scholarly journals Cellular Requirements for Systemic Control of Salmonella enterica Serovar Typhimurium Infections in Mice

2014 ◽  
Vol 82 (12) ◽  
pp. 4997-5004 ◽  
Author(s):  
Andreas Kupz ◽  
Sammy Bedoui ◽  
Richard A. Strugnell
Keyword(s):  
T Cell ◽  
Salmonella Enterica ◽  
Rational Design ◽  
Immune Cell ◽  
Early Death ◽  
Content Type ◽  
Immune Cell Subsets ◽  
Serovar Typhimurium ◽  
Ifn Γ ◽  
High Level

ABSTRACTThe rational design of vaccines requires an understanding of the contributions of individual immune cell subsets to immunity. With this understanding, targeted vaccine delivery approaches and adjuvants can be developed to maximize vaccine efficiency and to minimize side effects (S. H. E. Kaufmann et al., Immunity 33:555–577, 2010; T. Ben-Yedidia and R. Arnon, Hum. Vaccines 1:95–101, 2005). We have addressed the contributions of different immune cell subsets and their ability to contribute to the control and clearance of the facultative intracellular pathogenSalmonella entericaserovar Typhimurium (S. Typhimurium) in a murine model. Using a systematic and reproducible model of experimental attenuatedS. Typhimurium infection, we show that distinct lymphocyte deficiencies lead to one of four different infection outcomes: clearance, chronic infection, early death, or late death. Our study demonstrates a high level of functional redundancy in the ability of different lymphocyte subsets to provide interferon gamma (IFN-γ), a critical cytokine inSalmonellaimmunity. Whereas early control of the infection was entirely dependent on IFN-γ but not on any particular lymphocyte subset, clearance of the infection critically required CD4+T cells but appeared to be independent of IFN-γ. These data reinforce the idea of a bimodal immune response againstSalmonella: an early T cell-independent but IFN-γ-dependent phase and a late T cell-dependent phase that may be IFN-γ independent.

scholarly journals Flagellin from Recombinant Attenuated Salmonella enterica Serovar Typhimurium Reveals a Fundamental Role in Chicken Innate Immunity

2012 ◽  
Vol 19 (3) ◽  
pp. 304-312 ◽  
Author(s):  
Zhiming Pan ◽  
Qiuxia Cong ◽  
Shizhong Geng ◽  
Qiang Fang ◽  
Xilong Kang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune Responses ◽  
Salmonella Enterica ◽  
Rational Design ◽  
Bacterial Load ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Content Type ◽  
Serovar Typhimurium

ABSTRACTRecombinant attenuatedSalmonellavaccines have been extensively studied, with a focus on eliciting specific immune responses against foreign antigens. However, very little is known about the innate immune responses, particularly the role of flagellin, in the induction of innate immunity triggered by recombinant attenuatedSalmonellain chickens. In the present report, we describe twoSalmonella entericaserovar Typhimurium vaccine strains, wild-type (WT) or flagellin-deficient (flhD)Salmonella, both expressing the fusion protein (F) gene of Newcastle disease virus. We examined the bacterial load and spatiotemporal kinetics of expression of inflammatory cytokine, chemokine, and Toll-like receptor 5 (TLR5) genes in the cecum, spleen, liver, and heterophils following oral immunization of chickens with the twoSalmonellastrains. TheflhDmutant exhibited an enhanced ability to establish systemic infection compared to the WT. In contrast, the WT strain induced higher levels of interleukin-1β (IL-1β), CXCLi2, and TLR5 mRNAs in cecum, the spleen, and the heterophils than theflhDmutant at different times postinfection. Collectively, the present data reveal a fundamental role of flagellin in the innate immune responses induced by recombinant attenuatedSalmonellavaccines in chickens that should be considered for the rational design of novel vaccines for poultry.

scholarly journals Neutrophils Are a Source of Gamma Interferon during Acute Salmonella enterica Serovar Typhimurium Colitis

2014 ◽  
Vol 82 (4) ◽  
pp. 1692-1697 ◽  
Author(s):  
Alanna M. Spees ◽  
Dawn D. Kingsbury ◽  
Tamding Wangdi ◽  
Mariana N. Xavier ◽  
Renée M. Tsolis ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Intestinal Inflammation ◽  
Gamma Interferon ◽  
Content Type ◽  
Inflammatory Monocytes ◽  
Intestinal Lesions ◽  
Serovar Typhimurium ◽  
Cellular Source ◽  
Ifn Γ ◽  
Cecal Mucosa

