scholarly journals Neutrophils Are Essential for Containment of Vibrio cholerae to the Intestine during the Proinflammatory Phase of Infection

2012 ◽  
Vol 80 (8) ◽  
pp. 2905-2913 ◽  
Author(s):  
Jessica Queen ◽  
Karla J. Fullner Satchell
Keyword(s):  
Immune Response ◽  
Vibrio Cholerae ◽  
Diarrheal Disease ◽  
Innate Immune ◽  
Infection Model ◽  
Proinflammatory Response ◽  
Necrosis Factor Alpha ◽  
Live Attenuated Vaccine ◽  
Content Type

ABSTRACTCholera is classically considered a noninflammatory diarrheal disease, in comparison to invasive enteric organisms, although there is a low-level proinflammatory response during early infection withVibrio choleraeand a strong proinflammatory reaction to live attenuated vaccine strains. Using an adult mouse intestinal infection model, this study examines the contribution of neutrophils to host defense to infection. Nontoxigenic El Tor O1V. choleraeinfection is characterized by the upregulation of interleukin-6 (IL-6), IL-10, and macrophage inflammatory protein 2 alpha in the intestine, indicating an acute innate immune response. Depletion of neutrophils from mice with anti-Ly6G IA8 monoclonal antibody led to decreased survival of mice. The role of neutrophils in protection of the host is to limit the infection to the intestine and control bacterial spread to extraintestinal organs. In the absence of neutrophils, the infection spread to the spleen and led to increased systemic levels of IL-1β and tumor necrosis factor alpha, suggesting the decreased survival in neutropenic mice is due to systemic shock. Neutrophils were found not to contribute to either clearance of colonizing bacteria or to alter the local immune response. However, when genes for secreted accessory toxins were deleted, the colonizing bacteria were cleared from the intestine, and this clearance is dependent upon neutrophils. Thus, the requirement for accessory toxins in virulence is negated in neutropenic mice, which is consistent with a role of accessory toxins in the evasion of innate immune cells in the intestine. Overall, these data support that neutrophils impact disease progression and suggest that neutrophil effectiveness can be manipulated through the deletion of accessory toxins.

scholarly journals Promotion of Colonization and Virulence by Cholera Toxin Is Dependent on Neutrophils

2013 ◽  
Vol 81 (9) ◽  
pp. 3338-3345 ◽  
Author(s):  
Jessica Queen ◽  
Karla J. F. Satchell
Keyword(s):  
Immune Response ◽  
Cholera Toxin ◽  
Innate Immune Response ◽  
Host Response ◽  
Survival Rates ◽  
Innate Immune ◽  
Infection Model ◽  
High Dose ◽  
Content Type ◽  
Inflammatory Protein

ABSTRACTThe innate immune response toVibrio choleraeinfection is poorly understood, but this knowledge is critical for the design of safe, effective vaccines. Using an adult mouse intestinal infection model, this study examines the contribution of neutrophils to host immunity, as well as the effect of cholera toxin and other secreted factors on this response. Depletion of neutrophils from mice with anti-Ly6G IA8 monoclonal antibody led to similar survival rates of mice infected with low or moderate doses of toxigenicV. choleraeEl Tor O1. At a high dose, neutropenic mice showed increased rates of survival compared to neutrophil-replete animals. Expression of cholera toxin was found to be protective to the neutropenic host, and this phenotype can be replicated by the administration of purified toxin. Neutrophils do not effectively clear colonizing bacteria from the small intestine, nor do they alter induction of early immune-modulating signals. In both neutropenic and neutrophil-replete animals, the local response to infection is characterized by expression of interleukin 6 (IL-6), IL-10, and macrophage inflammatory protein 2 alpha (MIP-2). Overall, these data indicate that the innate immune response to toxigenicV. choleraeinfection differs dramatically from the host response to nontoxigenic infection or vaccination, where neutrophils are protective to the host. In the absence of neutrophils, cholera toxin induces immunomodulatory effects that increase host survival. In cholera toxin-producing strains, similar to nontoxigenic infection, accessory toxins are critical to virulence, indicating that cholera toxin and the other secreted toxins modulate the host response by different mechanisms, with both contributing to bacterial persistence and virulence.

scholarly journals Depletion of Complement Enhances the Clearance of Brucella abortus in Mice

