Bacteria live within all animals. While a small number of these microbes can cause disease, most promote the health and wellbeing of their host. Microbes that support their host and benefit from the close association are often referred to as symbionts. Animals can be negatively affected and even become diseased if their symbionts are disrupted. As a result, a more complete understanding of the molecular interactions between animal hosts and their beneficial microbes will lead to better treatments for a number of diseases.

Tsetse flies are insects that harbor two bacterial symbionts, which are transferred from pregnant females to their larval offspring. If the offspring mature without these microbes, they fail to develop cells called hemocytes. These cells are normally found in the insect’s equivalent of blood – a fluid called hemolymph – and they comprise an important component of the insect’s immune system. Adult tsetse flies that lack hemocytes are susceptible to certain infections. These findings indicate that the bacterial symbionts induce the production of hemocytes in tsetse fly larvae via an unknown mechanism.

Benoit et al. now reveal that the bacterial symbionts trigger tsetse flies to produce a small protein called “odorant binding protein 6”. This protein controls the generation of one specific type of hemocyte called crystal cells in developing larvae. Crystal cells are largely responsible for triggering the production of melanin, a protein involved in killing disease-causing microbes and inhibiting the loss of hemolymph from wound sites in the insect’s exoskeleton.

Benoit et al. discovered that bacterial symbionts associated with the larvae of fruit flies also support the development of their host’s immune system. Although these symbionts are acquired from the external environment rather than from the insect’s parent, they too control the production of an odorant binding protein and crystal cells in their larval host.

Collectively, these findings confirm that bacterial symbionts are critically important for the development of the immune systems of insects, and they show that this process has been conserved throughout evolution. Future studies are likely to focus on identifying which molecules from the symbionts stimulate their hosts to produce new hemolymph cells. Furthermore, identifying which tissues and cell types in the animal hosts are targets for these molecules will provide a more complete picture of the pathways that lead to the production of new hemolymph cells.

Mutualistic bacteria are functionally critical to the physiological well-being of their animal hosts. These microbes benefit their hosts by providing essential nutrients, aiding in digestion and maintaining intestinal equilibrium (Douglas, 2015; Marchesi et al., 2016). Additionally, mutualistic symbionts promote the development, differentiation and proper function of their host’s immune system (Chu and Mazmanian, 2013; Khosravi et al., 2014; Gomez de Agüero et al., 2016 ). Despite such an important role, the molecular mechanisms that underlie symbiont-mediated homeostasis of animal immunity remain largely unknown.

Insect models are useful for studying host-microbe interactions because, relative to their mammalian counterparts, they generally house taxonomically simple bacterial communities that can be easily manipulated during their host’s development. Tsetse flies (Glossina spp.) house two gut-associated bacterial symbionts, obligate Wigglesworthia glossinidia and commensal Sodalis glossinidius (Maltz et al., 2012; Wang et al., 2013). In adult flies Wigglesworthia resides within cells that collectively form a bacteriome organ that is attached to the anterior midgut. Sodalis can be found extracellularly in the gut lumen, or intracellularly within gut epithelial cells (Wang et al., 2013). Tsetse reproduce via adenotrophic viviparity, during which pregnant females give birth to one larva each reproductive, or ‘gonotrophic’ (GC), cycle. Individual larvae mature through three developmental instars within the uterus, all the while receiving nourishment in the form of a milk-like substance produced by a modified accessory gland (milk gland; Benoit et al., 2015). Both Wigglesworthia and Sodalis are also found extracellularly in tsetse milk, and these bacteria colonize the gut of developing intrauterine larvae as they imbibe this nutrient source (Attardo et al., 2008).

