Abstract
Lujo virus (LUJV) is a highly pathogenic zoonotic arenavirus first identified during a 2008 viral hemorrhagic fever (VHF) outbreak in Southern Africa, exhibiting an 80% case fatality rate. Despite its public health significance, LUJV remains poorly understood, with no approved treatments, vaccines, or known reservoir. Existing small animal models have shown limited disease recapitulation, with strain 13/N guinea pigs emerging as a promising model for LUJV pathogenesis. In this study, we evaluate the influence of age and sex on LUJV disease progression in strain 13/N guinea pigs. We show that young females exhibit markedly improved survival, while all young males, as well as juvenile and adult animals of both sexes, succumbed to infection. Despite similar high titers of LUJV detected in the lungs, liver, spleen, kidneys, and serum of infected animals, survival outcomes strongly correlated with immune responses rather than viral burden. Adult animals and young males developed more severe clinical signs, heightened hematological and biochemical abnormalities, and pronounced cytokine storms, particularly elevated IL-1β, IL-2, IL-6, and CXCL10 levels. In contrast, young females displayed lower inflammatory cytokine profiles, and attenuated clinical disease. These findings underscore that LUJV pathogenesis in guinea pigs is influenced by host immune responses rather than viral replication alone. Our results provide critical insight into age- and sex-dependent mechanisms of LUJV disease and support the utility of the strain 13/N guinea pig model for future medical countermeasures development.