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

Download asset Open asset

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.

1. 1. Joshua B Benoit
   2. Aurélien Vigneron
   3. Nichole A Broderick
   4. Yineng Wu
   5. Jennifer S Sun
   6. John R Carlson
   7. Serap Aksoy
   8. Brian L Weiss

   (2016) Glossina morsitans strain: Yale Transcriptome or Gene expression: 1st instar tsetse fly larvae (whole organism)

   Publicly available at NCBI BioProject (accession no. PRJNA309164).

   https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA309164

1. 1. Scolari F
   2. Benoit JB
   3. Michalkova V
   4. Aksoy E
   5. Takac P
   6. Abd-Alla AM
   7. Malacrida AR
   8. Aksoy S
   9. Attadro GM

   (2016) Glossina morsitans morsitans Male accessory gland and testes raw illumina reads

   Publicly available at NCBI BioProject (accession no. PRJNA295435).

   http://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA295435
2. 1. Ichalkova V
   2. Krause TB
   3. Bohova J
   4. Zhang Q
   5. Baumann AA
   6. Mireji PO
   7. Takac P
   8. Denlinger DL
   9. Ribeiro JM
   10. Aksoy S

   (2014) Glossina morsitans morsitans transcriptome during milk production

   Publicly available at NCBI BioProject (accession no. PRJNA205861).

   http://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA205861

1. 1. Aguilar R
   2. Jedlicka AE
   3. Mintz M
   4. Mahairaki V
   5. Scott AL
   6. Dimopoulos G

   (2005) Global gene expression analysis of Anopheles gambiae responses to microbial challenge

   Insect Biochemistry and Molecular Biology 35:709–719.

   https://doi.org/10.1016/j.ibmb.2005.02.019

   • PubMed
   • Google Scholar
2. 1. Alam U
   2. Medlock J
   3. Brelsfoard C
   4. Pais R
   5. Lohs C
   6. Balmand S
   7. Carnogursky J
   8. Heddi A
   9. Takac P
   10. Galvani A
   11. Aksoy S

   (2011) Wolbachia symbiont infections induce strong cytoplasmic incompatibility in the tsetse fly Glossina morsitans

   PLoS Pathogens 7:e1002415.

   https://doi.org/10.1371/journal.ppat.1002415

   • PubMed
   • Google Scholar
3. 1. Attardo GM
   2. Benoit JB
   3. Michalkova V
   4. Patrick KR
   5. Krause TB
   6. Aksoy S

   (2014) The homeodomain protein ladybird late regulates synthesis of milk proteins during pregnancy in the tsetse fly (Glossina morsitans)

   PLoS Neglected Tropical Diseases 8:e2645.

   https://doi.org/10.1371/journal.pntd.0002645

   • PubMed
   • Google Scholar
4. 1. Attardo GM
   2. Lohs C
   3. Heddi A
   4. Alam UH
   5. Yildirim S
   6. Aksoy S

   (2008) Analysis of milk gland structure and function in Glossina morsitans: milk protein production, symbiont populations and fecundity

   Journal of Insect Physiology 54:1236–1242.

   https://doi.org/10.1016/j.jinsphys.2008.06.008

   • PubMed
   • Google Scholar
5. 1. Attrill H
   2. Falls K
   3. Goodman JL
   4. Millburn GH
   5. Antonazzo G
   6. Rey AJ
   7. Marygold SJ
   8. FlyBase Consortium

   (2016) FlyBase: establishing a Gene Group resource for Drosophila melanogaster

   Nucleic Acids Research 44:D786–D792.

   https://doi.org/10.1093/nar/gkv1046

   • PubMed
   • Google Scholar
6. 1. Audrain B
   2. Farag MA
   3. Ryu CM
   4. Ghigo JM

   (2015) Role of bacterial volatile compounds in bacterial biology

   FEMS Microbiology Reviews 39:222–233.

   https://doi.org/10.1093/femsre/fuu013

   • PubMed
   • Google Scholar
7. 1. Babcock DT
   2. Brock AR
   3. Fish GS
   4. Wang Y
   5. Perrin L
   6. Krasnow MA
   7. Galko MJ

   (2008) Circulating blood cells function as a surveillance system for damaged tissue in Drosophila larvae

   PNAS 105:10017–10022.

   https://doi.org/10.1073/pnas.0709951105

   • PubMed
   • Google Scholar
8. 1. Baggerly KA
   2. Deng L
   3. Morris JS
   4. Aldaz CM

   (2003) Differential expression in SAGE: accounting for normal between-library variation

   Bioinformatics 19:1477–1483.

