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

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.

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Gamma Interferon Enhances Internalization and Early Nonoxidative Killing of Salmonella enterica Serovar Typhimurium by Human Macrophages and Modifies Cytokine Responses

Infection and Immunity ◽

10.1128/iai.73.6.3445-3452.2005 ◽

2005 ◽

Vol 73 (6) ◽

pp. 3445-3452 ◽

Cited By ~ 34

Author(s):

Melita A. Gordon ◽

Dominic L. Jack ◽

David H. Dockrell ◽

Margaret E. Lee ◽

Robert C. Read

Keyword(s):

Oxidative Burst ◽

Respiratory Burst ◽

Salmonella Enterica ◽

Gamma Interferon ◽

Cytokine Release ◽

Intracellular Killing ◽

Human Macrophages ◽

Salmonella Infections ◽

Serovar Typhimurium ◽

Ifn Γ

ABSTRACT Gamma interferon (IFN-γ) is a critical cytokine in host defense against salmonella infections, but its role in phagocytic killing of intracellular Salmonella spp. has been investigated mainly in animal rather than human cells. We measured the effect of recombinant IFN-γ (rIFN-γ) priming on bacterial internalization, intracellular killing, oxidative burst, and cytokine release during phagocytosis of Salmonella enterica serovar Typhimurium by human monocyte-derived macrophages (MDM). Eleven-day-old MDM, primed for 72 h with rIFN-γ (100 ng/ml) exhibited an increased proportion of cells with associated bacteria (31% versus 26%, P = 0.036) and a 67% increase in internalized bacteria per cell compared to unprimed cells (P = 0.025). Retrieval of viable bacteria following internalization was reduced 3.6-fold in 72-h primed versus unprimed MDM (interquartile range, 3.1 to 6.4) at 0.5 h due to enhanced early intracellular killing, and this difference was maintained up to 24 h. In contrast, cells primed for only 24 h exhibited no increase in early killing. MDM were competent to produce an early oxidative burst when stimulated with phorbol myristate acetate, which was fully abrogated by the respiratory burst inhibitor diphenyleneiodonium chloride (DPI), but infection of MDM with S. enterica serovar Typhimurium did not cause an increase in the early respiratory burst under unprimed or primed conditions, and DPI had no effect on the early killing of bacteria by primed or unprimed MDM. During 24 h following infection, rIFN-γ-primed MDM released more interleukin-12 (IL-12) and less IL-10 relative to unprimed cells. We conclude that 72-h priming with rIFN-γ increases the efficiency of internalization and nonoxidative early intracellular killing of S. enterica serovar Typhimurium by human macrophages and modifies subsequent cytokine release.

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Gamma Interferon-Independent Effects of Interleukin-12 on Immunity to Salmonella enterica Serovar Typhimurium

Infection and Immunity ◽

10.1128/iai.00971-07 ◽

2007 ◽

Vol 75 (12) ◽

pp. 5753-5762 ◽

Cited By ~ 9

Author(s):

Jason D. Price ◽

Kim R. Simpfendorfer ◽

Radhakrishnam R. Mantena ◽

James Holden ◽

William R. Heath ◽

...

Keyword(s):

T Cells ◽

Salmonella Enterica ◽

Bacterial Load ◽

Bacterial Pathogen ◽

Cell Receptor ◽

Gamma Interferon ◽

Interleukin 12 ◽

Mesenteric Lymph Nodes ◽

Serovar Typhimurium ◽

Ifn Γ

ABSTRACTInterleukin-12 (IL-12) and IL-18 are both central to the induction of gamma interferon (IFN-γ), and various roles for IL-12 and IL-18 in control of intracellular microbial infections have been demonstrated. We used IL-12p40−/−and IL-18−/−mice to further investigate the role of IL-12 and IL-18 in control ofSalmonella entericaserovar Typhimurium. While C57BL/6 and IL-18−/−mice were able to resolve attenuatedS. entericaserovar Typhimurium infections, the IL-12p40−/−mice succumbed to a high bacterial burden after 60 days. Using ovalbumin (OVA)-specific T-cell receptor transgenic T cells (OT-II cells), we demonstrated that following oral infection with recombinantS. entericaserovar Typhimurium expressing OVA, the OT-II cells proliferated in the mesenteric lymph nodes of C57BL/6 and IL-18−/−mice but not in IL-12p40−/−mice. In addition, we demonstrated by flow cytometry that equivalent or increased numbers of T cells produced IFN-γ in IL-12p40−/−mice compared with the numbers of T cells that produced IFN-γ in C57BL/6 and IL-18−/−mice. Finally, we demonstrated that removal of macrophages fromS. entericaserovar Typhimurium-infected C57BL/6 and IL-12p40−/−mice did not affect the bacterial load, suggesting that impaired control ofS. entericaserovar Typhimurium infection in the absence of IL-12p40 is not due to reduced macrophage bactericidal activities, while IL-18−/−mice did rely on the presence of macrophages for control of the infection. Our results suggest that IL-12p40, but not IL-18, is critical to resolution of infections with attenuatedS. entericaserovar Typhimurium and that especially the effects of IL-12p40 on proliferative responses of CD4+T cells, but not the ability of these cells to produce IFN-γ, are important in the resolution of infection by this intracellular bacterial pathogen.