ABSTRACTGamma interferon (IFN-γ) is an important driver of intestinal inflammation during colitis caused bySalmonella entericaserovar Typhimurium. Here we used the mouse colitis model to investigate the cellular sources of IFN-γ in the cecal mucosa during the acute phase of anS. Typhimurium infection. While IFN-γ staining was detected in T cells, NK cells, and inflammatory monocytes at 2 days after infection, the majority of IFN-γ-positive cells in the cecal mucosa were neutrophils. Furthermore, neutrophil depletion blunted mucosalIfngexpression and reduced the severity of intestinal lesions duringS. Typhimurium infection. We conclude that neutrophils are a prominent cellular source of IFN-γ during the innate phase ofS. Typhimurium-induced colitis.

scholarly journals Tpl2 Promotes Innate Cell Recruitment and Effector T Cell Differentiation To Limit Citrobacter rodentium Burden and Dissemination

2017 ◽  
Vol 85 (10) ◽  
Author(s):  
Nicole V. Acuff ◽  
Xin Li ◽  
Krishna Latha ◽  
Tamas Nagy ◽  
Wendy T. Watford
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Immune Cell ◽  
Cd4 T Cell ◽  
Citrobacter Rodentium ◽  
Wild Type ◽  
Content Type ◽  
Cell Recruitment ◽  
Ifn Γ

ABSTRACT Tumor progression locus 2 (Tpl2) is a serine-threonine kinase that regulates Th1 differentiation, secretion of the inflammatory cytokine gamma interferon (IFN-γ), and host defense against the intracellular pathogens Toxoplasma gondii, Listeria monocytogenes, and Mycobacterium tuberculosis. However, relatively little is known about the contribution of Tpl2 to Th17 differentiation and immune cell function during infection with an extracellular pathogen. The goal of this study was to determine whether Tpl2 influences the immune response generated to the extracellular bacterium Citrobacter rodentium, which induces a mixed Th1 and Th17 response. During peak infection with C. rodentium, Tpl2 −/− mice experienced greater bacterial burdens with evidence of dissemination to the liver and spleen but ultimately cleared the bacteria within 3 weeks postinfection, similar to the findings for wild-type mice. Tpl2 −/− mice also recruited fewer neutrophils and monocytes to the colon during peak infection, which correlated with increased bacterial burdens. In mixed bone marrow chimeras, Tpl2 was shown to play a T cell-intrinsic role in promoting both IFN-γ and interleukin-17A production during infection with C. rodentium. However, upon CD4 T cell transfer into Rag −/− mice, Tpl2 −/− CD4 T cells were as protective as wild-type CD4 T cells against the dissemination of bacteria and mortality. These data indicate that the enhanced bacterial burdens in Tpl2 −/− mice are not caused primarily by impairments in CD4 T cell function but result from defects in innate immune cell recruitment and function.

scholarly journals In Vivo Compartmentalization of Functionally Distinct, Rapidly Responsive Antigen-Specific T-Cell Populations in DNA-Immunized or Salmonella enterica Serovar Typhimurium-Infected Mice

2004 ◽  
Vol 72 (11) ◽  
pp. 6390-6400 ◽  
Author(s):  
Alun C. Kirby ◽  
Malin Sundquist ◽  
Mary Jo Wick
Keyword(s):  
T Cells ◽  
T Cell ◽  
Salmonella Enterica ◽  
Memory T Cells ◽  
Cell Populations ◽  
Memory T Cell ◽  
Specific Memory ◽  
Tnf Α ◽  
Serovar Typhimurium ◽  
Ifn Γ

ABSTRACT The location and functional properties of antigen-specific memory T-cell populations in lymphoid and nonlymphoid compartments following DNA immunization or infection with Salmonella were investigated. Epitope-specific CD8+-T-cell expansion and retention during the memory phase were analyzed for DNA-immunized mice by use of a 5-h peptide restimulation assay. These data revealed that epitope-specific gamma interferon (IFN-γ)-positive CD8+ T cells occur at higher frequencies in the spleen, liver, and blood than in draining or peripheral lymph nodes during the expansion phase. Moreover, this distribution is maintained into long-term memory. The location and function of both CD4+ and CD8+ Salmonella-specific memory T cells in mice who were given a single dose of Salmonella enterica serovar Typhimurium was also quantitated by an ex vivo restimulation with bacterial lysate to detect the total Salmonella-specific memory pool. Mice immunized up to 6 months previously with S. enterica serovar Typhimurium had bacterium-specific CD4+ T cells that were capable of producing IFN-γ or tumor necrosis factor alpha (TNF-α) at each site analyzed. Similar findings were observed for CD8+ T cells that were capable of producing IFN-γ, while a much lower frequency and more restricted distribution were associated with TNF-α-producing CD8+ T cells. This study is the first to assess the frequencies, locations, and functions of both CD4+ and CD8+ memory T-cell populations in the same Salmonella-infected individuals and demonstrates the organ-specific functional compartmentalization of memory T cells after Salmonella infection.