   https://doi.org/10.1093/bioinformatics/btg173

   • PubMed
   • Google Scholar
9. 1. Balmand S
   2. Lohs C
   3. Aksoy S
   4. Heddi A

   (2013) Tissue distribution and transmission routes for the tsetse fly endosymbionts

   Journal of Invertebrate Pathology 112:S116–S122.

   https://doi.org/10.1016/j.jip.2012.04.002

   • PubMed
   • Google Scholar
10. 1. Bartholomay LC
    2. Cho WL
    3. Rocheleau TA
    4. Boyle JP
    5. Beck ET
    6. Fuchs JF
    7. Liss P
    8. Rusch M
    9. Butler KM
    10. Wu RC
    11. Lin SP
    12. Kuo HY
    13. Tsao IY
    14. Huang CY
    15. Liu TT
    16. Hsiao KJ
    17. Tsai SF
    18. Yang UC
    19. Nappi AJ
    20. Perna NT
    21. Chen CC
    22. Christensen BM
    23. Rc W

    (2004) Description of the transcriptomes of immune response-activated hemocytes from the mosquito vectors Aedes aegypti and Armigeres subalbatus

    Infection and Immunity 72:4114–4126.

    https://doi.org/10.1128/IAI.72.7.4114-4126.2004

    • PubMed
    • Google Scholar
11. 1. Bartholomay LC

    (2014) Infection barriers and responses in mosquito–filarial worm interactions

    Current Opinion in Insect Science 3:37–42.

    https://doi.org/10.1016/j.cois.2014.08.006

    • Google Scholar
12. 1. Benoit JB
    2. Attardo GM
    3. Baumann AA
    4. Michalkova V
    5. Aksoy S

    (2015) Adenotrophic viviparity in tsetse flies: potential for population control and as an insect model for lactation

    Annual Review of Entomology 60:351–371.

    https://doi.org/10.1146/annurev-ento-010814-020834

    • PubMed
    • Google Scholar
13. 1. Benoit JB
    2. Attardo GM
    3. Michalkova V
    4. Krause TB
    5. Bohova J
    6. Zhang Q
    7. Baumann AA
    8. Mireji PO
    9. Takáč P
    10. Denlinger DL
    11. Ribeiro JM
    12. Aksoy S

    (2014) A novel highly divergent protein family identified from a viviparous insect by RNA-seq analysis: a potential target for tsetse fly-specific abortifacients

    PLoS Genetics 10:e1003874.

    https://doi.org/10.1371/journal.pgen.1003874

    • PubMed
    • Google Scholar
14. 1. Binggeli O
    2. Neyen C
    3. Poidevin M
    4. Lemaitre B

    (2014) Prophenoloxidase activation is required for survival to microbial infections in Drosophila

    PLoS Pathogens 10:e1004067.

    https://doi.org/10.1371/journal.ppat.1004067

    • PubMed
    • Google Scholar
15. 1. Blum JE
    2. Fischer CN
    3. Miles J
    4. Handelsman J

    (2013) Frequent replenishment sustains the beneficial microbiome of Drosophila melanogaster

    mBio 4:e00860–13.

    https://doi.org/10.1128/mBio.00860-13

    • PubMed
    • Google Scholar
16. 1. Bolger AM
    2. Lohse M
    3. Usadel B

    (2014) Trimmomatic: a flexible trimmer for Illumina sequence data

    Bioinformatics 30:2114–2120.

    https://doi.org/10.1093/bioinformatics/btu170

    • PubMed
    • Google Scholar
17. 1. Broderick NA
    2. Buchon N
    3. Lemaitre B

    (2014) Microbiota-induced changes in Drosophila melanogaster host gene expression and gut morphology

    mBio 5:e01117–14.

    https://doi.org/10.1128/mBio.01117-14

    • PubMed
    • Google Scholar
18. 1. Broderick NA
    2. Lemaitre B

    (2012) Gut-associated microbes of Drosophila melanogaster

    Gut Microbes 3:307–321.

    https://doi.org/10.4161/gmic.19896

    • PubMed
    • Google Scholar
19. 1. Buchon N
    2. Broderick NA
    3. Chakrabarti S
    4. Lemaitre B

    (2009) Invasive and indigenous microbiota impact intestinal stem cell activity through multiple pathways in Drosophila

    Genes & Development 23:2333–2344.

    https://doi.org/10.1101/gad.1827009

    • PubMed
    • Google Scholar
20. 1. Cerenius L
    2. Söderhäll K

    (2011) Coagulation in invertebrates

    Journal of Innate Immunity 3:3–8.

    https://doi.org/10.1159/000322066

    • PubMed
    • Google Scholar
21. 1. Chandler JA
    2. Lang JM
    3. Bhatnagar S
    4. Eisen JA
    5. Kopp A

