Sweet rejection: sugar-coated malaria parasite

Life is a competition, even for a parasite like a malaria. To infect the host the parasite needs to overcome not just host's defense system but to out-compete the local resident micro-flora as well. 

This new paper in Cell is a thorough research about the initial events of of malaria infection and the role of sugar molecules, called glycans, in the host defense against malaria.

It is well-known that hosts and their parasites may share molecular signature. Blood types, ABO system is one such example. Burnet's clonal selection theory predicts that any such similarity between host-pathogen prevents the host to mount an efficient immune response against shared antigens. As a consequence, based on pathogen burden and evolutionary pressure, the hosts started to loose the capacity to express such shared molecules.

It appears that at some point in their evolution human ancestors lost the capacity to make one type of sugar, alpha-gal, expressed by malaria. This change conferred an improved capacity to defend against malaria. 

This papers shows how exactly such modification provided protection. It turns out to be dependent of natural immunization conferred by gut resident microbes expressing the same exact sugars.

Analysis of serum samples across different age group from children in Mali (malaria endemic region), the authors noticed a gradual increase in anti-alpha-gal IgM level over time. Interestingly, 6-months parasite free condition correlated with higher level of anti-alpha-gal IgM in the serum.

To study this observation in laboratory setting, the authors used mice deficient in the capacity to make alpha-gal (alpha-gal KO). This "human-like" mice can produce anti-alpha-gal antibodies upon colonization with alpha-gal-positive E.coli O86:B7, but not alpha-gal-negative E.coli K12 strain. 

The authors showed that colonization of alpha-gal KO mice with alpha-gal-positive E.coli O86:B7 provided a protection against malaria transmission.

This protection after gut flora colonization was conferred by soluble germ-line, non-mutated IgM.

Immunization of alpha-gal KO mice with  (a) alpha-gal conjugated to BSA (protein carrier) or (b) rabbit RBC (naturally expressing high levels of alpha-gal) conferred protection against malaria transmission.

Deep analyses of mechanism of protection after immunization revealed it was dependent on T cell help and on both IgM and IgG (of note, immunization with rabbit RBC conferred protection even in IgM-deficient mice, unlike protection conferred after colonization with alpha-gal expressing E.coli O86:B7).

The protection could be conferred by passive transfer with IgM, IgG3 and IgG2b, but not IgG1 and IgG2a.

In summary, this study provides evidence how gut flora affects host's defense against parasites by a way of natural immunization. Of course, it is remains to be determined whether immunization against alpha-gal will protect humans as well as it does for "human-like" mice.

David Usharauli