Hepatic fibrosis attenuates virus-specific CD8 T cell immunity causing virus persistence

The impact of liver fibrosis or cirrhosis on hepatic immunity against infectious microorganisms is unknown. Patients suffering from liver fibrosis or cirrhosis are more susceptible to viral and bacterial infections, which often persist in these patients. Yet, the underlying cellular and molecular mechanisms have not been elucidated. Using a novel murine model system, we demonstrated that liver cirrhosis and fibrosis induced by CCL4 or bile-duct ligation rendered mice unable to clear infection with the Lymphocytic choriomeningitis virus LCMV (WE strain). These mice show impaired effector functions of virus-specific CD8⁺ CTL and re-colonization of NKT cells after initial depletion by viral infection, which collectively led to persistence of infection. Furthermore, we found that enhanced expression of the inhibitory factors IL–10, TGFβ and PD–1L during hepatic fibrosis to be responsible for T cell suppression and the persistent LCMV infection in mice with liver fibrosis and cirrhosis. Collectively, we did elucidate the cellular and molecular mechanisms by which fibrotic processes in the liver impair the anti-viral immune response, which not only explains persistence of viral infection but also provide insight why fibrotic processes persevere chronic infections that in turn perpetuate liver fibrosis.

Hepatic fibrosis - LCMV - viral infection