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Gut Microbiota Confers Protection Against Malaria

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Miguel Soares, hosted by Lalita Ramakrishnan

As for other self-antigens, self-glycans cannot be targeted by the immune system when also expressed by pathogens. However, this can be overcome via natural selection of loss-of-function mutations in genes regulating the expression of self-glycans. This phenomenon is well illustrated for the natural selection of loss-of-function mutations in the human UDP -Galactose:β-galactoside-α1-3-galactosyltransferase (α1,3GT) gene, which in other mammals encodes an enzyme producing the Galα1-3Galβ1-4GlcNAc-R (α-gal) glycan. Given that components of the human gut microbiota can express the α-gal glycan, we reasoned that anti-α-gal antibodies generated against these microbiota components might confer protection against pathogens expressing -gal. We found that this is the case for the human gut pathobiont E. coli O86 :B7, which induces the production of anti-α gal antibodies that confer protection against Plasmodium infection, the causative agent of malaria. This notion is supported by several independent observations: i) Both Plasmodium spp. and E. coli O86 :B7 express the α-gal glycan, ii) when colonized by E. coli O86 :B7, α1,3GT deficient mice, which like humans can produce anti-α-gal antibodies, are protected against malaria and iii) anti-α-gal antibodies are associated with protection against malaria in humans. The mechanism underlying the protective effect exerted by anti--gal antibodies is mediated via Plasmodium sporozoite targeting for complement-mediated cytotoxicity, immediately after inoculation in the skin by Anopheles mosquitoes. This cytotoxic effect prevents sporozoites from reaching the liver, thus avoiding the establishment of infection. Vaccination against synthetic α-gal confers sterile protection against malaria in α1,3GT deficient mice, suggesting that a similar approach may be used in humans.

This talk is part of the Immunology and Medicine Seminars series.

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