Tsetse that undergo larvagenesis in the absence of their indigenous microbiota are highly immuno-compromised as adults (Wang et al., 2013). These ‘aposymbiotic’ (hereafter referred to as ‘Gmm^Apo’) flies exhibit a dysfunctional cellular immune system that is characterized by the conspicuous absence of hemocytes. This phenotype results from the disruption of hematopoiesis (blood cell differentiation) during larval development (Weiss et al., 2011, 2012). In insects, distinct hemocyte lineages mediate essential immune-related functions, including the phagocytosis and encapsulation of foreign invaders and the closing of cuticular wounds via the deposition of melanin at the site of injury (Lemaitre and Hoffmann, 2007; Hillyer and Strand, 2014; Lee and Miura, 2014). These immune mechanisms serve as the first line of defense following systemic challenge with exogenous organisms. Actuation of host immune system development represents an evolution driven mechanism that steadfastly links the tsetse fly with its symbiotic bacterial partners.

In this study we identify symbiont regulated genes and pathways in tsetse larvae using RNA-seq. Functional studies revealed that one symbiont induced gene, which encodes an odorant binding protein (OBP), regulates hematopoietic pathways during tsetse’s larval development. We also demonstrate that Drosophila’s indigenous microbiota regulates expression of an orthologous, functionally conserved OBP-encoding gene. Our findings detail a newly characterized, evolutionarily conserved component of a blood cell differentiation regulatory pathway that occurs in response to the presence of enteric symbionts.

Tsetse flies must house their maternally transmitted enteric symbionts during larval development in order to present a functional cellular immune system as adults. In the absence of these microbes, tsetse larvae express reduced levels of the GATA and RUNX transcription factors serpent and lozenge. This inhibition prevents the production of blood cell progenitors and thus the differentiation of phagocyte and crystal cell lineages (Weiss et al., 2011, 2012). Herein, we characterize an obligate symbiont regulated tsetse gene that actuates a distinct component of the fly’s hematopoietic program. Specifically, these microbes regulate obp6 transcript abundance in developing intrauterine larvae. The encoded protein subsequently induces expression of lozenge, which drives a pool of larval hemocyte precursors to differentiate into functional crystal cells. When adult tsetse house a depleted population of this hemocyte subtype, which initiates the melanization cascade via the release of prophenoloxidase, cuticular wounds fail to clot, thus leaving the fly exposed to dehydration and/or infection with opportunistic environmental microbes. This phenotype is similar to that observed when Wigglesworthia-free flies are exposed to cuticular wounds (Weiss et al., 2011; Figure 6). We further discovered that Drosophila’s indigenous microbiota regulate orthologous components of their host’s hematopoietic program. Taken together, these findings accentuate the functional relevance of symbiotic bacteria as they relate to hematopoiesis, and detail an evolutionarily conserved component of the insect innate immune system that coordinates a cellular process essential for survival.

Figure 6

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When tsetse and Drosophila larvae express reduced levels of orthologous obp6 and obp28a, respectively, subsequent adults exhibit defective melanization cascades and thus perish unusually fast following wounding with a clean needle. These phenotypes result from reduced expression of hematopoietic lozenge and a consequently depleted population of PPO-producing crystal cells. In tsetse, obp6 expression is tightly linked with intrauterine larval recognition of obligate Wigglesworthia. Drosophila larvae are free-living and thus do not obtain bacteria trans-generationally. Instead, female Drosophila lay their eggs in decaying organic matter, and immediately following eclosion, larvae begin feeding on this substrate (Markow, 2015; Broderick and Lemaitre, 2012). Thus, the gut of larval Drosophila is colonized by a relatively diverse population of environmentally acquired bacteria (Chandler et al., 2011;Wong et al., 2013 ). Axenic Drosophila larvae develop slower and weigh less than wild-type individuals (Shin et al., 2011; Storelli et al., 2011), and adults exhibit reduced stem cell activity and epithelial turnover (Buchon et al., 2009; Broderick et al., 2014) and can be more susceptible to enteric viral and bacterial pathogens (Blum et al., 2013; Sansone et al., 2015). The immune-compromised phenotypes exhibited by axenic adult Drosophila may reflect a developmental deficiency that, similar to the situation in tsetse, occurs when larval stages mature in the absence of symbiotic bacteria. This scenario would suggest that Drosophila’s indigenous microbiota also influences hematopoietic processes via a mechanism homologous to Wigglesworthia’s influence on tsetse. These convergent mechanisms, which control crucial immune phenotypes that are coordinated by evolutionarily conserved genes and regulatory pathways, exist despite the divergent nature of these host-symbiont model systems. Specifically, the tsetse-Wigglesworthia symbiosis originated 50–80 million years ago (Chen et al., 1999), and due to the bacterium’s strict vertical route of transmission, is highly steadfast in nature. Conversely, Drosophila’s relationship with its microbiota is relatively transient and highly dependent on diet and local environmental factors (Blum et al., 2013; Broderick et al., 2014). The extent to which obp6 and obp28a orthologues are functionally conserved in other arthropods remains to be determined. Furthermore, although vertebrates lack direct obp6 and obp28a orthologues (Kriventseva et al., 2015), unrelated odorant binding proteins may present similar roles in these systems.

