Research Article: Drosophila as a model for homeostatic, antibacterial, and antiviral mechanisms in the gut

Date Published: May 4, 2017

Publisher: Public Library of Science

Author(s): Xi Liu, Jeffrey J. Hodgson, Nicolas Buchon, Kimberly A. Kline.


Partial Text

The gastrointestinal (GI) tract serves as an active barrier and a first layer of defense against the numerous microbes that populate the gut lumen. The fly GI tract is composed of self-renewing digestive and absorptive tissues and shares several properties with the mammalian counterparts, the stomach, small intestine, and colon. The gut epithelium is physically protected by the mucus layer in mammals and by a chitinous peritrophic matrix (PM) in Drosophila [1] (Fig 1). Underneath the protective layer is an epithelial monolayer surrounded by a basal lamina and visceral muscles (Fig 1). In both Drosophila and mammals, gut tissue maintenance is extremely important to help maintain physical barrier integrity and proper immune function. The GI epithelium is continuously renewed by intestinal stem cells (ISCs). In flies, ISCs self-renew and give rise to either a transient enteroblast (EB) that terminally differentiates into an absorptive enterocyte (EC) or a pre-enteroendocrine cell that becomes a secretory enteroendocrine cell (EE) [2] (Fig 1A). Similarly, in mammals, ISCs self-renew and differentiate into intermediate cell types the transit amplifying cells, which proliferate and further differentiate into ECs or secretory cells (EEs, Goblet cells, and Tuft cells), and dedicated Paneth cell progenitors that mature into Paneth cells (Fig 1B). This striking structural similarity, the fact that several key signaling pathways involved in immunity and tissue regeneration are conserved from Drosophila to humans, and the development of cutting edge techniques, including live imaging and RNA-seq of select cell types in the midgut [3], make the Drosophila midgut an ideal model for revelatory studies of host–microbiome associations, innate immunity, tissue regeneration, and arbovirus–vector interactions.

The microbial diversity in the Drosophila gut is lower compared to that of mammals. A major difference is that the Drosophila gut lumen is likely more of an aerobic environment because of its limited size, in contrast to some parts of the mammalian GI tract. Although around 30 bacterial species have been identified in the midgut of Drosophila, Acetobacter and Lactobacillus are the two genera predominantly isolated from both wild-caught and laboratory-reared flies [4–9]. Germ-free and derivative gnotobiotic flies (i.e., reassociated with one or more bacteria) provide a less complex approach for in-depth analyses of the impact individual microbes have on gut and/or whole fly homeostasis. For example, Acetobacter pomorum and Lactobacillus plantarum trigger the insulin and Target of Rapamycin (TOR) pathways (respectively), both of which provide growth advantages to fly larvae in limiting nutrient conditions [10,11]. Similarly, L. plantarum was found to benefit the growth of infant mice during chronic undernutrition [12]. Studies in flies have shown that the gut microbiota can also become deleterious with age. In aged flies, the load and diversity of gut microbes increase, perhaps as a consequence of immune dysregulation, and this dysbiosis impairs gut function, ultimately driving mortality [13–16].

Bacterial pathogens are also controlled by the conjunction of physical barriers and the production of ROS and antimicrobial peptides, but the immune responses are induced to a higher level compared to that caused by the microbiota [6,29]. In mammals, intracellular intestinal pathogens such as Salmonella, Listeria, and Shigella are commonly used, while in Drosophila, most pathogens studied are extracellular gram-negative bacteria (e.g., Pectinobacteria, Pseudomonas, and Serratia). In mice, intestinal infections trigger NF-κB activation downstream of Toll-like receptors (TLRs) and Nod-like receptors (NLRs). Similarly, activation of the Immune Deficiency (Imd) pathway in Drosophila depends on both membrane-bound (PGRP-LC) and cytoplasmic (PGRP-LE) receptors [30,31]. In mice, the intestine relies on the lumenal secretion of antimicrobial peptides by Paneth cells as well as the recruitment of immune cells such as neutrophils to prevent infection [32]. Recently, a role for hemocytes, the circulating immune cells of Drosophila, has been described in controlling inflammatory signaling and intestinal regeneration in the gut [33–35], suggesting that the interplay between immune cells and the gut epithelium is also conserved from flies to mammals.

The emergence of several arboviruses impacting human health (e.g., Zika, dengue, chikungunya, Rift Valley fever virus) in the past decade has instigated vast research into arbovirus–vector interactions. Mosquitoes and other biting insects are natural virus vectors, but arboviruses belonging to the Flavivirus, Alphavirus, and Bunyavirus families can infect Drosophila experimentally, thus establishing a pertinent model to study innate immune signaling and other aspects of virus vectoring capacity [48]. Systemic virus infections of Drosophila and other insects are controlled by a combination of RNA interference (RNAi), apoptosis, and immune responses downstream of key signaling pathways (e.g., Toll, NF-κB, JAK-STAT) [49]. However, little is known about the activation and function of antiviral pathways in the insect midgut.

The gut is a major interface between a host and microbes. Whether we consider the emerging notion that the gut microbiota influences host physiology, the relation of GI inflammation to health and disease, or that the gut of insect vectors is a first point of contact with human parasites, it is increasingly important to elucidate the complexity and plethora of interactions between the GI tract and microbes. Due to the strong conservation of both structure and function of the gut epithelium, the less complex microbial community that composes the Drosophila gut microbiota, and the ease of genetically manipulating Drosophila, the fruit fly will continue to thrive as a workhorse for biological discoveries in this area.




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