Composition of the gut microbiota modulates the severity of malaria

Abstract

Plasmodium infections result in clinical presentations that range from asymptomatic to severe malaria, resulting in ∼1 million deaths annually. Despite this toll on humanity, the factors that determine disease severity remain poorly understood. Here, we show that the gut microbiota of mice influences the pathogenesis of malaria. Genetically similar mice from different commercial vendors, which exhibited differences in their gut bacterial community, had significant differences in parasite burden and mortality after infection with multiple Plasmodium species. Germfree mice that received cecal content transplants from "resistant" or "susceptible" mice had low and high parasite burdens, respectively, demonstrating the gut microbiota shaped the severity of malaria. Among differences in the gut flora were increased abundances of Lactobacillus and Bifidobacterium in resistant mice. Susceptible mice treated with antibiotics followed by yogurt made from these bacterial genera displayed a decreased parasite burden. Consistent with differences in parasite burden, resistant mice exhibited an elevated humoral immune response compared with susceptible mice. Collectively, these results identify the composition of the gut microbiota as a previously unidentified risk factor for severe malaria and modulation of the gut microbiota (e.g., probiotics) as a potential treatment to decrease parasite burden.

Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

“…Interestingly, CD40 signaling was not absolutely essential for ECM development, as CD40L-deficient mice eventually developed ECM in the absence of added PbT-II T cells, although with a delayed kinetics. This contrasts a previous report that found CD40L-deficient mice were resistant to ECM (94), an observation that may be explained by differences in animal housing facilities, potentially microbiota, known to affect ECM (95). In summary, our work extends earlier findings by determining that CD4 + T cell help is required for optimal CD8 + T cell expansion after infection with different doses of parasites, and is relatively independent of the initial CD8 + T cell precursor frequency.…”

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

“…Sebina et al also recently reported reduced parasitemia in IFNAR -/-mice as compared with control mice infected with P. yoelii 17XNL starting at day 14 after infection (28). Another potential explanation for different experimental outcomes could be either mouse strain differences or differences in the microbiome, both of which have substantial effects on the host response to infection in murine models of blood-stage malaria (77)(78)(79). We used littermate controls to minimize the contribution of microbiome or strain background to our observations.…”

“…To examine antigen-specific CD4 + T cells responding to infection, P. yoelii were generated that constitutively express the Lymphocytic choriomeningitis virus-derived (LCMV-derived) glycoprotein (GP) epitope (GP [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] ). This allows for the identification and analysis of antigen-specific CD4 + T cells using previously described GP66:I-A B tetramer enrichment strategies (16).…”

Disease tolerance and immunity in host protection against infection

“…The bacterial endosymbiont, Wolbachia, for example, enhances resistance to Drosophila C virus in flies 10,131 and to dengue and chikungunya virus infections in mosquitoes 132 ( Figure 5). Symbiotic interactions between bacteria and mice can also promote immune-driven resistance mechanisms against viral 133 , bacterial 134 or protozoan 135,136 infections ( Figure 5). This argues that the establishment of stable symbiotic interactions between microcellular and multicellular organisms is a widespread recurrent trait that modulates host resistance against a variety of pathogens ( Figure 5).…”

“…Symbiotic neomycin-sensitive bacteria can promote immune-driven resistance mechanisms against influenza A virus infection in mice, via mechanism involving bacterial sensing by inflammasomes 133 . The gut E. coli O86B7 commensal elicits an IgM antibody response directed against the galα(1,3)gal glycan that confers resistance to Plasmodium infection in mice and possibly in humans 135 while Lactobacillus and Bifidobacterium confer resistance to Plasmodium infection in mice via a mechanism that has not been clearly established 136 . Other gram-negative bacterial components of the mouse gut microbiota are sensed by TLR4 and trigger an antigen-specific IgG antibody responses directed against Murein lipoprotein, which confer resistance to systemic E. coli infection 134 .…”