Intestinal Barrier Loss Enables Microbiota-Mediated Purinergic Suppression During Malaria

Abstract The gut microbiota shapes malaria immunity and disease severity, but the mechanisms underlying these effects remain unclear. In a murine model, susceptibility to Plasmodium yoelii hyperparasitemia was associated with elevated regulatory T cells and diminished IFN-γ. We demonstrate that the IgA-coated fraction of the microbiota is sufficient to transfer this susceptibility. Plasmodium infection disrupts the intestinal barrier regardless of microbiota composition. Mechanistically, barrier loss was associated with systemic adenosine persistence and an expansion of CD39+ plasmablasts in susceptible mice. Ugandan children with severe malaria exhibited a distinct purinergic immune signature compared to asymptomatic community children. Therapeutic reinforcement of the gut barrier or blockade of the downstream adenosine A2A receptor improved germinal centers and reduced disease severity in mice, independent of parasite burden, revealing a purinergic-dependent immunosuppression pathway that drives pathogenesis. This work defines an axis in which malaria-induced gut leakiness enables microbial-derived signals to trigger purinergic immunosuppression and severe disease.