scholarly journals Characterization of the Murine T-Lymphocyte Response to Salmonella enterica Serovar Typhimurium Infection

2002 ◽  
Vol 70 (1) ◽  
pp. 199-203 ◽  
Author(s):  
Hans-Willi Mittrücker ◽  
Anne Köhler ◽  
Stefan H. E. Kaufmann
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Salmonella Enterica ◽  
Large Population ◽  
T Cell Response ◽  
Brdu Incorporation ◽  
Cell Populations ◽  
Serovar Typhimurium ◽  
Ifn Γ

ABSTRACT Infection of mice with Salmonella enterica serotype Typhimurium induces a strong Th1 cell response that is central for the control of infection. We infected mice of a resistant background with a virulent strain of S. enterica serovar Typhimurium and analyzed the kinetics and magnitude of the T-cell response. After infection, the majority of CD4+ and CD8+ splenocytes acquired an activated phenotype, as indicated by expression levels of CD44 and CD62L. In addition, after 3 to 4 weeks of infection, more than 20% of the CD4+ and more than 30% of the CD8+ T cells produced gamma interferon (IFN-γ) in response to short-term polyclonal stimulation. In contrast, we detected only a moderate (two- to threefold) expansion of both T-cell populations, and BrdU incorporation revealed that there was either no or only a limited increase in the in vivo proliferation of CD4+ and CD8+ T cells, respectively. Our results indicate that although an unexpectedly large population of both CD4+ and CD8+ T cells is activated and acquires the potential to secrete IFN-γ, this activation is not paralleled by substantial expansion of these T-cell populations.

scholarly journals In Vivo Activation of Dendritic Cells and T Cells during Salmonella enterica Serovar Typhimurium Infection

2001 ◽  
Vol 69 (9) ◽  
pp. 5726-5735 ◽  
Author(s):  
Ulf Yrlid ◽  
Mattias Svensson ◽  
Anders Håkansson ◽  
Benedict J. Chambers ◽  
Hans-Gustaf Ljunggren ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Salmonella Enterica ◽  
T Cell Subsets ◽  
Effector Cells ◽  
Mhc Ii ◽  
Serovar Typhimurium ◽  
Ifn Γ

ABSTRACT The present study was initiated to gain insight into the interaction between splenic dendritic cells (DC) and Salmonella enterica serovar Typhimurium in vivo. Splenic phagocytic cell populations associated with green fluorescent protein (GFP)-expressing bacteria and the bacterium-specific T-cell response were evaluated in mice given S. enterica serovar Typhimurium expressing GFP and ovalbumin. Flow cytometry analysis revealed that GFP-positive splenic DC (CD11c+ major histocompatibility complex class II-positive [MHC-II+] cells) were present following bacterial administration, and confocal microscopy showed that GFP-expressing bacteria were contained within CD11c+MHC-II+ splenocytes. Furthermore, splenic DC and T cells were activated following Salmonella infection. This was shown by increased surface expression of CD86 and CD40 on CD11c+ MHC-II+ cells and increased CD44 and CD69 expression on CD4+ and CD8+ T cells.Salmonella-specific gamma interferon (IFN-γ)-producing cells in both of these T-cell subsets, as well as cytolytic effector cells, were also generated in mice given live bacteria. The frequency of Salmonella-specific CD4+ T cells producing IFN-γ was greater than that of specific CD8+ T cells producing IFN-γ in the same infected animal. This supports the argument that the predominant source of IFN-γ production by cells of the specific immune response is CD4+ T cells. Finally, DC that phagocytosed live or heat-killed Salmonella in vitro primed bacterium-specific IFN-γ-producing CD4+ and CD8+ T cells as well as cytolytic effector cells following administration into naı̈ve mice. Together these data suggest that DC are involved in priming naı̈ve T cells toSalmonella in vivo.

scholarly journals Small Intestinal Intraepithelial Lymphocytes Expressing CD8 and T Cell Receptor γδ Are Involved in Bacterial Clearance during Salmonella enterica Serovar Typhimurium Infection

