High-risk microbial signatures are associated with severe parasitemia in controlledPlasmodiuminfections of both humans and rhesus macaques

Abstract

While functions of the gastrointestinal (GI) microbiome include maintenance of immune homeostasis and protection against infectious disease, its role in determining disease severity during Plasmodium infection has been limited to mouse models and observational human cohorts. Here, we performed controlled Plasmodium infection in both humans and rhesus macaques (RMs) to experimentally determine the impact of GI microbiome composition on disease progression. Through analysis of serially collected microbiome samples, we identified a high-risk microbial signature that strongly associated with increased risk of developing severe parasitemia in human participants. Importantly, we identified a parallel phenomenon in RMs. The combined weight of this evidence demonstrates that pre-infection GI microbiome composition is highly indicative of P. falciparum disease risk. Moreover, our observation that P. fragile-microbiome dynamics in RMs closely mirrors P. falciparum-microbiome interactions in humans strongly supports the use of this model in pre-clinical investigations of novel microbiome-targeting approaches to reduce malaria burden.

Gut Bacteroides act in a microbial consortium to cause susceptibility to severe malaria

“…Bifidobacterium is associated with decreased Plasmodium parasitemia 6,18 . Bifidobacterium species are prevalent probiotic bacteria that confer myriad health benefits which have a role in antiinfection, anti-cancer, anti-inflammation, anti-obesity, and others 75 .…”

“…We previously demonstrated that gentamicin, including other antibiotics, could significantly decrease the severity of malaria in mice 11 . Bifidobacterium is a common probiotic that confers health benefits 23 , B. adolescentis exerts anti-inflammatory properties in the gut via inhibition of NF-κB activation and lipopolysaccharide secretion 24 , and Bifidobacterium has been correlated with protection from P. falciparum infection and Py hyperparasitemia 6,18 . To determine the ability of these bacteria to mitigate severe malaria, hyperparasitemia-susceptible CR mice were gavaged daily from −7 to 7 days post-infection (p.i.)…”

“…Further, lung microbiota is correlated with the severity of malaria-associated acute respiratory distress syndrome (MA-ARDS), where Plasmodium-induced T cells stimulate the production of the anti-inflammatory cytokine IL-10 in the lung, leading to compromised control of lung microbiota 16 . Among these studies, gut microbiota that included Bacteroides, Prevotella, Lachnospiraceae spps., Lactobacillus, among others, were shown to be associated with higher Plasmodium parasitemia 6,[10][11][12]15,17,18 . Yet, none of the studies in mice or humans have delineated the causal role of a specific member or defined consortium of gut microbiota in severe malaria.…”