    (2011) Bacterial communities of diverse Drosophila species: ecological context of a host-microbe model system

    PLoS Genetics 7:e1002272.

    https://doi.org/10.1371/journal.pgen.1002272

    • PubMed
    • Google Scholar
22. 1. Chen X
    2. Li S
    3. Aksoy S

    (1999) Concordant evolution of a symbiont with its host insect species: molecular phylogeny of genus Glossina and its bacteriome-associated endosymbiont, Wigglesworthia glossinidia

    Journal of Molecular Evolution 48:49–58.

    https://doi.org/10.1007/PL00006444

    • PubMed
    • Google Scholar
23. 1. Chu H
    2. Mazmanian SK

    (2013) Innate immune recognition of the microbiota promotes host-microbial symbiosis

    Nature Immunology 14:668–675.

    https://doi.org/10.1038/ni.2635

    • PubMed
    • Google Scholar
24. 1. Clarke TB
    2. Davis KM
    3. Lysenko ES
    4. Zhou AY
    5. Yu Y
    6. Weiser JN

    (2010) Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity

    Nature Medicine 16:228–231.

    https://doi.org/10.1038/nm.2087

    • PubMed
    • Google Scholar
25. 1. Clarke TB

    (2014a) Microbial programming of systemic innate immunity and resistance to infection

    PLoS Pathogens 10:e1004506.

    https://doi.org/10.1371/journal.ppat.1004506

    • Google Scholar
26. 1. Clarke TB

    (2014b) Early innate immunity to bacterial infection in the lung is regulated systemically by the commensal microbiota via nod-like receptor ligands

    Infection and Immunity 82:4596–4606.

    https://doi.org/10.1128/IAI.02212-14

    • PubMed
    • Google Scholar
27. 1. Collins FH
    2. Sakai RK
    3. Vernick KD
    4. Paskewitz S
    5. Seeley DC
    6. Miller LH
    7. Collins WE
    8. Campbell CC
    9. Gwadz RW

    (1986) Genetic selection of a Plasmodium-refractory strain of the malaria vector Anopheles gambiae

    Science 234:607–610.

    https://doi.org/10.1126/science.3532325

    • PubMed
    • Google Scholar
28. 1. Conesa A
    2. Götz S
    3. García-Gómez JM
    4. Terol J
    5. Talón M
    6. Robles M

    (2005) Blast2GO: a universal tool for annotation, visualization and analysis in functional genomics research

    Bioinformatics 21:3674–3676.

    https://doi.org/10.1093/bioinformatics/bti610

    • PubMed
    • Google Scholar
29. 1. Deshmukh HS
    2. Liu Y
    3. Menkiti OR
    4. Mei J
    5. Dai N
    6. O'Leary CE
    7. Oliver PM
    8. Kolls JK
    9. Weiser JN
    10. Worthen GS

    (2014) The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice

    Nature Medicine 20:524–530.

    https://doi.org/10.1038/nm.3542

    • PubMed
    • Google Scholar
30. 1. Dietzl G
    2. Chen D
    3. Schnorrer F
    4. Su KC
    5. Barinova Y
    6. Fellner M
    7. Gasser B
    8. Kinsey K
    9. Oppel S
    10. Scheiblauer S
    11. Couto A
    12. Marra V
    13. Keleman K
    14. Dickson BJ

    (2007) A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila

    Nature 448:151–156.

    https://doi.org/10.1038/nature05954

    • PubMed
    • Google Scholar
31. 1. Douglas AE

    (2015) Multiorganismal insects: diversity and function of resident microorganisms

    Annual Review of Entomology 60:17–34.

    https://doi.org/10.1146/annurev-ento-010814-020822

    • PubMed
    • Google Scholar
32. 1. Eleftherianos I
    2. Revenis C

    (2011) Role and importance of phenoloxidase in insect hemostasis

    Journal of Innate Immunity 3:28–33.

    https://doi.org/10.1159/000321931

    • PubMed
    • Google Scholar
33. 1. Evans CJ
    2. Banerjee U

    (2003) Transcriptional regulation of hematopoiesis in Drosophila

    Blood Cells, Molecules, and Diseases 30:223–228.

    https://doi.org/10.1016/S1079-9796(03)00028-7

    • Google Scholar
34. 1. Evans CJ
    2. Hartenstein V
    3. Banerjee U

    (2003) Thicker than blood: conserved mechanisms in Drosophila and vertebrate hematopoiesis

    Developmental Cell 5:673–690.

