Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America.
PLoS Pathog. 2013;9(4):e1003318. doi: 10.1371/journal.ppat.1003318. Epub 2013 Apr 18.
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.
采采蝇（ Glossina spp.）传播导致人类昏睡病和家畜纳尼亚病的致病性非洲锥虫。此外，采采蝇还携带 3 种母系传递的共生内细菌，这些细菌调节宿主的生理机能。采采蝇对锥虫感染具有很强的抵抗力，这种表型取决于挑战时的多种生理因素。这些因素包括宿主年龄、肠道中存在的母体衍生的锥虫溶解效应分子的密度以及发育过程中的共生体状态。在这项研究中，我们研究了导致采采蝇对锥虫产生抗性的分子机制。我们发现，在寄生虫挑战后，年幼易感的采采蝇表现出高度减弱的免疫反应。相比之下，成熟的抗性苍蝇表达更高水平与体液（attacin 和 pgrp-lb）和上皮（诱导型一氧化氮合酶和双氧化酶）免疫相关的基因。此外，我们发现，采采蝇必须在子宫内幼虫发育过程中保留其内共生微生物组，以便在成年期表现出对寄生虫的抗性表型。有趣的是，成熟的无菌蝇（Gmm（Apo））在感染过程的早期比整个生命周期都携带共生细菌的 WT 蝇表现出更强的免疫反应。然而，这种早期反应并不能赋予对锥虫的显著抗性。Gmm（Apo）成虫表现出结构受损的围食膜（PM），该膜沿蝇中肠排列，作为物理屏障，将腔内容物与免疫反应性上皮细胞隔开。我们提出，我们在寄生虫挑战后观察到的 Gmm（Apo）蝇中的早期免疫反应是由于在没有强大 PM 的情况下，肠道上皮过早暴露于寄生虫衍生的免疫原。因此，采采蝇的 PM 似乎调节了宿主免疫诱导的时间，以应对寄生虫的挑战。我们的研究结果记录了一个新的发现，即采采蝇幼虫微生物组与成年 PM 肠道免疫屏障完整性之间存在正相关关系。
