Bacterial Co-Infection Delays Hepatitis B Virus Clearance in a Chronic Replication Mouse Model by Inducing T Cell Exhaustion.

Hepatitis B virus (HBV) and bacterial infections are major global health concerns. However, the impact of bacterial co-infection on HBV clearance remains unclear. To investigate how bacterial co-infection affects HBV clearance, we used a mouse model with chronic HBV replication and Klebsiella pneumoniae co-infection. We evaluated HBV virological markers, innate immune responses, inflammation, and intrahepatic HBV-specific T cell responses, with and without antibiotic treatment or MDSCs depletion. Our findings demonstrate that bacterial co-infection activates innate immunity and inflammation in the liver, leading to initial activation followed by exhaustion of HBV-specific CD4 and CD8 T cells, which delays HBV clearance. Antibiotic treatment alleviated inflammation and restored HBV elimination, while MDSCs depletion exacerbated inflammation and induced premature exhaustion of HBV-specific T cells. These results suggest that bacterial co-infection disrupts HBV-specific T cell responses and impairs HBV clearance, with MDSCs playing an indispensable role in indirectly regulating T cell activation, primarily through modulating the innate immune response and inflammatory pathways.