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Abstract
Bats (Order: Chiroptera) are drawing increased attention as reservoirs for viruses that cause severe and sometimes fatal disease in humans but cause no apparent disease in bats. Marburg virus (family Filoviridae) is one such pathogen, for which the Egyptian rousette bat (ERB; family Pteropodidae) is the only known natural reservoir host. The ERB is host to several other RNA viruses, including Sosuga (SOSV) and Kasokero viruses (KASV), both of which are associated with systemic illness in humans, but no clinical disease in ERBs. Studies have shown that ERBs immunologically control MARV infection, but the mechanisms remain poorly understood. The goal of this work was to study ERB-host virus interactions within a spatial context using formalin-fixed paraffin-embedded tissues derived from experimental infection studies with MARV, KASV, and SOSV. By studying the pathology of three RNA viruses in a single host, the ERB, we aimed to uncover unique and/or potentially generalizable anti-viral mechanisms applicable to multiple virus families in this host, which could inform public health preventative countermeasures in non-reservoir spillover hosts that suffer from severe systemic disease (i.e. primates).
In the first phase of this study, the histopathologic and immunohistochemical data showed that the small intestines and salivary glands are primary target tissues for SOSV in ERBs, and that the host immune responses may favor viral persistence (and shedding) in the intestines and clearance from the salivary glands. In the second phase, histopathological, immunohistochemical, and in situ hybridization studies showed that, while ERBs develop acute viral hepatitis following KASV infection, they possess immunologic mechanisms to quickly control and clear the infection. The final phase showed that recruitment of CD3+ cells and mononuclear phagocytes to foci of hepatocellular infection and the early induction of apoptosis in monocyte-derived macrophages contribute to viral clearance and resolution of MARV- and KASV-induced hepatitis in ERBs. These data support long-standing evolutionary relationships between ERBs and MARV and SOSV that favor disease tolerance mechanisms and milder immune responses, whereas KASV is associated with a more robust immune response (i.e., disease resistance), and this tick-borne virus may be more limited in its ability to co-evolve with either host.
In the first phase of this study, the histopathologic and immunohistochemical data showed that the small intestines and salivary glands are primary target tissues for SOSV in ERBs, and that the host immune responses may favor viral persistence (and shedding) in the intestines and clearance from the salivary glands. In the second phase, histopathological, immunohistochemical, and in situ hybridization studies showed that, while ERBs develop acute viral hepatitis following KASV infection, they possess immunologic mechanisms to quickly control and clear the infection. The final phase showed that recruitment of CD3+ cells and mononuclear phagocytes to foci of hepatocellular infection and the early induction of apoptosis in monocyte-derived macrophages contribute to viral clearance and resolution of MARV- and KASV-induced hepatitis in ERBs. These data support long-standing evolutionary relationships between ERBs and MARV and SOSV that favor disease tolerance mechanisms and milder immune responses, whereas KASV is associated with a more robust immune response (i.e., disease resistance), and this tick-borne virus may be more limited in its ability to co-evolve with either host.