    https://doi.org/10.1016/s1534-5807(03)00335-6

    • PubMed
    • Google Scholar
35. 1. Ferjoux G
    2. Augé B
    3. Boyer K
    4. Haenlin M
    5. Waltzer L

    (2007) A GATA/RUNX cis-regulatory module couples Drosophila blood cell commitment and differentiation into crystal cells

    Developmental Biology 305:726–734.

    https://doi.org/10.1016/j.ydbio.2007.03.010

    • PubMed
    • Google Scholar
36. 1. Fischer CN
    2. Trautman EP
    3. Crawford JM
    4. Stabb EV
    5. Broderick NA
    6. Handelsman J

    (2016) Metabolite exchange within the microbiome produces compounds that influence Drosophila behavior

    bioRxiv 066035.

    https://doi.org/10.1101/066035

    • Google Scholar
37. 1. Furusawa Y
    2. Obata Y
    3. Fukuda S
    4. Endo TA
    5. Nakato G
    6. Takahashi D
    7. Nakanishi Y
    8. Uetake C
    9. Kato K
    10. Kato T
    11. Takahashi M
    12. Fukuda NN
    13. Murakami S
    14. Miyauchi E
    15. Hino S
    16. Atarashi K
    17. Onawa S
    18. Fujimura Y
    19. Lockett T
    20. Clarke JM
    21. Topping DL
    22. Tomita M
    23. Hori S
    24. Ohara O
    25. Morita T
    26. Koseki H
    27. Kikuchi J
    28. Honda K
    29. Hase K
    30. Ohno H

    (2013) Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells

    Nature 504:446–450.

    https://doi.org/10.1038/nature12721

    • PubMed
    • Google Scholar
38. 1. Gauguet S
    2. D'Ortona S
    3. Ahnger-Pier K
    4. Duan B
    5. Surana NK
    6. Lu R
    7. Cywes-Bentley C
    8. Gadjeva M
    9. Shan Q
    10. Priebe GP
    11. Pier GB

    (2015) Intestinal Microbiota of mice influences resistance to Staphylococcus aureus pneumonia

    Infection and Immunity 83:4003–4014.

    https://doi.org/10.1128/IAI.00037-15

    • PubMed
    • Google Scholar
39. 1. Giraldo-Calderón GI
    2. Emrich SJ
    3. MacCallum RM
    4. Maslen G
    5. Dialynas E
    6. Topalis P
    7. Ho N
    8. Gesing S
    9. Madey G
    10. Collins FH
    11. Lawson D
    12. VectorBase Consortium

    (2015) VectorBase: an updated bioinformatics resource for invertebrate vectors and other organisms related with human diseases

    Nucleic Acids Research 43:D707–713.

    https://doi.org/10.1093/nar/gku1117

    • PubMed
    • Google Scholar
40. 1. Gomez de Agüero M
    2. Ganal-Vonarburg SC
    3. Fuhrer T
    4. Rupp S
    5. Uchimura Y
    6. Li H
    7. Steinert A
    8. Heikenwalder M
    9. Hapfelmeier S
    10. Sauer U
    11. McCoy KD
    12. Macpherson AJ

    (2016) The maternal microbiota drives early postnatal innate immune development

    Science 351:1296–1302.

    https://doi.org/10.1126/science.aad2571

    • PubMed
    • Google Scholar
41. 1. Grabherr MG
    2. Haas BJ
    3. Yassour M
    4. Levin JZ
    5. Thompson DA
    6. Amit I
    7. Adiconis X
    8. Fan L
    9. Raychowdhury R
    10. Zeng Q
    11. Chen Z
    12. Mauceli E
    13. Hacohen N
    14. Gnirke A
    15. Rhind N
    16. di Palma F
    17. Birren BW
    18. Nusbaum C
    19. Lindblad-Toh K
    20. Friedman N
    21. Regev A

    (2011) Full-length transcriptome assembly from RNA-Seq data without a reference genome

    Nature Biotechnology 29:644–652.

    https://doi.org/10.1038/nbt.1883

    • PubMed
    • Google Scholar
42. 1. Grigorian M
    2. Hartenstein V

    (2013) Hematopoiesis and hematopoietic organs in arthropods

    Development Genes and Evolution 223:103–115.

    https://doi.org/10.1007/s00427-012-0428-2

    • PubMed
    • Google Scholar
43. 1. Hartenstein V

    (2006) Blood cells and blood cell development in the animal kingdom

    Annual Review of Cell and Developmental Biology 22:677–712.

    https://doi.org/10.1146/annurev.cellbio.22.010605.093317

    • PubMed
    • Google Scholar
44. 1. Hillyer JF
    2. Strand MR

    (2014) Mosquito hemocyte-mediated immune responses

    Current Opinion in Insect Science 3:14–21.

