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Machupo virus (MACV), a member of the Arenaviridae family and causative agent of Bolivian hemorrhagic fever, results in lethality rates of 25–35% in humans. Mice lacking the signal transducer and activator of transcription 1 (STAT-1^−/−) have previously been shown to succumb to MACV infection within 7–8 days via the intraperitoneal route. Despite these reports, we observed partial lethality in STAT-1^−/− mice following challenge with wild-type MACV. Serial sampling studies to evaluate the temporal progression of infection and pathologic changes after challenge revealed a two-phase disease course. The first phase was characterized by viral load and pathological lesions in the spleen, liver, and kidney followed by a second, lethal phase, defined by high viral titers and inflammation in the brain and spinal cord resulting in neurological manifestations and subsequent mortality. Tissue adaptation in the brains of challenged STAT-1^−/− mice resulted in a fully lethal model in STAT-1^−/− mice (mouse-adapted; maMACV). A similar two-phase disease course was observed following maMACV challenge, but more rapid dissemination of the virus to the brain and overall pathology in this region was observed. The outcome of these studies is a lethal small rodent model of MACV that recapitulates many aspects of human disease. Full article

The family members of Arenaviridae include members of the genus Machupo virus, which have bi-segmented negative sense RNA inside the envelope and can be transferred to humans through rodent carriers. Machupo virus, a member of the mammarenavirus genus, causes Bolivian hemorrhage fever, its viral nucleocapsid protein being a significant virulence factor. Currently, no treatment is available for Bolivian hemorrhage fever and work to develop a protective as well as post-diagnosis treatment is underway. Adding to these efforts, this study employed a reverse-vaccinology approach to design a vaccine with B and T-cell epitopes of the viral nucleocapsid protein of the Machupo virus. Five B-cell specific, eight MHC-I restricted, and 14 MHC-II restricted epitopes were finalized for the construct based on an antigenicity score of >0.5 and non-allergenicity as a key characteristic. The poly-histidine tag was used to construct an immunogenic and stable vaccine construct and 50S ribosomal 46 protein L7/L12 adjuvant with linkers (EAAAK, GPGPG, and AYY). It covers 99.99% of the world’s population, making it highly efficient. The physicochemical properties like the aliphatic index (118.31) and the GRAVY index (0.302) showed that the vaccine is easily soluble. The overall Ramachandran score of the construct was 90.7%, and the instability index was 35.13, endorsing a stable structure. The immune simulations demonstrated a long-lasting antibody response even after the excretion of the antigen from the body in the first 5 days of injection. The IgM + IgG titers were predicted to rise to 6000 10 days post-injection and were illustrated to be stable (around 3000) after a month, elucidating that the vaccine would be effective and provide enduring protection. Lastly, the molecular interaction between the construct and the IKBKE receptor was significant and a higher eigenfactor value in MD simulations confirmed the stable molecular interaction between the receptor and the vaccine, validating our construct. Full article