Innate immunity is germ-line encoded and regulated by highly conserved pathways (Rubin et al., 2000; Lemaitre and Hoffmann, 2007), some of which are actuated by systemically derived signals. This type of molecular coordination is well characterized in Drosophila, where insulin secreted by insulin-producing cells in the brain, and essential amino acids emanating from the gut, promote Wingless signaling that maintains blood cell progenitors in the hematopoietic niche (Shim et al., 2012). Smell also contributes to progenitor maintenance in larval Drosophila. Specifically, olfactory receptor neurons, stimulated by the detection of small food-derived volatile molecules, secrete GABA into the larval hemocoel where it subsequently binds to blood cell progenitors in the lymph gland. This interaction increases cytosolic calcium concentrations that are necessary and sufficient to maintain the progenitor population. When larval Drosophila are reared on an odor-free diet, they fail to retain a pool of these cells (Shim et al., 2013a). These findings highlight the intriguing association between smell and homeostasis of innate immune-related activities. For the experiments performed herein, Drosophila and tsetse were reared in the absence of indigenous microbes, but on diets (sterilized) and in environments that emitted normal food odors. Under these conditions both flies presented dysfunctional hematopoietic programs, indicating that microbe-derived factors may also influence hematopoiesis. While the exact chemical structure of these molecules is currently unknown, they could take the form of microbe-associated molecular patterns (MAMPs), including bacterial cell wall components such as polysaccharide A, peptidoglycan and Nod-like receptor ligand, which in mammals actuate differentiation of T cell lineages (Mazmanian et al., 2005), enhance bone marrow-derived neutrophil killing (Clarke et al., 2010) and stimulate macrophage activity in lung tissues (Clarke, 2014b; Gauguet et al., 2015), respectively. Additionally, microbial metabolites mediate regulatory T cell abundance in colonic tissues, as germ-free mice that lack gut microbiota-derived fatty acids present fewer of this immune cell type (Smith et al., 2013; Furusawa et al., 2013). These findings accentuate the concept that general metabolic defects associated with dysbiosis can give rise to cellular immunity-related pathologies (Norata et al., 2015), including impairment of hematopoietic programs (Shim et al., 2012, 2013b).

Bacteria also release a wide variety of volatile compounds (Audrain et al., 2015), some of which, following chemosensory detection, influence animal immune phenotypes. A situation of this nature occurs when adult Drosophila detect geosmin, which is a microbial odorant that signals the presence of harmful microbes. This stimulus induces expression of olfactory receptor Or56a in olfactory sensory neurons, which leads to an aversion behavior, reduction in the activity of other olfactory pathways, and inhibition of positive chemotaxis, oviposition and feeding behavior (Stensmyr et al., 2012). A similar phenomenon occurs in the nematode Caenorhabditis elegans, which executes a protective avoidance behavior following chemosensory detection of the aromatic compounds phenazine-1-carboxamide and pyochelin that are produced by pathogenic Pseudomonas aeruginosa (Meisel et al., 2014). Drosophila detects and prefers specific odors produced by members of its microbiome (Fischer et al., 2016). As such, odorant molecules derived from tsetse and Drosophila enteric microbes could modulate the expression of obp6 and obp28a in the gut of larval flies, thus serving as the signal that activates hematopoiesis.

