Trypanosome Infection Establishment in the Tsetse Fly Gut Is Influenced by Microbiome-Regulated Host Immune Barriers

Abstract

Tsetse flies (Glossina spp.) vector pathogenic African trypanosomes, which cause sleeping sickness in humans and nagana in domesticated animals. Additionally, tsetse harbors 3 maternally transmitted endosymbiotic bacteria that modulate their host's physiology. Tsetse is highly resistant to infection with trypanosomes, and this phenotype depends on multiple physiological factors at the time of challenge. These factors include host age, density of maternally-derived trypanolytic effector molecules present in the gut, and symbiont status during development. In this study, we investigated the molecular mechanisms that result in tsetse's resistance to trypanosomes. We found that following parasite challenge, young susceptible tsetse present a highly attenuated immune response. In contrast, mature refractory flies express higher levels of genes associated with humoral (attacin and pgrp-lb) and epithelial (inducible nitric oxide synthase and dual oxidase) immunity. Additionally, we discovered that tsetse must harbor its endogenous microbiome during intrauterine larval development in order to present a parasite refractory phenotype during adulthood. Interestingly, mature aposymbiotic flies (Gmm Apo) present a strong immune response earlier in the infection process than do WT flies that harbor symbiotic bacteria throughout their entire lifecycle. However, this early response fails to confer significant resistance to trypanosomes. Gmm Apo adults present a structurally compromised peritrophic matrix (PM), which lines the fly midgut and serves as a physical barrier that separates luminal contents from immune responsive epithelial cells. We propose that the early immune response we observe in Gmm Apo flies following parasite challenge results from the premature exposure of gut epithelia to parasite-derived immunogens in the absence of a robust PM. Thus, tsetse's PM appears to regulate the timing of host immune induction following parasite challenge. Our results document a novel finding, which is the existence of a positive correlation between tsetse's larval microbiome and the integrity of the emerging adult PM gut immune barrier.

Antimicrobial peptides play a functional role in bumblebee anti-trypanosome defense

“…This seems to contradict recent findings that found a central role for gut microbiota in the bumblebee's defense against Crithidia (Koch and Schmid-Hempel, 2011). It is clear that the outcome of a Crithidia infection is not the result of the immune system or the gut microbiota but rather the interaction between the parasite, the gut microbiota and the host immune system (Castro et al, 2012;Garcia et al, 2009;Weiss et al, 2013). This interaction will be the focus of much future research.…”

Interwoven Biology of the Tsetse Holobiont

“…The immunocompromised phenotype of aposymbiotic larvae can be reversed by feeding their moms a diet supplemented with Wigglesworthia cell extracts (57). The presence of the tsetse's larval microbiota also contributes to the proper development of the adult peritrophic matrix, separating epithelial cells from the contents of the lumen, which regulates the timing of immune induction following parasite challenge (60). Wigglesworthia also impacts tsetse digestion, temperature sensitivity, and susceptibility to infection with trypanosomes (56,58,60).…”

Mosquito vector‐associated microbiota: Metabarcoding bacteria and eukaryotic symbionts across habitat types in Thailand endemic for dengue and other arthropod‐borne diseases

“…Recent evidence is mounting that the transmission of vector‐borne pathogens can be inhibited by other vector‐associated microbes (Sinkins, 2013). In the past decade, studies have shown that certain microbes associated with insect vectors could be used to mediate the transmission of diseases including those transmitted by mosquitoes (Capone et al., 2013; Cirimotich et al., 2011; Dong, Manfredini, & Dimopoulos, 2009; Mourya, Pidiyar, Patole, Gokhale, & Shouche, 2002; Ramirez et al., 2014; Tchioffo et al., 2013; Xi, Ramirez, & Dimopoulos, 2008), tsetse flies (Pais, Lohs, Wu, Wang, & Aksoy, 2008; Wang, Wu, Yang, & Aksoy, 2009; Weiss, Wang, Maltz, Wu, & Aksoy, 2013), sand flies (Sant'Anna et al., 2014), and ticks (Gall et al., 2016; Narasimhan et al., 2014). The most striking example is the inhibition by bacterium Wolbachia pipientis of virus and parasite infection in mosquito vectors (Bian, Xu, Lu, Xie, & Xi, 2010; Blagrove, Arias‐Goeta, Di Genua, Failloux, & Sinkins, 2013; Frentiu et al., 2014; van den Hurk et al., 2012; Hussain et al., 2012; Moreira et al., 2009).…”