    https://doi.org/10.1016/j.cois.2014.07.002

    • PubMed
    • Google Scholar
45. 1. Honti V
    2. Csordás G
    3. Kurucz É
    4. Márkus R
    5. Andó I

    (2014) The cell-mediated immunity of Drosophila melanogaster: hemocyte lineages, immune compartments, microanatomy and regulation

    Developmental & Comparative Immunology 42:47–56.

    https://doi.org/10.1016/j.dci.2013.06.005

    • PubMed
    • Google Scholar
46. 1. Hrusa G
    2. Farmer W
    3. Weiss BL
    4. Applebaum T
    5. Roma JS
    6. Szeto L
    7. Aksoy S
    8. Runyen-Janecky LJ

    (2015) TonB-dependent heme iron acquisition in the tsetse fly symbiont Sodalis glossinidius

    Applied and Environmental Microbiology 81:2900–2909.

    https://doi.org/10.1128/AEM.04166-14

    • PubMed
    • Google Scholar
47. 1. International Glossina Genome Initiative

    (2014) Genome sequence of the tsetse fly (Glossina morsitans): vector of African trypanosomiasis

    Science 344:380–386.

    https://doi.org/10.1126/science.1249656

    • PubMed
    • Google Scholar
48. 1. Khosravi A
    2. Yáñez A
    3. Price JG
    4. Chow A
    5. Merad M
    6. Goodridge HS
    7. Mazmanian SK

    (2014) Gut microbiota promote hematopoiesis to control bacterial infection

    Cell Host & Microbe 15:374–381.

    https://doi.org/10.1016/j.chom.2014.02.006

    • PubMed
    • Google Scholar
49. 1. Kondo S
    2. Ueda R

    (2013) Highly improved gene targeting by germline-specific Cas9 expression in Drosophila

    Genetics 195:715–721.

    https://doi.org/10.1534/genetics.113.156737

    • PubMed
    • Google Scholar
50. 1. Kriventseva EV
    2. Tegenfeldt F
    3. Petty TJ
    4. Waterhouse RM
    5. Simão FA
    6. Pozdnyakov IA
    7. Ioannidis P
    8. Zdobnov EM

    (2015) OrthoDB v8: update of the hierarchical catalog of orthologs and the underlying free software

    Nucleic Acids Research 43:D250–D256.

    https://doi.org/10.1093/nar/gku1220

    • PubMed
    • Google Scholar
51. 1. Kurucz E
    2. Márkus R
    3. Zsámboki J
    4. Folkl-Medzihradszky K
    5. Darula Z
    6. Vilmos P
    7. Udvardy A
    8. Krausz I
    9. Lukacsovich T
    10. Gateff E
    11. Zettervall CJ
    12. Hultmark D
    13. Andó I

    (2007) Nimrod, a putative phagocytosis receptor with EGF repeats in Drosophila plasmatocytes

    Current Biology 17:649–654.

    https://doi.org/10.1016/j.cub.2007.02.041

    • PubMed
    • Google Scholar
52. 1. Larter NK
    2. Sun JS
    3. Carlson JR

    (2016) Organization and function of Drosophila odorant binding proteins

    eLife 5:e20242.

    https://doi.org/10.7554/eLife.20242

    • PubMed
    • Google Scholar
53. 1. Leal WS

    (2013) Odorant reception in insects: roles of receptors, binding proteins, and degrading enzymes

    Annual Review of Entomology 58:373–391.

    https://doi.org/10.1146/annurev-ento-120811-153635

    • PubMed
    • Google Scholar
54. 1. Lebestky T
    2. Chang T
    3. Hartenstein V
    4. Banerjee U

    (2000) Specification of Drosophila hematopoietic lineage by conserved transcription factors

    Science 288:146–149.

    https://doi.org/10.1126/science.288.5463.146

    • PubMed
    • Google Scholar
55. 1. Lee WJ
    2. Miura M

    (2014) Mechanisms of systemic wound response in Drosophila

    Current Topics in Developmental Biology 108:153–183.

    https://doi.org/10.1016/B978-0-12-391498-9.00001-2

    • PubMed
    • Google Scholar
56. 1. Lemaitre B
    2. Hoffmann J

    (2007) The host defense of Drosophila melanogaster

    Annual Review of Immunology 25:697–743.

    https://doi.org/10.1146/annurev.immunol.25.022106.141615

    • Google Scholar
57. 1. Liu R
    2. Lehane S
    3. He X
    4. Lehane M
    5. Hertz-Fowler C
    6. Berriman M
    7. Pickett JA
    8. Field LM
    9. Zhou JJ

