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

ABSTRACT 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.