In vitro experiments have shown that antibodies targeting α-Gal are cytotoxic towards α-Gal-expressing pathogens; the authors set out to explore whether such antibodies can provide resistance to malaria in vivo. Initial experiments identified α-Gal expression on the surface of sporozoites of the human malaria parasite Plasmodium falciparum and that of the rodent malaria parasites Plasmodium berghei and Plasmodium yoelii. When the authors assessed the levels of α-Gal-specific antibodies in healthy uninfected children before and during the malaria season in Mali, they found that the children who remained uninfected during the malaria season had higher levels of pre-existing α-Gal-specific IgM antibodies compared with the children who became infected. No correlation was found between the levels of α-Gal-specific IgG and malaria incidence, suggesting that only IgM natural antibodies that recognize α-Gal are important for protection. Interestingly, the levels of α-Gal-specific antibodies increased with age and were lowest in children under 2–3 years old, an age group that is particularly vulnerable to malaria infection.
To test the protective effects of α-Gal-specific antibodies in vivo, the authors turned to mouse models of malaria infection. As wild-type mice express α-Gal, they used mice deficient in Ggta1 (also known as α1,3Gt), which encodes an enzyme that is necessary for α-Gal synthesis. This gene has become inactivated in the human genome and this prevents humans from expressing α-Gal as a self-antigen. Previous work showed that Ggta1-deficient mice produce α-Gal-specific antibodies under steady-state conditions and that the production of these antibodies is enhanced by the intestinal microbiota. In addition, the production of α-Gal-specific antibodies in Ggta1-deficient mice is increased if they are colonized with Escherichia coli O86:B7, a pathobiont that is found in the human gut. The authors confirmed that E. coli O86:B7, but not the laboratory strain E. coli K12, expresses high levels of α-Gal and found that colonization of Ggta1-deficient mice with E. coli O86:B7 boosted circulating levels of α-Gal-specific IgM. Furthermore, they showed that colonization of Ggta1-deficient mice with E. coli O86:B7, but not with E. coli K12, provided protection against parasite transmission when mice were exposed to P. berghei-infected mosquitoes. Immunization of Ggta1-deficient mice against α-Gal led to even greater resistance against Plasmodium transmission, with α-Gal-specific IgM, IgG2b and IgG3 antibodies mediating protection.
This is a preview of subscription content, access via your institution
