Editors' ChoiceHost-Pathogen Interactions

Microbes Thwart Malaria

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Sci. Signal.  16 Dec 2014:
Vol. 7, Issue 356, pp. ec346
DOI: 10.1126/scisignal.aaa4753

Malaria-causing protozoa (Plasmodium spp.) are transmitted to humans in the saliva of female mosquitoes. However, only a fraction of successful transmissions progress to disease. Host organisms recognize pathogen-associated molecular patterns, including glycans. However, glycans that exist in both pathogens and host organisms cannot be targeted by the immune system without causing an autoimmune response. During evolution, selective pressures for an effective host immune system result in genetic polymorphisms that prevent the biosynthesis of certain glycans, including Galα1-3Galβ1-4GlnAc-R (α-gal) in humans. Thus, human exposure to common α-gal-positive pathogens, including enterobacteria, such as Escherichia coli, induces the production of high titers of circulating antibodies against α-gal. In cell culture, α-gal antibodies are cytotoxic to many different α-gal-positive pathogens, including bacteria, viruses, and protozoa. Yilmaz et al. found that α-gal was present on the surface of malaria-causing Plasmodium spp. Inoculation of α-gal-deficient mice with E. coli O86:B7 induced the production of immunoglobulin (Ig)M antibodies against α-gal and protected mice against Plasmodium transmission by infected mosquitoes. Eliminating genes important for IgM production or B cell development in α-gal-deficient mice prevented E. coli O86:B7 colonization from inhibiting Plasmodium transmission. Immunization of α-gal-deficient mice against α-gal inhibited Plasmodium transmission by infected mosquitoes or intradermal injection, but not by intravenous injection. Moreover, the abundance of ribosomal RNA specific to Plasmodium was increased in the skin of immunized mice compared with control mice, suggesting the importance of an immune response specifically in the skin. Protection from infection by immunization was enhanced by inhibition of Toll-like receptor 9 (TLR9) during immunization and required functional B cells, activation of the complement system, and the synthesis of IgM, but not IgG, antibodies. In cell culture, antibodies to α-gal were cytotoxic to Plasmodium in the presence of complement and prevented Plasmodium invasion of hepatic cells. In humans in Mali, Africa, where malaria is an important health risk, the amount of IgG and IgM antibodies against α-gal increased with age. Moreover, the average amount of IgM antibodies against α-gal prior to the malarial season was greater in children who did not subsequently get the disease, compared to those that did. Thus, circulating antibodies against α-gal derived from exposure to common pathogens may limit transmission of the parasites that cause malaria and immunization with α-gal may be an effective malaria prophylactic.

B. Yilmaz, S. Portugal, T. M. Tran, R. Gozzelino, S. Ramos, J. Gomes, A. Regalado, P. J. Cowan, A. J. F. d’Apice, A. S. Chong, O. K. Doumbo, B. Traore, P. D. Crompton, H. Silveira, M. P. Soares, Gut microbiota elicits a protective immune response against malaria transmission. Cell 159, 1277–1289 (2014). [PubMed]