2018 ◽  
Vol 86 (10) ◽  
Author(s):  
Gabriela González-Espinoza ◽  
Elías Barquero-Calvo ◽  
Esteban Lizano-González ◽  
Alejandro Alfaro-Alarcón ◽  
Berny Arias-Gómez ◽  
...  
Keyword(s):  
Immune System ◽  
Brucella Abortus ◽  
Innate Immune ◽  
Control Group ◽  
Bacterial Disease ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Brucellosis is a bacterial disease of animals and humans. Brucella abortus barely activates the innate immune system at the onset of infection, and this bacterium is resistant to the microbicidal action of complement. Since complement stands as the first line of defense during bacterial invasions, we explored the role of complement in B. abortus infections. Brucella abortus-infected mice depleted of complement with cobra venom factor (CVF) showed the same survival rate as mice in the control group. The complement-depleted mice readily eliminated B. abortus from the spleen and did so more efficiently than the infected controls after 7 days of infection. The levels of the proinflammatory cytokines tumor necrosis factor alpha and interleukin-6 (IL-6) remained within background levels in complement-depleted B. abortus-infected mice. In contrast, the levels of the immune activator cytokine gamma interferon and the regulatory cytokine IL-10 were significantly increased. No significant histopathological changes in the liver and spleen were observed between the complement-depleted B. abortus-infected mice and the corresponding controls. The action exerted by Brucella on the immune system in the absence of complement may correspond to a broader phenomenon that involves several components of innate immunity.

scholarly journals Interleukin-1 Receptor-Associated Kinase 4 Is Essential for Initial Host Control of Brucella abortus Infection

2011 ◽  
Vol 79 (11) ◽  
pp. 4688-4695 ◽  
Author(s):  
Fernanda S. Oliveira ◽  
Natália B. Carvalho ◽  
Ana Paula M. S. Brandão ◽  
Marco Túlio R. Gomes ◽  
Leonardo A. de Almeida ◽  
...  
Keyword(s):  
Immune Response ◽  
Brucella Abortus ◽  
Interleukin 1 ◽  
Bacterial Pathogen ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Ifn Γ

ABSTRACTBrucella abortusis a facultative intracellular bacterial pathogen that causes abortion in domestic animals and undulant fever in humans. Recent studies have revealed that Toll-like receptor (TLR)-initiated immune response toBrucellaspp. depends on myeloid differentiation factor 88 (MyD88) signaling. Therefore, we decided to study the role of the interleukin-1 receptor-associated kinase 4 (IRAK-4) in host innate immune response againstB. abortus. AfterBrucellainfection, it was shown that the number of CFU in IRAK-4−/−mice was high compared to that in IRAK-4+/−animals only at 1 week postinfection. At 3 and 6 weeks postinfection, IRAK-4−/−mice were able to control the infection similarly to heterozygous animals. Furthermore, the type 1 cytokine profile was evaluated. IRAK-4−/−mice showed lower production of systemic interleukin-12 (IL-12) and gamma interferon (IFN-γ). Additionally, a reduced percentage of CD4+and CD8+T cells expressing IFN-γ was observed compared to IRAK-4+/−. Further, the production of IL-12 and tumor necrosis factor alpha (TNF-α) by macrophages and dendritic cells from IRAK-4−/−mice was abolished at 24 h after stimulation withB. abortus. To investigate the role of IRAK-4 in mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways, macrophages were stimulated withB. abortus, and the signaling components were analyzed by protein phosphorylation. Extracellular signal-regulated kinase 1 (ERK1) and ERK2 and p38 as well as p65 NF-κB phosphorylation was profoundly impaired in IRAK-4−/−and MyD88−/−macrophages activated byBrucella. In summary, the results shown in this study demonstrated that IRAK-4 is critical to trigger the initial immune response againstB. abortusbut not at later phases of infection.

scholarly journals TREM-1 Signaling Promotes Host Defense during the Early Stage of Infection with Highly Pathogenic Streptococcus suis

2015 ◽  
Vol 83 (8) ◽  
pp. 3293-3301 ◽  
Author(s):  
Chao Yang ◽  
Bo Chen ◽  
Jianqing Zhao ◽  
Lan Lin ◽  
Li Han ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Opposite Effect ◽  
Early Stage ◽  
Streptococcus Suis ◽  
Innate Immune ◽  
Proinflammatory Response ◽  
Highly Pathogenic ◽  
Content Type ◽  
Pathogen Clearance