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The Actin-Polymerizing Activity of SipA Is Not Essential for Salmonella enterica Serovar Typhimurium-Induced Mucosal Inflammation

Infection and Immunity ◽

10.1128/iai.00337-12 ◽

2013 ◽

Vol 81 (5) ◽

pp. 1541-1549 ◽

Cited By ~ 7

Author(s):

Dongju Li ◽

Xueqin Wang ◽

Lu Wang ◽

Daoguo Zhou

Keyword(s):

Inflammatory Response ◽

Mouse Model ◽

Salmonella Enterica ◽

Intestinal Inflammation ◽

Host Cells ◽

Bacterial Invasion ◽

Content Type ◽

Type Iii ◽

Serovar Typhimurium ◽

Mouse Model Of Infection

ABSTRACTSalmonella entericaserovar Typhimurium depends on type III secretion systems to inject effector proteins into host cells to promote bacterial invasion and to induce intestinal inflammation. SipA, a type III effector, is known to play important roles in both the invasion and the elicitation of intestinal inflammation. The actin-modulating activity of SipA has been shown to promoteSalmonellaentry into epithelial cells. To investigate whether the actin-modulating activity of SipA is required for its ability to induce an inflammatory responsein vivo, we generated the SipAK635A E637Wmutant, which is deficient in actin-modulating activity.Salmonellastrains expressing the chromosomal SipAK635A E637Wpoint mutation had reduced invasion abilities but still caused colitis similar to that caused by the wild-type strain in a mouse model of infection. Our data indicate that the SipA actin-polymerizing activity is not essential for the SipA-induced inflammatory response in the mouse model of infection.

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

Infection and Immunity ◽

10.1128/iai.02192-14 ◽

2014 ◽

Vol 82 (12) ◽

pp. 4997-5004 ◽

Cited By ~ 21

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.

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Coinfection with an Intestinal Helminth Impairs Host Innate Immunity against Salmonella enterica Serovar Typhimurium and Exacerbates Intestinal Inflammation in Mice

Infection and Immunity ◽

10.1128/iai.02023-14 ◽

2014 ◽

Vol 82 (9) ◽

pp. 3855-3866 ◽

Cited By ~ 34

Author(s):

Libo Su ◽

Chien-wen Su ◽

Yujuan Qi ◽

Guilian Yang ◽

Mei Zhang ◽

...

Keyword(s):