    (2010) Characterisations of odorant-binding proteins in the tsetse fly Glossina morsitans morsitans

    Cellular and Molecular Life Sciences 67:919–929.

    https://doi.org/10.1007/s00018-009-0221-1

    • PubMed
    • Google Scholar
58. 1. Makhijani K
    2. Brückner K

    (2012) Of blood cells and the nervous system: hematopoiesis in the Drosophila larva

    Fly 6:254–260.

    https://doi.org/10.4161/fly.22267

    • PubMed
    • Google Scholar
59. 1. Maltz MA
    2. Weiss BL
    3. O'Neill M
    4. Wu Y
    5. Aksoy S

    (2012) OmpA-mediated biofilm formation is essential for the commensal bacterium Sodalis glossinidius to colonize the tsetse fly gut

    Applied and Environmental Microbiology 78:7760–7768.

    https://doi.org/10.1128/AEM.01858-12

    • PubMed
    • Google Scholar
60. 1. Marchesi JR
    2. Adams DH
    3. Fava F
    4. Hermes GD
    5. Hirschfield GM
    6. Hold G
    7. Quraishi MN
    8. Kinross J
    9. Smidt H
    10. Tuohy KM
    11. Thomas LV
    12. Zoetendal EG
    13. Hart A

    (2016) The gut microbiota and host health: a new clinical frontier

    Gut 65:330–339.

    https://doi.org/10.1136/gutjnl-2015-309990

    • PubMed
    • Google Scholar
61. 1. Markow TA

    (2015) The secret lives of Drosophila flies

    eLife 4:06793.

    https://doi.org/10.7554/eLife.06793

    • Google Scholar
62. 1. Marygold SJ
    2. Leyland PC
    3. Seal RL
    4. Goodman JL
    5. Thurmond J
    6. Strelets VB
    7. Wilson RJ
    8. FlyBase consortium

    (2013) FlyBase: improvements to the bibliography

    Nucleic Acids Research 41:D751–757.

    https://doi.org/10.1093/nar/gks1024

    • PubMed
    • Google Scholar
63. 1. Mazmanian SK
    2. Liu CH
    3. Tzianabos AO
    4. Kasper DL

    (2005) An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system

    Cell 122:107–118.

    https://doi.org/10.1016/j.cell.2005.05.007

    • Google Scholar
64. 1. Meisel JD
    2. Panda O
    3. Mahanti P
    4. Schroeder FC
    5. Kim DH

    (2014) Chemosensation of bacterial secondary metabolites modulates neuroendocrine signaling and behavior of C. elegans

    Cell 159:267–280.

    https://doi.org/10.1016/j.cell.2014.09.011

    • PubMed
    • Google Scholar
65. 1. Michalkova V
    2. Benoit JB
    3. Weiss BL
    4. Attardo GM
    5. Aksoy S

    (2014) Vitamin B6 generated by obligate symbionts is critical for maintaining proline homeostasis and fecundity in tsetse flies

    Applied and Environmental Microbiology 80:5844–5853.

    https://doi.org/10.1128/AEM.01150-14

    • PubMed
    • Google Scholar
66. 1. Nam HJ
    2. Jang IH
    3. You H
    4. Lee KA
    5. Lee WJ

    (2012) Genetic evidence of a redox-dependent systemic wound response via hayan protease-phenoloxidase system in Drosophila

    The EMBO Journal 31:1253–1265.

    https://doi.org/10.1038/emboj.2011.476

    • PubMed
    • Google Scholar
67. 1. Norata GD
    2. Caligiuri G
    3. Chavakis T
    4. Matarese G
    5. Netea MG
    6. Nicoletti A
    7. O'Neill LA
    8. Marelli-Berg FM

    (2015) The cellular and molecular basis of translational immunometabolism

    Immunity 43:421–434.

    https://doi.org/10.1016/j.immuni.2015.08.023

    • PubMed
    • Google Scholar
68. 1. Pais R
    2. Lohs C
    3. Wu Y
    4. Wang J
    5. Aksoy S

    (2008) The obligate mutualist Wigglesworthia glossinidia influences reproduction, digestion, and immunity processes of its host, the tsetse fly

    Applied and Environmental Microbiology 74:5965–5974.

    https://doi.org/10.1128/AEM.00741-08

    • PubMed
    • Google Scholar
69. 1. Perdomo-Morales R
    2. Montero-Alejo V
    3. Perera E
    4. Pardo-Ruiz Z
    5. Alonso-Jiménez E

    (2007) Phenoloxidase activity in the hemolymph of the spiny lobster Panulirus argus

