Our research projects
Pathological host responses to Lassa virus infection – from mice to men
Hemorrhagic fever viruses (VHFs) like Lassa virus (LASV), Ebola virus (EBOV) or Crimean- Congo hemorrhagic fever virus (CCHFV) can cause severe diseases in humans that are characterized by high morbidity and mortality. LASV is a zoonotic pathogen that was discovered in 1969 in Nigeria and is endemic in Nigeria and several other West African countries.
Despite the importance of LASV as a human pathogen, very little is known about the pathophysiology of LASV. Severe LF is characterized by high virus concentrations, inflammation, terminal shock and multi organ failure. The extent of the organ damage however is insufficient to account for death, which is mirrored in non human primate (NHP) experiments. Despite many years of research, the exact cause of death during LF is still completely unclear. The data from humans and NHPs indicates that deregulated host responses plays a key role in LASV pathophysiology but no all-encompassing model outlining beneficial and pathological immune responses exists so far, highlighting the urgent need to address the role of immune responses during LF.
We have previously developed a lethal, immune competent mouse model that is susceptible to the infection with LASV and that reproduces key features of severe human LF. This model allowed mechanistic studies of the host response to LASV in a small animal model for the first time. This model allows us to determine the role of antigen presenting cells (APC) and lymphocytes in LASV pathogenesis.
In vivo experiments in NHPs and mouse models as well as preliminary findings from human samples, identified APCs such as macrophages and dendritic cells (DCs) as target cells during infection. Migratory APCs, such as DCs might play an important role spreading the infection as they migrate to lymph nodes to prime naïve T cells and might transport the virus along. In vitro experiments with infected DCs and macrophages revealed a lack of maturation and no release of inflammatory cytokines or upregulation of activation molecules on their surface. In vivo data however showed that survival is correlated with a robust activation of the immune response. To this end, we investigate virus replication in APC, their functional status, their participation in virus dissemination, and their contribution to activation and regulation of innate and adaptive immune responses. Due to the late appearance of neutralizing antibodies and the ambivalent results of treatments with convalescent plasma, T cells are considered to play a major role in the clearance of the virus.
NHP experiments and data from humans support the importance of the early and strong activation of CD4+ and CD8+ T cells. Many vaccines are thus designed to induce a robust T cell response as well as a humeral response. Previous experiments however revealed CD8+ T cells as a major pathogenicity factor. The depletion of CD8+ T cells prevented death, reduced amount of proinflammatory cytokines in serum and prevented vascular leakage. These findings emphasize that further research is needed to understand the role of T cells in LF.
Lassa virus immunology in the natural host
No adequate data exist on the mode of transmission (vertical, perinatal, in adulthood, sexual) of Lassa virus or any other Old World arenavirus among the natural host population (Mastomys natalensis), the period of infectivity (persistent for life or limited) and the relation between rodent density and the prevalence of the virus in the rodent population. These parameters have dramatic effects on the outcome of ecological disease models. Knowing how a virus is transmitted is crucial to develop useful models that can predict how, how fast and when the infection will spread in a host population.
