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bioRxiv · 10.64898/2026.01.30.702752

Reduced Complex III assembly dampens host inflammation as an adaptive response to viral infection

Ho, L.·Beh, S.·Lee, C. Q.·Shen, K.·Zhong, C.·Mantri, C. K.·Chao, L.·Lim, R.·Sobota, R.·Chen, J.·St John, A. L.
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Abstract

Mitochondrial electron transport and oxidative respiration are required for immunity and host tolerance. How the ETC contributes to viral infections - where a proinflammatory anti-viral response needs to be finely balanced with host-protective anti-inflammatory mechanisms - remains unclear. Here, we demonstrate that following infection by H1N1 influenza virus, murine macrophages reduce Complex III levels by downregulating the early CIII assembly factor called the COMB complex. To determine the effect of CIII suppression, we utilized Brawnin (Br or UQCC6) knockout mice, which lack COMB complexes and have reduced Complex III. Following H1N1 infection, Br KO bone marrow-derived macrophages (BMDMs) had reduced inflammation due to reduced CIII Qo site ROS. Br KO mice infected with a non-lethal dose of H1N1 had reduced lung immune pathology, viral burden and enhanced recovery following H1N1 infection. Single-cell RNAseq analysis revealed that H1N1-infected Br KO lungs had reduced abundance of hyper-inflammatory monocytes known to cause severe respiratory disease and reduced monocyte chemotaxis. Our study demonstrates that ETC Complex III suppression is part of an innate immune response to viral infection, and is a potential strategy to control host inflammation in acute respiratory viral infections.

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Ho, L., Beh, S., Lee, C. Q., Shen, K., Zhong, C., Mantri, C. K., Chao, L., Lim, R., Sobota, R., Chen, J., St John, A. L.. 2026-02-05. Reduced Complex III assembly dampens host inflammation as an adaptive response to viral infection. https://doi.org/10.64898/2026.01.30.702752

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