In larval tsetse Wigglesworthia is found exclusively within the gut-bacteriome axis (Balmand et al., 2013), and obp6 expression is restricted to this same environment. Conversely, lozenge transcripts are found solely in the carcass, indicating that the fly’s hematopoietic niche is likely not attached to the gut. The spatial expression pattern of these genes indicates that OBP6 exerts a systemic effect on tsetse hematopoiesis, and this process could occur in one of two ways. First, this protein could act locally at the mucosal interface to induce the production and secretion of a distinct immuno-stimulatory molecule that subsequently acts in tsetse’s hematopoietic niche. A mechanism of this nature occurs in mice, where enteric symbiont-derived molecules induce group three innate lymphoid cells in the intestine to increase production of the cytokine interleukin-17 (IL-17). Circulating IL-17 subsequently induces production of peripheral granulocyte colony-stimulating factor, which actuates neutrophil differentiation in bone marrow tissues (Deshmukh et al., 2014). Insect OBPs are widely believed to serve as vehicles that carry odorant molecules from sensory sensillum pores to corresponding dendritic odorant receptors (Leal, 2013). Based on this definition, tsetse OBP6 could also serve a carrier-like function following translocation from the fly’s gut into its circulatory system. More specifically, this protein could complex with another hematopoietic molecule produced either in tsetse’s gut or extra-intestinally, and then both together, or the latter molecule alone, stimulate hemocyte development in the hematopoietic niche. Notably, the function of insect OBPs was defined based on experiments performed in the chemosensory apparatus, and the role of these proteins in other insect tissue types is largely unknown. Interestingly, a recent study exploring the roles of OBPs in Drosophila sensilla found that deletion of obp28a did not reduce the magnitude of fly olfactory responses, suggesting a novel role for the encoded protein (Larter et al., 2016). As such, tsetse OBP6 could also function unconventionally by directly stimulating hematopoiesis following secretion into the larval hemocoel. Further studies are required to determine the specific cell type within larval tsetse’s gut and/or bacteriome that express obp6. Additionally, identification of OBP6 target tissues will provide valuable insight into the immuno-stimulatory function of this protein.

Finally, we speculate that our tsetse fly related findings reported herein are directly relevant to the transmission of vector-borne pathogens. Melanization is a cellular immune response that occurs across invertebrate taxa (Cerenius and Söderhäll, 2011), and this mechanism influences the transmission of several pathogens through their respective insect vectors (Collins et al., 1986; Zou et al., 2008; Bartholomay, 2014). Thus, an increased understanding of the physiological processes that regulate melanization may have translational implications pertinent to the development of pathogen-refractory insects.

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Author details

1. Joshua B Benoit

   Department of Biological Sciences, University of Cincinnati, Cincinnati, United States

   Contribution

   JBB, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

2. Aurélien Vigneron

   Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, United States

   Contribution

   AV, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

3. Nichole A Broderick

   1. Department of Molecular and Cell Biology, University of Connecticut, Storrs, United States
   2. Institute for Systems Genomics, University of Connecticut, Storrs, United States

   Contribution

   NAB, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-6830-9456

4. Yineng Wu

   Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, United States

   Contribution

   YW, performed experiments, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

5. Jennifer S Sun

   Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, United States

   Contribution

   JSS, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-4274-0504

6. John R Carlson

   1. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, United States
   2. Interdepartmental Neuroscience Program, Yale University, New Haven, United States

   Contribution

   JRC, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-0244-5180

7. Serap Aksoy

   Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, United States

   Contribution

   SA, Conception and design, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0001-9941-143X

8. Brian L Weiss

   Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, United States

   Contribution

   BLW, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

   For correspondence

   brian.weiss@yale.edu

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0003-1576-3556

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