    Fish & Shellfish Immunology 23:1187–1195.

    https://doi.org/10.1016/j.fsi.2007.04.001

    • PubMed
    • Google Scholar
70. 1. Round JL
    2. Mazmanian SK

    (2009) The gut microbiota shapes intestinal immune responses during health and disease

    Nature Reviews Immunology 9:313–323.

    https://doi.org/10.1038/nri2515

    • PubMed
    • Google Scholar
71. 1. Rubin GM
    2. Yandell MD
    3. Wortman JR
    4. Gabor Miklos GL
    5. Nelson CR
    6. Hariharan IK
    7. Fortini ME
    8. Li PW
    9. Apweiler R
    10. Fleischmann W
    11. Cherry JM
    12. Henikoff S
    13. Skupski MP
    14. Misra S
    15. Ashburner M
    16. Birney E
    17. Boguski MS
    18. Brody T
    19. Brokstein P
    20. Celniker SE
    21. Chervitz SA
    22. Coates D
    23. Cravchik A
    24. Gabrielian A
    25. Galle RF
    26. Gelbart WM
    27. George RA
    28. Goldstein LS
    29. Gong F
    30. Guan P
    31. Harris NL
    32. Hay BA
    33. Hoskins RA
    34. Li J
    35. Li Z
    36. Hynes RO
    37. Jones SJ
    38. Kuehl PM
    39. Lemaitre B
    40. Littleton JT
    41. Morrison DK
    42. Mungall C
    43. O'Farrell PH
    44. Pickeral OK
    45. Shue C
    46. Vosshall LB
    47. Zhang J
    48. Zhao Q
    49. Zheng XH
    50. Lewis S

    (2000) Comparative genomics of the eukaryotes

    Science 287:2204–2215.

    https://doi.org/10.1126/science.287.5461.2204

    • PubMed
    • Google Scholar
72. 1. Sabatier L
    2. Jouanguy E
    3. Dostert C
    4. Zachary D
    5. Dimarcq JL
    6. Bulet P
    7. Imler JL

    (2003) Pherokine-2 and -3. two Drosophila molecules related to pheromone/odor-binding proteins induced by viral and bacterial infections

    European Journal of Biochemistry 270:3398–3407.

    https://doi.org/10.1046/j.1432-1033.2003.03725.x

    • Google Scholar
73. 1. Sansone CL
    2. Cohen J
    3. Yasunaga A
    4. Xu J
    5. Osborn G
    6. Subramanian H
    7. Gold B
    8. Buchon N
    9. Cherry S

    (2015) Microbiota-dependent priming of antiviral intestinal immunity in Drosophila

    Cell Host & Microbe 18:571–581.

    https://doi.org/10.1016/j.chom.2015.10.010

    • PubMed
    • Google Scholar
74. 1. Scolari F
    2. Benoit JB
    3. Michalkova V
    4. Aksoy E
    5. Takac P
    6. Abd-Alla AM
    7. Malacrida AR
    8. Aksoy S
    9. Attardo GM

    (2016) The spermatophore in Glossina morsitans morsitans: Insights into Male Contributions to Reproduction

    Scientific Reports 6:20334.

    https://doi.org/10.1038/srep20334

    • PubMed
    • Google Scholar
75. 1. Shim J
    2. Gururaja-Rao S
    3. Banerjee U

    (2013b) Nutritional regulation of stem and progenitor cells in Drosophila

    Development 140:4647–4656.

    https://doi.org/10.1242/dev.079087

    • PubMed
    • Google Scholar
76. 1. Shim J
    2. Mukherjee T
    3. Banerjee U

    (2012) Direct sensing of systemic and nutritional signals by haematopoietic progenitors in Drosophila

    Nature Cell Biology 14:394–400.

    https://doi.org/10.1038/ncb2453

    • PubMed
    • Google Scholar
77. 1. Shim J
    2. Mukherjee T
    3. Mondal BC
    4. Liu T
    5. Young GC
    6. Wijewarnasuriya DP
    7. Banerjee U

    (2013a) Olfactory control of blood progenitor maintenance

    Cell 155:1141–1153.

    https://doi.org/10.1016/j.cell.2013.10.032

    • PubMed
    • Google Scholar
78. 1. Shin SC
    2. Kim SH
    3. You H
    4. Kim B
    5. Kim AC
    6. Lee KA
    7. Yoon JH
    8. Ryu JH
    9. Lee WJ

    (2011) Drosophila microbiome modulates host developmental and metabolic homeostasis via insulin signaling

    Science 334:670–674.

