Vibrio cholerae O395 Outer Membrane Vesicles Modulate Intestinal Epithelial Cells in a NOD1 Protein-dependent Manner and Induce Dendritic Cell-mediated Th2/Th17 Cell Responses

Chatterjee, Debashree; Chaudhuri, Keya

doi:10.1074/jbc.m112.408302

Cited by 73 publications

(78 citation statements)

References 40 publications

(52 reference statements)

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“…The B-subunit of CTX was also identified in our OMVs, which is consistent with its being a periplasmic substrate for the T2SS (53,54), its presence in previously characterized OMVs of V. cholerae (26,37), and other studies that have detected surface-bound toxin subunits (68).…”

Section: Resultssupporting

confidence: 72%

“…OMVs also show promise as vaccine antigen platforms, given their composition and physico-chemical properties (30)(31)(32)(33)(34). For example, OMVs of V. cholerae have been shown to induce protective immunity in experimental animals (35)(36)(37)(38)(39)(40)(41). Although these immunization studies demonstrate the potential of OMVs as novel vaccine immunogens, such investigations have not been fully Significance Identifying proteins localized on the surface and envelope of Gram-negative bacterial cells is an important problem in vaccine development and antibiotic target discovery.…”

mentioning

confidence: 99%

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Proteomic analysis of Vibrio cholerae outer membrane vesicles

Altındiş

Mekalanos

2014

Proc. Natl. Acad. Sci. U.S.A.

139

110

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Outer membrane vesicles (OMVs) produced by Gram-negative bacteria provide an interesting research material for defining cellenvelope proteins without experimental cell disruption. OMVs are also promising immunogenic platforms and may play important roles in bacterial survival and pathogenesis. We used in-solution trypsin digestion coupled to mass spectrometry to identify 90 proteins present in OMVs of Vibrio cholerae when grown under conditions that activate the TCP pilus virulence regulatory protein (ToxT) virulence regulon. The ToxT expression profile and potential contribution to virulence of these proteins were assessed using ToxT and in vivo RNA-seq, Tn-seq, and cholera stool proteomic and other genome-wide data sets. Thirteen OMV-associated proteins appear to be essential for cell growth, and therefore may represent antibacterial drug targets. Another 12 nonessential OMV proteins, including DegP protease, were required for intestinal colonization in rabbits. Comparative proteomics of a degP mutant revealed the importance of DegP in the incorporation of nine proteins into OMVs, including ones involved in biofilm matrix formation and various substrates of the type II secretion system. Taken together, these results suggest that DegP plays an important role in determining the content of OMVs and also affects phenotypes such as intestinal colonization, proper function of the type II secretion system, and formation of biofilm matrix.HtrA family | in-solution digestion | biofilm formation | CTXϕ phage

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Section: Resultssupporting

confidence: 72%

mentioning

confidence: 99%

Proteomic analysis of Vibrio cholerae outer membrane vesicles

Altındiş

Mekalanos

2014

Proc. Natl. Acad. Sci. U.S.A.

139

110

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“…The IL-8 response of Vibrio cholerae OMVs was shown by Chatterjee and Chaudhuri. They showed that OMVs from classical V. cholerae strain O395 induce IL-8 secretion from intestinal epithelial cells, which activates dendritic cells to promote T-cell polarization (54). However, our results showed that HAP-associated OMVs from El Tor strain C6709 failed to induce significant IL-8 secretion from T84 cells.…”

Section: Discussioncontrasting

confidence: 55%

Cytotoxic and Inflammatory Responses Induced by Outer Membrane Vesicle-Associated Biologically Active Proteases from Vibrio cholerae

et al. 2016

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e Proteases in Vibrio cholerae have been shown to play a role in its pathogenesis. V. cholerae secretes Zn-dependent hemagglutinin protease (HAP) and calcium-dependent trypsin-like serine protease (VesC) by using the type II secretion system (TIISS). Our present studies demonstrated that these proteases are also secreted in association with outer membrane vesicles (OMVs) and transported to human intestinal epithelial cells in an active form. OMV-associated HAP induces dose-dependent apoptosis in Int407 cells and an enterotoxic response in the mouse ileal loop (MIL) assay, whereas OMV-associated VesC showed a hemorrhagic fluid response in the MIL assay, necrosis in Int407 cells, and an increased interleukin-8 (IL-8) response in T84 cells, which were significantly reduced in OMVs from VesC mutant strain. Our results also showed that serine protease VesC plays a role in intestinal colonization of V. cholerae strains in adult mice. In conclusion, our study shows that V. cholerae OMVs secrete biologically active proteases which may play a role in cytotoxic and inflammatory responses. Vibrio cholerae is the causative agent of the life-threatening disease cholera. Cholera epidemics in Haiti in 2010 provide evidence that it still remains an ongoing public health threat (1). Strains of the El Tor biotype O1 serogroup are responsible for seventh pandemic and recent cholera outbreaks (2). Cholera toxin (CT) and toxin-coregulated pilus (TCP) have been identified as the major virulence factors for V. cholerae pathogenesis. CT is responsible for profuse watery diarrhea, whereas TCP is essential for sustaining colonization of human small intestine. V. cholerae also secretes several proteases which may also play a role in its pathogenesis (3).The major protease secreted by V. cholerae strains is the 35-kDa hemagglutinin protease (HAP) (4). HAP has been reported to accelerate the bacterial detachment from cultured cells by digestion of V. cholerae adhesins (5). HAP modulates the enterotoxigenicity of cholera toxin by nicking the A subunit of CT (6). HAP also plays a role in processing hemolysin to its mature form by removal of a 15-kDa N-terminal peptide (7). As shown in the above-mentioned studies, HAP plays an indirect role in V. cholerae pathogenesis. The possibility of its direct role in pathogenesis has been shown by Ghosh et al. (8). They reported that purified HAP from a V. cholerae non-O1, non-O139 strain showed a hemorrhagic response in rabbit ileal loops (RILs) and an increase in intestinal short-circuit current in Ussing's chamber (8). Besides HAP, the other major well-characterized metalloprotease is a 97-kDa Vibrio cholerae protease, PrtV which has been shown to play a role in virulence in the Caenorhabditis elegans infection model (9). In an earlier study, we also reported the presence of a novel serine protease encoded by VC1649 (VesC) in a hapA prtV mutant Vibrio cholerae O1 strain and showed its role in the hemorrhagic response in the rabbit ileal loop model (10).Gram-negative bacteria, including V. cholerae, us...

