Understanding Asymptomatic Malaria: The Utility of Wild-Derived Mouse Diversity

Abstract With over 200 million clinical cases per year leading to over 600,000 deaths, malaria is still a significant global health problem. Up to 80% of individuals in some malaria-endemic areas can have asymptomatic carriage of Plasmodium infections (no overt symptoms) and are thought to be a significant reservoir for malaria transmission. Many asymptomatic Plasmodium-infected individuals show mild anemia and vascular activation and have an increased risk for co-morbidities such as typhoidal Salmonella. Currently, the immunological mechanisms governing asymptomatic Plasmodium carriage are poorly understood, partly due to a lack of immunologically intact asymptomatic animal models. Here, utilizing a unique genetically diverse SPF wild-derived mouse colony we address the immunological underpinnings of asymptomatic malaria. This model shows that asymptomatic Plasmodium carriage is genetically controlled. Furthermore, wild-derived mice have varying levels of anemia associated with non-lethal Plasmodium yoelii XNL infection; some mice exhibit an asymptomatic phenotype with mild anemia independently of parasitemia. Anemia levels correlate with the production of TNF-a and IL-10, which is consistent with patterns seen in asymptomatic children in Cameroon. CD4 T cells producing IL-10 and IFN-g were also correlated with the severity of anemia, with few T regulatory cells that expanded during infection, consistent with the pattern of circulating CD4 T cells responses seen in pediatric asymptomatic malaria. Previously unknown genes are also found in GWAS analysis in these mice. Our results highlight that this novel model can be used to determine the immune mechanisms that underpin the asymptomatic carriage of Plasmodium parasites. Supported by a grant from NIH (R01AI167422)