Abstract
SUMMARYGut microbiota composition is associated with human and rodent Plasmodium infections, yet the mechanism by which gut microbiota affects the severity of malaria remains unknown. Humoral immunity is critical in mediating the clearance of Plasmodium blood stage infections, prompting the hypothesis that mice with gut microbiota-dependent decreases in parasite burden exhibit better germinal center (GC) responses. In support of this hypothesis, mice with a low parasite burden exhibit increases in GC B cell numbers and parasite-specific antibody titers, as well as better maintenance of GC structures and a more targeted, qualitatively different antibody response. This enhanced humoral immunity affects memory, as mice with a low parasite burden exhibit robust protection against challenge with a heterologous, lethal Plasmodium species. These results demonstrate that gut microbiota composition influences the biology of spleen GCs as well as the titer and repertoire of parasite-specific antibodies, identifying potential approaches to develop optimal treatments for malaria.
Highlights
Plasmodium infections led to an estimated 228 million cases of malaria and 405,000 deaths in 2018 (World Health Organization, 2019)
It has since been shown that this acquired resistance correlates with humoral immunity, but antibody responses in children are typically short-lived and long-term resistance is the result of years of gradually increasing Plasmodium-specific antibodies (Crompton et al, 2010; Weiss et al, 2010), which includes a combination of increased numbers of Plasmodium-specific antibodies in circulation along with an increased breadth of antigens that these antibodies recognize (Osier et al, 2008; Nogaro et al, 2011)
Gut Microbiota Composition Causes Differential germinal center (GC) Reactions following P. yoelii Infection That Correlate with Resistance to Hyperparasitemia It has been shown that C57BL/6 mice ordered from different vendors exhibit profound differences in their susceptibility to P. yoelii 17XNL infection due to differences in gut microbiota composition (Villarino et al, 2016; Denny et al, 2019)
Summary
Plasmodium infections led to an estimated 228 million cases of malaria and 405,000 deaths in 2018 (World Health Organization, 2019). Malaria poses a significant health risk worldwide, with an economic impediment reaching an estimated US$12 billion/year owing to clinical costs, distributing antimalarial drugs, and the distribution of other preventive measures (Gallup and Sachs, 2001; Nonvignon et al, 2016). This illustrates the growing need for novel, inexpensive, and deployable treatment options. Resistance to Plasmodium infection can be acquired in individuals living in endemic regions, but only after a period of years and repeated exposures This delayed resistance is evident in the higher incidence of severe disease and mortality in young children (Marsh and Kinyanjui, 2006). It is not presently known whether gut microbiota composition contributes to interindividual variation in antibody responses or whether it affects the magnitude and repertoire of Plasmodium-specific antibodies
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