Innate Immunity ◽

Salmonella Enterica ◽

Intestinal Inflammation ◽

Interleukin 10 ◽

Neutrophil Recruitment ◽

Intestinal Helminth ◽

Helminth Parasites ◽

Content Type ◽

Infectious Gastroenteritis ◽

Serovar Typhimurium

ABSTRACTSalmonella entericaserovar Typhimurium is a Gram-negative food-borne pathogen that is a major cause of acute gastroenteritis in humans. The ability of the host to control such bacterial pathogens may be influenced by host immune status and by concurrent infections. Helminth parasites are of particular interest in this context because of their ability to modulate host immune responses and because their geographic distribution coincides with those parts of the world where infectious gastroenteritis is most problematic. To test the hypothesis that helminth infection may negatively regulate host mucosal innate immunity against bacterial enteropathogens, a murine coinfection model was established by using the intestinal nematodeHeligmosomoides polygyrusandS. Typhimurium. We found that mice coinfected withS. Typhimurium andH. polygyrusdeveloped more severe intestinal inflammation than animals infected withS. Typhimurium alone. The enhanced susceptibility toSalmonella-induced intestinal injury in coinfected mice was found to be associated with diminished neutrophil recruitment to the site of bacterial infection that correlated with decreased expression of the chemoattractants CXCL2/macrophage inflammatory protein 2 (MIP-2) and CXCL1/keratinocyte-derived chemokine (KC), poor control of bacterial replication, and exacerbated intestinal inflammation. The mechanism of helminth-induced inhibition of MIP-2 and KC expression involved interleukin-10 (IL-10) and, to a lesser extent, IL-4 and IL-13. Ly6G antibody-mediated depletion of neutrophils reproduced the adverse effects ofH. polygyrusonSalmonellainfection. Our results suggest that impaired neutrophil recruitment is an important contributor to the enhanced severity ofSalmonellaenterocolitis associated with helminth coinfection.

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Induction of Guanylate Binding Protein 5 by Gamma Interferon Increases Susceptibility to Salmonella enterica Serovar Typhimurium-Induced Pyroptosis in RAW 264.7 Cells

Infection and Immunity ◽

10.1128/iai.01437-07 ◽

2008 ◽

Vol 76 (6) ◽

pp. 2304-2315 ◽

Cited By ~ 27

Author(s):

Adam C. Rupper ◽

James A. Cardelli

Keyword(s):

Cell Death ◽

Host Defense ◽

Salmonella Enterica ◽

Gamma Interferon ◽

Raw 264.7 Cells ◽

Raw 264.7 ◽

Caspase 1 ◽

Serovar Typhimurium ◽

Ifn Γ ◽

Guanylate Binding Protein

ABSTRACT The regulation of caspase-1 activation in macrophages plays a central role in host defense against bacterial pathogens. The activation of caspase-1 by the detection of bacterial products through Nod-like receptors leads to the secretion of mature interleukin-1β (IL-1β) and IL-18 and the induction of rapid host cell death (pyroptosis). Here, we report that pyroptosis induced by Salmonella enterica serovar Typhimurium can be positively regulated by prior gamma interferon (IFN-γ) stimulation of RAW 264.7 cells. This increase in cell death is dependent on both caspase-1 activation and, in part, Salmonella pathogenicity island 1 (SPI-1) expression by Salmonella. Furthermore, the exogenous expression of the IFN-γ-induced protein guanylate binding protein 5 (GBP-5) is sufficient to induce a heightened susceptibility of RAW 264.7 cells to Salmonella-induced pyroptosis, and the endogenous expression of GBP-5 is important for this phenomenon. RAW 264.7 cells with decreased expression of GBP-5 mRNA (inhibited by short hairpin RNA against GBP-5) release twofold less lactate dehydrogenase (a marker of membrane permeability) upon infection by invasive S. enterica serovar Typhimurium than do infected control cells. Importantly, 3× FLAG-tagged GBP-5 is localized to membrane ruffles, which contact invasive Salmonella, and is found on the membranes of spacious phagosomes containing Salmonella (although it is also found in the cytoplasm and on other cellular membranes), placing 3× FLAG GBP-5 at the interface of secreted SPI-1 effectors and host protein machinery. The regulation of pyroptosis by the IFN-γ-induced protein GBP-5 may play an important role in the host defense against Salmonella enterica serovar Typhimurium and perhaps other invasive bacterial pathogens.

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Increased Susceptibility of Melanin-Concentrating Hormone-Deficient Mice to Infection with Salmonella enterica Serovar Typhimurium

Infection and Immunity ◽

10.1128/iai.00572-12 ◽

2012 ◽

Vol 81 (1) ◽

pp. 166-172 ◽

Cited By ~ 5

Author(s):

Apostolos K. A. Karagiannis ◽

Dimitrios C. Ziogas ◽

Beatriz Gras-Miralles ◽

Brenda M. Geiger ◽

Jutta Nagel ◽

...

