Characterization of Cellular Immune Responses during Lassa Virus Infection in Mice and Humans

Abstract

Shortend abstract: Lassa fever (LF) is a widespread viral infectious disease in West Africa that is estimated to infect up to 300,000 people per year. LF is caused by the Lassa mammarenavirus (LASV), which occurs naturally in the Natal-multimammate mouse (Mastomys natalensis), and belongs to the virus family Arenaviridae. Using a small animal model previously newly established by Dr. Lisa Oestereich, it could be shown in this thesis that the pathology of LASV in the IFNAR-BL6 chimeric mice is associated with a dysregulated activation of the CD8 T cell response. Besides a strong expression of activation markers such as KLRG1 and CD44 on CD8 T cells, an increased expression of the inhibitory cell markers CTLA-4 and PD-1 in the highly acute phase of the disease could also be detected. Moreover, OT-I T cells in a mixed bone marrow model showed that the dysregulation is not due to a general activation of nonspecific CD8 T cells. A similar expression of activation markers on CD8 T cells in humans could, however, not be confirmed in this study. The investigations undertaken on-site in a LASV-endemic area in Nigeria showed increased incidences of CTLA-4- and PD-1-positive CD8 T cells in linked to severe progressions of LF. T-cell transfer experiments in RAG1-/- mice additionally indicated that the pathology observed during LASV infection is not solely T cell-dependent, as assumed from previous T cell depletion studies. Furthermore, establishment of a labeled antibody against LASV-NP for the first time enabled the identification of LASV-infected immune cells in the course of the disease by means of flow cytometry from in vivo samples. In this way, a tropism of LASV for antigen-presenting cells (APC) could be shown within the animal model, detected only from the seventh day after infection onward. Previous postulations from in vitro studies on APCs as early targets of infection by LASV can therefore no longer be fully maintained. The results of this work provide important insights into the immunology of LASV disease, allow a more profound characterization of the IFNAR-BL6 mouse model for LASV infections, and point out possible target markers for future immunomodulatory studies in order to control Lassa fever pathology.