Gut Microbiome Can Train Immune System to Fight Malaria

Lara C. Pullen, PhD

December 10, 2014

Vaccination of mice with the glycan α-gal confers sterile protection against Plasmodium species, the causative agent of malaria. The results in mice suggest that the success of recent "attenuated" malaria vaccine trials may rest, at least partially, on the anti-α-gal antibody response.

The glycan α-gal is found in all mammals except humans. Many bacteria express α-gal, including specific members of the Klebsiella species, Serratia species, and Escherichia coli species.

Bahtiyar Yilmaz, PhD, from the Instituto Gulbenkian de Ciencia of Oeiras, Portugal, and colleagues published the results of their microbiome study online December 4 in Cell. They performed their research using knockout mice (α1,3GT-deficient mice) that are genetically engineered to not produce the α-gal glycan.

The investigators report that both Plasmodium species and the human gut bacteria E. coli 086:B7 express α-gal. Moreover, anti-α-gal antibodies are protective against malaria transmission in both humans and mice. The anti-α-gal antibodies bind to Plasmodium sporozoites in the skin and fix complement, thereby providing protection immediately after inoculation by Anopheles mosquitoes.

When the researchers immunized the α1,3GT-deficient mice with α-gal, the mice developed an antibody response that protected them from Plasmodium transmission.

Moreover, when unvaccinated knockout mice were colonized by E. coli O86:B7, they produced protective anti-α-gal antibodies. This finding is an important addition to our growing understanding that the gut microbiome can influence immunity and resistance to infection.

Humans become infected with malaria when they are bitten by Anopheles mosquitoes that carry Plasmodium sporozoites. It appears that some individuals have circulating anti-α-gal immunoglobulin M antibodies that can protect against malaria transmission. The investigators report that in mice, as well as humans, the levels of circulating α-gal immunoglobulin M antibodies are approximately 50-fold higher than the levels of circulating α-gal immunoglobulin G antibodies.

Although children younger than 3 years are particularly vulnerable to malaria, only a fraction of adults who are bitten by the Anopheles mosquito become infected with Plasmodium. The protective effect of anti-α-gal antibodies may be the reason why only a small fraction of inoculated Plasmodium sporozoites progress to establish an infection in adults.

Investigators are still uncertain as to whether α-gal is produced by Plasmodium and/or by the Anopheles mosquito. They acknowledge, however, that α-gal is likely only one of many glycans that stimulate a protective immune response against malaria and other vector-borne protozoan parasites.

The research was funded, in part, by the Bill and Melinda Gates Foundation.

Cell. 2014;159:1277-1289. Full text

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