Keyword(s):

Knockout Mice ◽

Salmonella Enterica ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Peripheral Tissues ◽

Content Type ◽

Serovar Typhimurium ◽

Intestinal Pathogens ◽

Melanin Concentrating Hormone ◽

Deficient Mice

Melanin-concentrating hormone (MCH) was initially identified in mammals as a hypothalamic neuropeptide regulating appetite and energy balance. However, the wide distribution of MCH receptors in peripheral tissues suggests additional functions for MCH which remain largely unknown. We have previously reported that mice lacking MCH develop attenuated intestinal inflammation when exposed toClostridium difficiletoxin A. To further characterize the role of MCH in host defense mechanisms against intestinal pathogens,Salmonellaenterocolitis (usingSalmonella entericaserovar Typhimurium) was induced in MCH-deficient mice and their wild-type littermates. In the absence of MCH, infected mice had increased mortality associated with higher bacterial loads in blood, liver, and spleen. Moreover, the knockout mice developed more-severe intestinal inflammation, based on epithelial damage, immune cell infiltrates, and local and systemic cytokine levels. Paradoxically, these enhanced inflammatory responses in the MCH knockout mice were associated with disproportionally lower levels of macrophages infiltrating the intestine. Hence, we investigated potential direct effects of MCH on monocyte/macrophage functions critical for defense against intestinal pathogens. Using RAW 264.7 mouse monocytic cells, which express endogenous MCH receptor, we found that treatment with MCH enhanced the phagocytic capacity of these cells. Taken together, these findings reveal a previously unappreciated role for MCH in host-bacterial interactions.

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

mBio ◽

10.1128/mbio.00254-15 ◽

2015 ◽

Vol 6 (2) ◽

Cited By ~ 38

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.

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A Salmonella Virulence Factor Activates the NOD1/NOD2 Signaling Pathway

mBio ◽

10.1128/mbio.00266-11 ◽

2011 ◽

Vol 2 (6) ◽

Cited By ~ 18

Author(s):

A. Marijke Keestra ◽

Maria G. Winter ◽

Daisy Klein-Douwel ◽

Mariana N. Xavier ◽

Sebastian E. Winter ◽

...

Keyword(s):

Signaling Pathway ◽

Type Iii Secretion ◽

Salmonella Enterica ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Type Iii Secretion System ◽

Secretion System ◽

Content Type ◽

Type Iii

ABSTRACTThe invasion-associated type III secretion system (T3SS-1) ofSalmonella entericaserotype Typhimurium (S. Typhimurium) activates the transcription factor NF-κB in tissue culture cells and induces inflammatory responses in animal models through unknown mechanisms. Here we show that bacterial delivery or ectopic expression of SipA, a T3SS-1-translocated protein, led to the activation of the NOD1/NOD2 signaling pathway and consequent RIP2-mediated induction of NF-κB-dependent inflammatory responses. SipA-mediated activation of NOD1/NOD2 signaling was independent of bacterial invasionin vitrobut required an intact T3SS-1. In the mouse colitis model, SipA triggered mucosal inflammation in wild-type mice but not in NOD1/NOD2-deficient mice. These findings implicate SipA-driven activation of the NOD1/NOD2 signaling pathway as a mechanism by which the T3SS-1 induces inflammatory responsesin vitroandin vivo.IMPORTANCESalmonella entericaserotype Typhimurium (S. Typhimurium) deploys a type III secretion system (T3SS-1) to induce intestinal inflammation and benefits from the ensuing host response, which enhances growth of the pathogen in the intestinal lumen. However, the mechanisms by which the T3SS-1 triggers inflammatory responses have not been resolved. Here we show that the T3SS-1 effector protein SipA induces NF-κB activation and intestinal inflammation by activating the NOD1/NOD2 signaling pathway. These data suggest that the T3SS-1 escalates innate responses through a SipA-mediated activation of pattern recognition receptors in the host cell cytosol.

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Whole-Genome Sequence of Salmonella enterica subsp. enterica Serovar Typhimurium Strain UPM 260, Isolated from a Broiler Chicken in Perak, Malaysia

Genome Announcements ◽

10.1128/genomea.01272-17 ◽

2017 ◽

Vol 5 (46) ◽

Author(s):

Najwa Syahirah Roslan ◽

Shagufta Jabeen ◽

Nurulfiza Mat Isa ◽

Abdul Rahman Omar ◽

Mohd Hair Bejo ◽

...

Keyword(s):

Genome Sequence ◽

Salmonella Enterica ◽

Broiler Chicken ◽

Whole Genome Sequence ◽

Whole Genome ◽

Content Type ◽

Typhimurium Strain ◽

Serovar Typhimurium

ABSTRACT Salmonella enterica subsp. enterica serovar Typhimurium is one of several well-categorized Salmonella serotypes recognized globally. Here, we report the whole-genome sequence of S. Typhimurium strain UPM 260, isolated from a broiler chicken.

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