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“…Nevertheless, the interaction of MVs with intestinal epithelial cells have, surprisingly, been little studied, with only a recent investigation demonstrating that MVs isolated from the enteropathogen Vibrio cholerae elicit IL-8 from Int407 intestinal epithelial cells, via a NOD-1-mediated pathway (Chatterjee & Chaudhuri, 2013). In addition, despite the large population of Gramnegative bacteria present in the intestinal lumen, the immunological role of MVs produced by non-pathogenic enteric bacteria is yet to be elucidated.…”

Section: Membrane Vesicles (Mvs)mentioning

confidence: 99%

“…Additionally, MVs from P. aeruginosa have been shown to be potent activators of the proinflammatory response, stimulating the secretion of IL-8 in human lung epithelial cells (Bauman & Kuehn, 2006) and MIP-2 and IL-6 from murine macrophages (Ellis et al, 2010). Nevertheless, the interaction of MVs with intestinal epithelial cells have, surprisingly, been little studied, with only a recent investigation demonstrating that MVs isolated from the enteropathogen Vibrio cholerae elicit IL-8 from Int407 intestinal epithelial cells, via a NOD-1-mediated pathway (Chatterjee & Chaudhuri, 2013). In addition, despite the large population of Gramnegative bacteria present in the intestinal lumen, the immunological role of MVs produced by non-pathogenic enteric bacteria is yet to be elucidated.…”

Section: Membrane Vesicles (Mvs)mentioning

confidence: 99%

Exploring the immunomodulatory potential of microbial-associated molecular patterns derived from the enteric bacterial microbiota

Patten

Collett

2013

Microbiology

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The human intestinal lumen represents one of the most densely populated microbial niches in the biological world and, as a result, the intestinal innate immune system exists in a constant state of stimulation. A key component in the innate defence system is the intestinal epithelial layer, which acts not only as a physical barrier, but also as an immune sensor. The expression of pattern recognition receptors, such as Toll-like receptors, in epithelial cells allows innate recognition of a wide range of highly conserved bacterial moieties, termed microbial-associated molecular patterns (MAMPs), from both pathogenic and non-pathogenic bacteria. To date, studies of epithelial immunity have largely concentrated on inflammatory pathogenic antigens; however, this review discusses the major types of MAMPs likely to be produced by the enteric bacterial microbiota and, using data from in vitro studies, animal model systems and clinical observations, speculates on their immunomodulatory potential. IntroductionThe intestine represents the body's largest mucosal surface, with the adult human intestine estimated to cover an area of about 250 m 2 (Artis, 2008). The highly folded luminal surface of the intestinal wall significantly increases absorption efficiency and, as such, is the largest surface area of the body exposed to the environment and its high microbial load (DeSesso & Jacobson, 2001). Humans have co-evolved with indigenous microbial populations, termed microbiota, which inhabit various niches of the body (Hooper et al., 2012) and the adult intestine is one of the most densely populated microbial habitations in the biological world (Artis, 2008). The enteric microbiota predominantly consists of bacteria, with estimated populations of~10 14 bacteria, with up to 500 species represented (Gill et al., 2006;Guarner & Malagelada, 2003); however, methanogenic archaea, eukaryotes (yeasts) and viruses (mainly bacteriophages) are also present (Lozupone et al., 2012). Due to the vast expanse of intestinal tissue exposed to the microbiota, the local innate immune system is in a constant state of stimulation, and a chronic, low-level proinflammatory response is characteristic of enteric immune homeostasis (Macpherson & Harris, 2004;Artis, 2008).The intestinal epithelium plays an active role in innate immunity, and pattern recognition receptors (PRRs) are utilized to detect the presence of bacteria and their associated antigens. PRRs are germline-encoded, sensory molecules which recognize a range of highly conserved bacterial motifs, termed 'pathogen-associated molecular patterns' (PAMPs) (Medzhitov, 2001). However, the ability of PRRs to recognize these bacterial moieties is not limited to just pathogens, and so the term 'microbial-associated molecular patterns' (MAMPs) may be more accurate (Medzhitov, 2001; Sanderson & Walker, 2007) and will be used throughout this review. Epithelium-associated, enteric immune cells, such as macrophages, dendritic cells, T-cells and B-cells, differentially express two major groups of PRRs, th...

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Vibrio cholerae O395 Outer Membrane Vesicles Modulate Intestinal Epithelial Cells in a NOD1 Protein-dependent Manner and Induce Dendritic Cell-mediated Th2/Th17 Cell Responses

Cited by 73 publications

References 40 publications

Proteomic analysis of Vibrio cholerae outer membrane vesicles

Proteomic analysis of Vibrio cholerae outer membrane vesicles

Cytotoxic and Inflammatory Responses Induced by Outer Membrane Vesicle-Associated Biologically Active Proteases from Vibrio cholerae

Exploring the immunomodulatory potential of microbial-associated molecular patterns derived from the enteric bacterial microbiota

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