viral infections.”
The breakthrough was made possible by a cross-disciplinary effort drawing on Wistar’s cutting-edge imaging, proteomics, and drug screening capabilities.
“This discovery shows the power of collaboration in science,” said Liang. “We began by studying a viral protein and uncovered a new way mitochondria regulate immunity, opening doors for new KSHV treatments.”
With no current vaccine or cure for KSHV, and rising concern over herpesvirus-driven cancers in immunocompromised patients, this research may offer a new route to protect those most at risk.
More information online

1. Kaposi’s Sarcoma-Associated Herpesvirus Induces Mitochondrial Fission to Evade Host Immune Responses and Promote Viral Production published in Nature Microbiology