    https://doi.org/10.1126/science.1212782

    • PubMed
    • Google Scholar
79. 1. Smith PM
    2. Howitt MR
    3. Panikov N
    4. Michaud M
    5. Gallini CA
    6. Bohlooly-Y M
    7. Glickman JN
    8. Garrett WS

    (2013) The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis

    Science 341:569–573.

    https://doi.org/10.1126/science.1241165

    • PubMed
    • Google Scholar
80. 1. Stensmyr MC
    2. Dweck HK
    3. Farhan A
    4. Ibba I
    5. Strutz A
    6. Mukunda L
    7. Linz J
    8. Grabe V
    9. Steck K
    10. Lavista-Llanos S
    11. Wicher D
    12. Sachse S
    13. Knaden M
    14. Becher PG
    15. Seki Y
    16. Hansson BS

    (2012) A conserved dedicated olfactory circuit for detecting harmful microbes in Drosophila

    Cell 151:1345–1357.

    https://doi.org/10.1016/j.cell.2012.09.046

    • PubMed
    • Google Scholar
81. 1. Storelli G
    2. Defaye A
    3. Erkosar B
    4. Hols P
    5. Royet J
    6. Leulier F

    (2011) Lactobacillus plantarum promotes Drosophila systemic growth by modulating hormonal signals through TOR-dependent nutrient sensing

    Cell Metabolism 14:403–414.

    https://doi.org/10.1016/j.cmet.2011.07.012

    • PubMed
    • Google Scholar
82. 1. Swarup S
    2. Williams TI
    3. Anholt RRH

    (2011) Functional dissection of odorant binding protein genes in Drosophila melanogaster

    Genes, Brain and Behavior 10:648–657.

    https://doi.org/10.1111/j.1601-183X.2011.00704.x

    • Google Scholar
83. 1. Tang H

    (2009) Regulation and function of the melanization reaction in Drosophila

    Fly 3:105–111.

    https://doi.org/10.4161/fly.3.1.7747

    • PubMed
    • Google Scholar
84. 1. Thomas T
    2. De TD
    3. Sharma P
    4. Lata S
    5. Saraswat P
    6. Pandey KC
    7. Dixit R

    (2016) Hemocytome: deep sequencing analysis of mosquito blood cells in Indian malarial vector Anopheles stephensi

    Gene 585:177–190.

    https://doi.org/10.1016/j.gene.2016.02.031

    • PubMed
    • Google Scholar
85. 1. Vlisidou I
    2. Wood W

    (2015) Drosophila blood cells and their role in immune responses

    FEBS Journal 282:1368–1382.

    https://doi.org/10.1111/febs.13235

    • PubMed
    • Google Scholar
86. 1. Wang J
    2. Weiss BL
    3. Aksoy S

    (2013) Tsetse fly microbiota: form and function

    Frontiers in Cellular and Infection Microbiology 3:69.

    https://doi.org/10.3389/fcimb.2013.00069

    • PubMed
    • Google Scholar
87. 1. Weiss BL
    2. Maltz M
    3. Aksoy S

    (2012) Obligate symbionts activate immune system development in the tsetse fly

    The Journal of Immunology 188:3395–3403.

    https://doi.org/10.4049/jimmunol.1103691

    • PubMed
    • Google Scholar
88. 1. Weiss BL
    2. Wang J
    3. Aksoy S

    (2011) Tsetse immune system maturation requires the presence of obligate symbionts in larvae

    PLoS Biology 9:e1000619.

    https://doi.org/10.1371/journal.pbio.1000619

    • PubMed
    • Google Scholar
89. 1. Weiss BL
    2. Wang J
    3. Maltz MA
    4. Wu Y
    5. Aksoy S

    (2013) Trypanosome infection establishment in the tsetse fly gut is influenced by microbiome-regulated host immune barriers

    PLoS Pathogens 9:e1003318.

    https://doi.org/10.1371/journal.ppat.1003318

    • PubMed
    • Google Scholar
90. 1. Wong AC
    2. Chaston JM
    3. Douglas AE

    (2013) The inconstant gut microbiota of Drosophila species revealed by 16S rRNA gene analysis

    The ISME Journal 7:1922–1932.

    https://doi.org/10.1038/ismej.2013.86

    • PubMed
    • Google Scholar
91. 1. Zou Z
    2. Shin SW
    3. Alvarez KS
    4. Bian G
    5. Kokoza V
    6. Raikhel AS

    (2008) Mosquito RUNX4 in the immune regulation of PPO gene expression and its effect on avian malaria parasite infection

    PNAS 105:18454–18459.

    https://doi.org/10.1073/pnas.0804658105

    • PubMed
    • Google Scholar

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

• 3,477

  views

• 661

  downloads

• 108

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.