Aging alters the langat virus infection and pathogenesis in region-specific manner

Abstract

The type I interferon (IFN) system, including a key player MAVS, is essential for the antiviral immune response. The interaction between the innate and the adaptive immune system is particularly critical here. Age-related phenomena such as immunosenescence and inflammaging lead to decreased number and function of immune cells and an imbalance between pro- and anti-inflammatory signaling pathways. All of these factors can contribute to older people developing more severe infections. Especially concerning neurotropic viral infections such as Tick-borne encephalitis virus (TBEV), the mortality in the elderly is significantly increased. Therefore, an efficient local immune response within the central nervous system (CNS) is crucial. In this study, we used the Langat Virus (LGTV), a Flavivirus of the TBEV serocomplex. We report that MAVS is essential in the antiviral response because Mavs-/- mice develop severe LGTV infection. MAVS protects the mice from high viral replication in the periphery and brain and increased mortality upon intraperitoneal infection. We report that aging increases the relevance of the antiviral activity of MAVS during LGTV infection because old Mavs-/- mice succumb to LGTV infection earlier than younger Mavs-/- mice. Age-related impairments of immune cells have often been discussed in the literature. In particular, it has been shown that innate immune cells in the CNS are affected during aging. There is a reduction in the number and activation of macrophages and dendritic cells in aged Mavs-/- mice. Furthermore, aging reduces type-I- and type-II-interferon-expression as well as IRF-1- and IRF-7-expression. There are many indications in the literature that the local antiviral response seems to be differentially regulated in specific brain regions and that this depends on aging processes. Our data show that cerebellar cells of young Mavs- /- mice were more susceptible to LGTV infection than those in old Mavs- /- mice. This correlates with the increased local expression of Ifi27Ia in old Mavs- /- mice. However, this locally increased antiviral activity in old Mavs-/- mice failed to protect against the increased viral spread or lethal LGTV infection. Accordingly, antiviral activity during LGTV infection appears to be age- and region-specifically regulated within the CNS.