2011 ◽  
Vol 80 (2) ◽  
pp. 565-574 ◽  
Author(s):  
Zhiyuan Li ◽  
Cai Zhang ◽  
Zhixia Zhou ◽  
Jianhua Zhang ◽  
Jian Zhang ◽  
...  
Keyword(s):  
Immune System ◽  
T Cell ◽  
Epithelial Cells ◽  
Salmonella Enterica ◽  
Intraepithelial Lymphocytes ◽  
Oral Infection ◽  
Content Type ◽  
Intestinal Intraepithelial Lymphocytes ◽  
Intestinal Immune System ◽  
Serovar Typhimurium

ABSTRACTThe intestinal immune system is crucial for the maintenance of mucosal homeostasis and has evolved under the dual pressure of protecting the host from pathogenic infection and coexisting with the dense and diverse commensal organisms in the lumen. Intestinal intraepithelial lymphocytes (iIELs) are the first element of the host T cell compartment available to respond to oral infection by pathogens. This study demonstrated that oral infection bySalmonella entericaserovar Typhimurium promoted the expansion of iIELs, particularly CD8+TCRγδ+IELs, enhanced expression of NKG2D on iIELs, increased expression of MULT1, and decreased expression of Qa-1 by intestinal epithelial cells (IECs), leading to activation of, particularly, CD8+TCRγδ+iIELs and cytolytic activity againstS. Typhimurium-infected IECs. Blockade of NKG2D recognition or depletion of TCRγδ+cells using a depleting monoclonal antibody significantly attenuated the clearance ofS. Typhimuriumin the intestine and other tissues. This study suggests that iIELs, particularly CD8+TCRγδ+iIELs, play important roles in the detection of pathogenic bacteria and eradication of infected epithelial cells and, thus, provide protection against invading pathogens. These data further our understanding of the mechanisms by which the immune system of the intestinal mucosa discriminates between pathogenic and commensal organisms.

scholarly journals Toll-Like Receptor 5-Dependent Immunogenicity and Protective Efficacy of a Recombinant Fusion Protein Vaccine Containing the Nontoxic Domains of Clostridium difficile Toxins A and B and Salmonella enterica Serovar Typhimurium Flagellin in a Mouse Model of Clostridium difficile Disease

2013 ◽  
Vol 81 (6) ◽  
pp. 2190-2196 ◽  
Author(s):  
Chandrabali Ghose ◽  
Janneke M. Verhagen ◽  
Xinhua Chen ◽  
Jian Yu ◽  
Yaoxing Huang ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Mouse Model ◽  
Salmonella Enterica ◽  
Animal Studies ◽  
Protective Efficacy ◽  
Protein Vaccine ◽  
Content Type ◽  
Serovar Typhimurium ◽  
Toll Like Receptor 5 ◽  
High Level

ABSTRACTClostridium difficileis a spore-forming bacillus that produces toxin-mediated enteric disease.C. difficileexpresses two major virulence factors, toxin A (TcdA) and toxin B (TcdB). Human and animal studies demonstrate a clear association between humoral immunity to these toxins and protection againstC. difficileinfection (CDI). The receptor binding-domains (RBDs) of TcdA and TcdB are known to be immunogenic. Here, we tested the immunoadjuvant properties ofSalmonella entericaserovar Typhimurium flagellin (FliC) subunit D1 as an innate immune agonist expressed as a recombinant fusion vaccine targeting the RBDs of TcdA and TcdB in mice. Intraperitoneally immunized mice developed prominent anti-TcdA and anti-TcdB immunoglobulin G in serum. The protective efficacy of the recombinant vaccines, with or without an adjuvant, was tested in a mouse model of CDI that closely represents the human disease. Following intraperitoneal immunization equivalent to two doses of toxoid A and toxoid B vaccine adjuvanted with alum and oral challenge withC. difficileVPI 10463, C57BL/6 mice were able to mount a protective immune response that prevented diarrhea and death compared to mice immunzed with alum alone. These results are significantly different from those for control mice (P< 0.001). These results provide evidence that a recombinant protein-based vaccine targeting the RBDs of theC. difficiletoxins adjuvanted withS. Typhimurium flagellin can induce rapid, high-level protection in a mouse model of CDI when challenged with the homologous strain from which the vaccine antigens were derived and warrant further preclinical testing against clinically relevantC. difficilestrains in the mouse and hamster models of CDI.

scholarly journals CCL19 enhances CD8+ T-cell responses and accelerates HBV clearance

