TY - JOUR TI - Linking functional and molecular mechanisms of host resilience to malaria infection AU - Kamiya, Tsukushi AU - Davis, Nicole M AU - Greischar, Megan A AU - Schneider, David AU - Mideo, Nicole A2 - Flegg, Jennifer A2 - Davenport, Miles P A2 - Flegg, Jennifer VL - 10 PY - 2021 DA - 2021/10/12 SP - e65846 C1 - eLife 2021;10:e65846 DO - 10.7554/eLife.65846 UR - https://doi.org/10.7554/eLife.65846 AB - It remains challenging to understand why some hosts suffer severe illnesses, while others are unscathed by the same infection. We fitted a mathematical model to longitudinal measurements of parasite and red blood cell density in murine hosts from diverse genetic backgrounds to identify aspects of within-host interactions that explain variation in host resilience and survival during acute malaria infection. Among eight mouse strains that collectively span 90% of the common genetic diversity of laboratory mice, we found that high host mortality was associated with either weak parasite clearance, or a strong, yet imprecise response that inadvertently removes uninfected cells in excess. Subsequent cross-sectional cytokine assays revealed that the two distinct functional mechanisms of poor survival were underpinned by low expression of either pro- or anti-inflammatory cytokines, respectively. By combining mathematical modelling and molecular immunology assays, our study uncovered proximate mechanisms of diverse infection outcomes across multiple host strains and biological scales. KW - bayesian hierarchical model KW - within-host model KW - innate immunity KW - Malaria KW - Plasmodium chabaudi JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -