Gut Microbiota Elicits a Protective Immune Response against Malaria Transmission

Abstract

SummaryGlycosylation processes are under high natural selection pressure, presumably because these can modulate resistance to infection. Here, we asked whether inactivation of the UDP-galactose:β-galactoside-α1-3-galactosyltransferase (α1,3GT) gene, which ablated the expression of the Galα1-3Galβ1-4GlcNAc-R (α-gal) glycan and allowed for the production of anti-α-gal antibodies (Abs) in humans, confers protection against Plasmodium spp. infection, the causative agent of malaria and a major driving force in human evolution. We demonstrate that both Plasmodium spp. and the human gut pathobiont E. coli O86:B7 express α-gal and that anti-α-gal Abs are associated with protection against malaria transmission in humans as well as in α1,3GT-deficient mice, which produce protective anti-α-gal Abs when colonized by E. coli O86:B7. Anti-α-gal Abs target Plasmodium sporozoites for complement-mediated cytotoxicity in the skin, immediately after inoculation by Anopheles mosquitoes. Vaccination against α-gal confers sterile protection against malaria in mice, suggesting that a similar approach may reduce malaria transmission in humans.PaperFlick

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 .…”

Purification of Plasmodium Sporozoites Enhances Parasite-Specific CD8 + T Cell Responses

“…Sanaria's in-house data indicate that the purification process provides for a near absence of mosquito-derived protein in the PfSPZ material based on mosquito-specific enzyme-linked immunosorbent assay (S. Hoffman, personal communication), although it remains unknown whether these sporozoites contain any other mosquito-derived carbohydrate and/or lipid moieties. For instance, salivary gland sporozoites were recently shown to possess a likely mosquito-derived ␣-gal glycan that was able to serve as a protective IgM antibody target in the reported mouse studies (50). Dose escalation of PfSPZ has generally shown increased efficacy (44), but if further escalation were to reveal a paradoxical reduction in efficacy at extremely high doses, anti-mosquito responses could be involved.…”

An Expanding Toolkit for Preclinical Pre-Erythrocytic Malaria Vaccine Development: Bridging Traditional Mouse Malaria Models and Human Trials

“…For antibody-based responses this issue could have significant consequences, as Fc mediated functions such as sporozoite lysis by complement fixation, and sporozoite opsonization for phagocytosis by antigen-presenting cells, are not measured. Our understanding of the Fc-dependent mechanisms involved in antibody-mediated inhibition of sporozoites is poor, with limited studies providing evidence both for and against a significant role of Fc functions [59,60]. Indeed, while opsonization of recombinant P. falciparum CSP has been correlated with protection in RTS,S clinical trials [61], these studies were not performed with whole sporozoites and as such, this assay is unsuitable to investigate other candidate targets.…”