2021 ◽  
Author(s):  
Yan Yan ◽  
Wei Zhao ◽  
Wei Liu ◽  
Yan Li ◽  
Xu Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Crucial Role ◽  
Cell Activation ◽  
Hbv Infection ◽  
Host Immune System ◽  
Tnf Α ◽  
Ifn Γ ◽  
High Level

Abstract Background Chemokine (C–C motif) ligand 19 (CCL19) is a leukocyte chemoattractant that plays a crucial role in cell trafficking and leukocyte activation. Dysfunctional CD8+ T cells play a crucial role in persistent HBV infection. However, whether HBV can be cleared by CCL19-activated immunity remains unclear. Methods We assessed the effects of CCL19 on the activation of PBMCs in patients with HBV infection. We also examined how CCL19 influences HBV clearance and modulates HBV-responsive T cells in a mouse model of chronic hepatitis B (CHB). In addition, C–C chemokine-receptor type 7 (CCR7) knockdown mice were used to elucidate the underlying mechanism of CCL19/CCR7 axis-induced immune activation. Results From in vitro experiments, we found that CCL19 enhanced the frequencies of Ag-responsive IFN-γ+ CD8+ T cells from patients by approximately twofold, while CCR7 knockdown (LV-shCCR7) and LY294002 partially suppressed IFN-γ secretion. In mice, CCL19 overexpression led to rapid clearance of intrahepatic HBV likely through increased intrahepatic CD8+ T-cell proportion, decreased frequency of PD-1+ CD8+ T cells in blood and compromised suppression of hepatic APCs, with lymphocytes producing a significantly high level of Ag-responsive TNF-α and IFN-γ from CD8+ T cells. In both CCL19 over expressing and CCR7 knockdown (AAV-shCCR7) CHB mice, the frequency of CD8+ T-cell activation-induced cell death (AICD) increased, and a high level of Ag-responsive TNF-α and low levels of CD8+ regulatory T (Treg) cells were observed. Conclusions Findings in this study provide insights into how CCL19/CCR7 axis modulates the host immune system, which may promote the development of immunotherapeutic strategies for HBV treatment by overcoming T-cell tolerance.

scholarly journals Efficiency of Conditionally Attenuated Salmonella enterica Serovar Typhimurium in Bacterium-Mediated Tumor Therapy

mBio ◽  
2015 ◽  
Vol 6 (2) ◽  
Author(s):  
Michael Frahm ◽  
Sebastian Felgner ◽  
Dino Kocijancic ◽  
Manfred Rohde ◽  
Michael Hensel ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Tumor Targeting ◽  
Antitumor Effect ◽  
Treatment Options ◽  
Tumor Therapy ◽  
Therapeutic Benefit ◽  
Industrialized Countries ◽  
Content Type ◽  
Serovar Typhimurium ◽  
Therapeutic Molecules

ABSTRACTIncreasing numbers of cancer cases generate a great urge for new treatment options. Applying bacteria likeSalmonella entericaserovar Typhimurium for cancer therapy represents an intensively explored option. These bacteria have been shown not only to colonize solid tumors but also to exhibit an intrinsic antitumor effect. In addition, they could serve as tumor-targeting vectors for therapeutic molecules. However, the pathogenicS. Typhimurium strains used for tumor therapy need to be attenuated for safe application. Here, lipopolysaccharide (LPS) deletion mutants (ΔrfaL, ΔrfaG, ΔrfaH, ΔrfaD, ΔrfaP, and ΔmsbBmutants) ofSalmonellawere investigated for efficiency in tumor therapy. Of such variants, the ΔrfaDand ΔrfaGdeep rough mutants exhibited the best tumor specificity and lowest pathogenicity. However, the intrinsic antitumor effect was found to be weak. To overcome this limitation, conditional attenuation was tested by complementing the mutants with an inducible arabinose promoter. The chromosomal integration of the respective LPS biosynthesis genes into thearaBADlocus exhibited the best balance of attenuation and therapeutic benefit. Thus, the present study establishes a basis for the development of an applicably cancer therapeutic bacterium.IMPORTANCECancer has become the second most frequent cause of death in industrialized countries. This and the drawbacks of routine therapies generate an urgent need for novel treatment options. Applying appropriately modifiedS. Typhimurium for therapy represents the major challenge of bacterium-mediated tumor therapy. In the present study, we demonstrated thatSalmonellabacteria conditionally modified in their LPS phenotype exhibit a safe tumor-targeting phenotype. Moreover, they could represent a suitable vehicle to shuttle therapeutic compounds directly into cancerous tissue without harming the host.

Sign in / Sign up

Export Citation Format

Share Document