Lassa virus circumvents macrophage and dendritic cell antiviral defences in its natural reservoir, the Natal multimammate mouse (Mastomys natalensis).

Lassa virus (LASV) is a zoonotic arenavirus that causes severe hemorrhagic fever in humans but persists asymptomatically in its natural reservoir, the Natal multimammate mouse (Mastomys natalensis, NMM). The mechanisms underlying this disease tolerance remain poorly understood. Here, we establish and characterize macrophages (bmMΦs) and dendritic cells (bmDCs) derived from NMM bone marrow, and assess their response to LASV infection. Both cell types are permissive to LASV and remain viable throughout infection. However, LASV fails to induce transcriptional activation of antiviral or maturation-associated genes in either cell type, in stark contrast to the robust and stimulus-specific responses elicited by LPS, Poly I:C, and Sendai virus. A modest increase in CD80 surface expression was observed in LASV-infected DCs, uncoupled from transcriptional induction, suggesting post-transcriptional modulation. These data reveal a striking circumvention of innate immune activation in NMM myeloid cells despite productive LASV infection, supporting a model in which early immune evasion facilitates reservoir tolerance. This work provides mechanistic insight into LASV-host co-adaptation and establishes a functional in vitro system for dissecting immune responses in the natural reservoir.