Infection with highly pathogenicStreptococcus suiscan cause septic shock, which is characterized by high levels of inflammatory cytokines and a high mortality rate. Our previous study indicated that TREM-1 (triggering receptor expressed on myeloid cells 1) was upregulated in swine spleen cells in response toS. suisinfection. The role of TREM-1 signaling in enhancement of the proinflammatory response promoted us to examine its effect on the outcome ofS. suisinfection. In the present study, the recombinant extracellular domain of TREM-1 (rTREM-1) and an agonistic TREM-1 antibody were used to inhibit and activate TREM-1 signaling to evaluate its role in neutrophil activation, pathogen clearance, proinflammatory cytokine response, and the outcome of highly pathogenicS. suisinfection in a mouse model. Blockage of TREM-1 signaling caused a more severe proinflammatory response toS. suisinfection and increased the mortality rate, while its activation had the opposite effect. Blockage or activation of TREM-1 signaling lowered or raised the number of neutrophils in the blood, which correlated well with host clearance ofS. suis. In conclusion, the TREM-1-mediated innate immune response played an essential role in the activation of neutrophils andS. suisclearance, which further reduced severe inflammation and finally benefited the outcome of the infection.

scholarly journals Calcium Enhances Bile Salt-Dependent Virulence Activation in Vibrio cholerae

2016 ◽  
Vol 85 (1) ◽  
Author(s):  
Amanda J. Hay ◽  
Menghua Yang ◽  
Xiaoyun Xia ◽  
Zhi Liu ◽  
Justin Hammons ◽  
...  
Keyword(s):  
Bile Salt ◽  
Vibrio Cholerae ◽  
Bile Salts ◽  
Diarrheal Disease ◽  
Content Type ◽  
Inner Membrane Protein ◽  
Virulence Regulator ◽  
Host Signals

ABSTRACT Vibrio cholerae is the causative bacteria of the diarrheal disease cholera, but it also persists in aquatic environments, where it displays an expression profile that is distinct from that during infection. Upon entry into the host, a tightly regulated circuit coordinates the induction of two major virulence factors: cholera toxin and a toxin-coregulated pilus (TCP). It has been shown that a set of bile salts, including taurocholate, serve as host signals to activate V. cholerae virulence through inducing the activity of the transmembrane virulence regulator TcpP. In this study, we investigated the role of calcium, an abundant mental ion in the gut, in the regulation of virulence. We show that whereas Ca2+ alone does not affect virulence, Ca2+ enhances bile salt-dependent virulence activation for V. cholerae. The induction of TCP by murine intestinal contents is counteracted when Ca2+ is depleted by the high-affinity calcium chelator EGTA, suggesting that the calcium present in the gut is a relevant signal for V. cholerae virulence induction in vivo. We further show that Ca2+ enhances virulence by promoting bile salt-induced TcpP-TcpP interaction. Moreover, fluorescence recovery after photobleaching (FRAP) analysis demonstrated that exposure to bile salts and Ca2+ together decreases the recovery rate for fluorescently labeled TcpP, but not for another inner membrane protein (TatA). Together, these data support a model in which physiological levels of Ca2+ may result in altered bile salt-induced TcpP protein movement and activity, ultimately leading to an increased expression of virulence.

scholarly journals Receptor-Interacting Protein 2 Controls Pulmonary Host Defense to Escherichia coli Infection via the Regulation of Interleukin-17A

2011 ◽  
Vol 79 (11) ◽  
pp. 4588-4599 ◽  
Author(s):  
Theivanthiran Balamayooran ◽  
Sanjay Batra ◽  
Gayathriy Balamayooran ◽  
Shanshan Cai ◽  
Koichi S. Kobayashi ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Host Defense ◽  
Adhesion Molecule ◽  
Intercellular Adhesion Molecule ◽  
Infection Model ◽  
Necrosis Factor Alpha ◽  
Interacting Protein ◽  
Gram Negative ◽  
Content Type

ABSTRACTRecognition of microbial patterns by host receptors is the first step in a multistep sequence leading to neutrophil-dependent host resistance. Although the role of membrane-bound sensors in bacterial recognition has been examined in detail, the importance of cytosolic sensors in the lungs is largely unexplored. In this context, there is a major lack of understanding related to the downstream signaling mediators, such as cells and/or molecules, during acute extracellular Gram-negative bacterial pneumonia. In order to determine the role of NOD-like receptors (NLRs), we used an experimentalEscherichia coliinfection model using mice deficient in the gene coding for the NLR adaptor, receptor-interacting protein 2 (RIP2). RIP2−/−mice withE. coliinfection displayed higher bacterial burden and reduced neutrophil recruitment and tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), macrophage inflammatory protein 2 (MIP-2), and CXCL5/LIX expression, along with attenuated histopathological changes in the lungs. Decreased IL-17A levels were observed, along with lower numbers of IL-17A-producing T cells, in RIP2−/−mice after infection. RIP2−/−mice also show reduced IL-6 and IL-23 levels in the lungs, along with decreased activation of STAT3 after infection. Furthermore, activation of NF-κB and mitogen-activated protein kinases (MAPKs) and expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in the lungs of infected RIP2−/−mice were attenuated following infection. Although neutrophil mobilization to the blood was impaired in RIP2−/−mice following infection, the expression of CD62P, CD11a/18, CD11b, and CXCR2 on blood and lung neutrophils was not altered between infected wild-type (WT) and RIP2−/−mice. Thus, RIP2 contributes to neutrophil-dependent host defense against an extracellular Gram-negative pathogen via (i) IL-17A regulation and (ii) neutrophil mobilization to the blood.

scholarly journals Role of Toll-Like Receptor 4 in the Proinflammatory Response to Vibrio cholerae O1 El Tor Strains Deficient in Production of Cholera Toxin and Accessory Toxins

2005 ◽  
Vol 73 (9) ◽  
pp. 6157-6164 ◽  
Author(s):  
G. Kenneth Haines ◽  
Blayne Amir Sayed ◽  
Melissa S. Rohrer ◽  
Verena Olivier ◽  
Karla J. Fullner Satchell
Keyword(s):  
Vibrio Cholerae ◽  
Toll Like Receptor ◽  
Proinflammatory Response ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Vibrio Cholerae O1 ◽  
Factor Alpha ◽  
El Tor ◽  
Necrosis Factor

ABSTRACT Following intranasal inoculation, Vibrio cholerae KFV101 (ΔctxAB ΔhapA ΔhlyA ΔrtxA) colonizes and stimulates tumor necrosis factor alpha and interleukin 1β (IL-1β) in mice, similar to what occurs with isogenic strain P4 (ΔctxAB), but is less virulent and stimulates reduced levels of IL-6, demonstrating a role for accessory toxins in pathogenesis. Morbidity is enhanced in C3H/HeJ mice, indicating that Toll-like receptor 4 is important for infection containment.

scholarly journals CD38 Controls the Innate Immune Response against Listeria monocytogenes

2013 ◽  
Vol 81 (11) ◽  
pp. 4091-4099 ◽  
Author(s):  
Timo Lischke ◽  
Kira Heesch ◽  
Valéa Schumacher ◽  
Michael Schneider ◽  
Friedrich Haag ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Listeria Monocytogenes ◽  
Innate Immune Response ◽  
Cell Activation ◽  
Cell Types ◽  
Innate Immune ◽  
Infection Model ◽  
Content Type ◽  
Inflammatory Monocytes

ABSTRACTCD38, adenosine-5′-diphosphate-ribosyl cyclase 1, is a multifunctional enzyme, expressed on a wide variety of cell types. CD38 has been assigned diverse functions, including generation of calcium-mobilizing metabolites, cell activation, and chemotaxis. Using a murineListeria monocytogenesinfection model, we found that CD38 knockout (KO) mice were highly susceptible to infection. Enhanced susceptibility was already evident within 3 days of infection, suggesting a function of CD38 in the innate immune response. CD38 was expressed on neutrophils and inflammatory monocytes, and especially inflammatory monocytes further upregulated CD38 during infection. Absence of CD38 caused alterations of the migration pattern of both cell types to sites of infection. We observed impaired accumulation of cells in the spleen but surprisingly similar or even higher accumulation of cells in the liver. CD38 KO and wild-type mice showed similar changes in the composition of neutrophils and inflammatory monocytes in blood and bone marrow, indicating that mobilization of these cells from the bone marrow was CD38 independent.In vitro, macrophages of CD38 KO mice were less efficient in uptake of listeria but still able to kill the bacteria. Dendritic cells also displayed enhanced CD38 expression following infection. However, absence of CD38 did not impair the capacity of mice to prime CD8+T cells againstL. monocytogenes, and CD38 KO mice could efficiently control secondary listeria infection. In conclusion, our results demonstrate an essential role for CD38 in the innate immune response againstL. monocytogenes.

scholarly journals Sublingual Adjuvant Delivery by a Live AttenuatedVibrio cholerae-Based Antigen Presentation Platform

mSphere ◽  
2018 ◽  
Vol 3 (3) ◽  
Author(s):  
Julie Liao ◽  
Jacob A. Gibson ◽  
Bradley S. Pickering ◽  
Paula I. Watnick
Keyword(s):  
Immune Response ◽  
Antigen Presentation ◽  
Vibrio Cholerae ◽  
Matrix Protein ◽  
Diarrheal Disease ◽  
Mucosal Immune Response ◽  
Mucosal Adjuvant ◽  
Content Type ◽  
Heterologous Antigens ◽  
Biofilm Matrix

ABSTRACTA sublingually delivered heterologous antigen presentation platform that does not depend on antigen or adjuvant purification would be of great benefit in protection against diarrheal disease. In proof-of-concept studies, we previously showed that when a fusion protein comprised of theVibrio choleraebiofilm matrix protein RbmA and the B subunit of cholera toxin (R-CTB) is expressed from a plasmid withinV. cholerae, R-CTB is sequestered in the biofilm matrix, leading to decoration of the cell surface. Sublingual delivery of live attenuated R-CTB-decorated cells results in a mucosal immune response to CTB. To improve the immune response to diarrheal antigens presented by this platform, we have engineered our live attenuated vaccine to express the mucosal adjuvant mmCT (i.e., multiply mutated CT). Here we report that delivery of this adjuvant via sublingual administration of our vaccine enhances the mucosal immune response toV. choleraeLPS and elicits a systemic and mucosal immune response to CTB. However, provision of R-CTB with mmCT selectively blunts the mucosal immune response to CTB. We propose that mmCT delivered by this live attenuatedVibrio choleraevaccine platform may serve as a mucosal adjuvant for heterologous antigens, provided they are not too similar to mmCT.IMPORTANCEDiarrheal disease is the most common infectious disease of children in the developing world. Our goal is to develop a diarrheal antigen presentation platform based on wholeVibrio choleraecells that does not depend on protein purification. We have previously shown the feasibility of genetically fusing antigens to theV. choleraebiofilm matrix protein RbmA for presentation on the cell surface. A mucosal adjuvant could improve immunogenicity of such a vaccine at the mucosal surface. Here we engineer a live attenuatedV. choleraevaccine to constitutively synthesize mmCT, a nontoxic form of cholera toxin. When this vaccine is delivered sublingually,in vivo-synthesized mmCT acts as both an adjuvant and antigen. This could greatly increase the magnitude and duration of the immune response elicited by codelivered heterologous antigens.

scholarly journals Role of Zooplankton Diversity in Vibrio cholerae Population Dynamics and in the Incidence of Cholera in the Bangladesh Sundarbans

2011 ◽  
Vol 77 (17) ◽  
pp. 6125-6132 ◽  
Author(s):  
Guillaume Constantin de Magny ◽  
Pronob K. Mozumder ◽  
Christopher J. Grim ◽  
Nur A. Hasan ◽  
M. Niamul Naser ◽  
...  
Keyword(s):  
Population Dynamics ◽  
Vibrio Cholerae ◽  
Diarrheal Disease ◽  
Ecological Factors ◽  
Crustacean Zooplankton ◽  
Content Type ◽  
Life Threatening ◽  
Bodies Of Water ◽  
Zooplankton Communities

ABSTRACTVibrio cholerae, a bacterium autochthonous to the aquatic environment, is the causative agent of cholera, a severe watery, life-threatening diarrheal disease occurring predominantly in developing countries.V. cholerae, including both serogroups O1 and O139, is found in association with crustacean zooplankton, mainly copepods, and notably in ponds, rivers, and estuarine systems globally. The incidence of cholera and occurrence of pathogenicV. choleraestrains with zooplankton were studied in two areas of Bangladesh: Bakerganj and Mathbaria. Chitinous zooplankton communities of several bodies of water were analyzed in order to understand the interaction of the zooplankton population composition with the population dynamics of pathogenicV. choleraeand incidence of cholera. Two dominant zooplankton groups were found to be consistently associated with detection ofV. choleraeand/or occurrence of cholera cases, namely, rotifers and cladocerans, in addition to copepods. Local differences indicate there are subtle ecological factors that can influence interactions betweenV. cholerae, its plankton hosts, and the incidence of cholera.

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