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

2005 ◽  
Vol 73 (6) ◽  
pp. 3445-3452 ◽  
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.

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

2007 ◽  
Vol 75 (12) ◽  
pp. 5753-5762 ◽  
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.

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

2008 ◽  
Vol 76 (6) ◽  
pp. 2304-2315 ◽  
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.

scholarly journals An Attenuated Salmonella enterica Serovar Typhimurium Strain and Galacto-Oligosaccharides Accelerate Clearance of Salmonella Infections in Poultry through Modifications to the Gut Microbiome

2017 ◽  
Vol 84 (5) ◽  
Author(s):  
M. Andrea Azcarate-Peril ◽  
Natasha Butz ◽  
Maria Belen Cadenas ◽  
Matthew Koci ◽  
Anne Ballou ◽  
...  
Keyword(s):  
United States ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Salmonella Enterica ◽  
The United States ◽  
Wild Type ◽  
Content Type ◽  
Salmonella Infections ◽  
Serovar Typhimurium ◽  
The Impact

ABSTRACT Salmonella is estimated to cause one million foodborne illnesses in the United States every year. Salmonella -contaminated poultry products are one of the major sources of salmonellosis. Given the critical role of the gut microbiota in Salmonella transmission, a manipulation of the chicken intestinal microenvironment could prevent animal colonization by the pathogen. In Salmonella , the global regulator gene fnr ( f umarate n itrate r eduction) regulates anaerobic metabolism and is essential for adapting to the gut environment. This study tested the hypothesis that an attenuated Fnr mutant of Salmonella enterica serovar Typhimurium (attST) or prebiotic galacto-oligosaccharides (GOS) could improve resistance to wild-type Salmonella via modifications to the structure of the chicken gut microbiome. Intestinal samples from a total of 273 animals were collected weekly for 9 weeks to evaluate the impact of attST or prebiotic supplementation on microbial species of the cecum, duodenum, jejunum, and ileum. We next analyzed changes to the gut microbiome induced by challenging the animals with a wild-type Salmonella serovar 4,[5],12:r:− (Nal r ) strain and determined the clearance rate of the virulent strain in the treated and control groups. Both GOS and the attenuated Salmonella strain modified the gut microbiome but elicited alterations of different taxonomic groups. The attST produced significant increases of Alistipes and undefined Lactobacillus , while GOS increased Christensenellaceae and Lactobacillus reuteri . The microbiome structural changes induced by both treatments resulted in a faster clearance after a Salmonella challenge. IMPORTANCE With an average annual incidence of 13.1 cases/100,000 individuals, salmonellosis has been deemed a nationally notifiable condition in the United States by the Centers for Disease Control and Prevention (CDC). Earlier studies demonstrated that Salmonella is transmitted by a subset of animals (supershedders). The supershedder phenotype can be induced by antibiotics, ascertaining an essential role for the gut microbiota in Salmonella transmission. Consequently, modulation of the gut microbiota and modification of the intestinal microenvironment could assist in preventing animal colonization by the pathogen. Our study demonstrated that a manipulation of the chicken gut microbiota by the administration of an attenuated Salmonella strain or prebiotic galacto-oligosaccharides (GOS) can promote resistance to Salmonella colonization via increases of beneficial microorganisms that translate into a less hospitable gut microenvironment.

scholarly journals Genetic Requirements for Salmonella-Induced Cytopathology in Human Monocyte-Derived Macrophages

2002 ◽  
Vol 70 (12) ◽  
pp. 7126-7135 ◽  
Author(s):  
Sara H. Browne ◽  
Marc L. Lesnick ◽  
Donald G. Guiney
Keyword(s):  
Salmonella Enterica ◽  
Human Monocyte ◽  
Intracellular Bacteria ◽  
Wild Type ◽  
Site Specific ◽  
Human Macrophages ◽  
Serovar Typhimurium ◽  
Protein Secretion System ◽  
Type Iii Protein Secretion ◽  
A Site

ABSTRACT Infection of human macrophages with Salmonella enterica serovar Typhimurium or Salmonella enterica serovar Dublin produces delayed cytotoxicity characterized by cell detachment and associated apoptosis. Using a site-specific mutant in the SpvB active site, we verify that the ADP-ribosylation activity of SpvB is required for delayed cytotoxicity in human macrophages infected with Salmonella. SipB and the type III protein secretion system (TTSS) encoded by Salmonella pathogenicity island 1 (SPI1) are not involved, whereas the SPI2 TTSS is absolutely required for SpvB-dependent cytotoxicity. Furthermore, we show that infection of macrophage cultures with wild-type or sipB mutant bacteria led to a complete loss of polymerized actin in over half of the cells after 24 h. In contrast, macrophages infected with the spvB or SPI2 (ssaV or ssaJ) mutant strain retained normal F-actin filaments, despite similar numbers of intracellular bacteria. We conclude that SpvB and a functional SPI2 TTSS are essential for Salmonella-induced delayed cytotoxicity of human macrophages.

scholarly journals Expression, Extracellular Secretion, and Immunogenicity of the Plasmodium falciparum Sporozoite Surface Protein 2 in Salmonella Vaccine Strains

2001 ◽  
Vol 69 (2) ◽  
pp. 1192-1198 ◽  
Author(s):  
Oscar G. Gómez-Duarte ◽  
Marcela F. Pasetti ◽  
Araceli Santiago ◽  
Marcelo B. Sztein ◽  
Stephen L. Hoffman ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Salmonella Enterica ◽  
Surface Protein ◽  
Secretion System ◽  
Gamma Interferon ◽  
Type I ◽  
Extracellular Secretion ◽  
Serovar Typhimurium ◽  
Falciparum Sporozoite ◽  
Α Helix

ABSTRACT Deleting transmembrane α-helix motifs from Plasmodium falciparum sporozoite surface protein (SSP-2) allowed its secretion from Salmonella enterica serovar Typhimurium SL3261 and S. enterica serovar Typhi CVD 908-htrA by the Hly type I secretion system. In mice immunized intranasally, serovar Typhimurium constructs secreting SSP-2 stimulated greater gamma interferon splenocyte responses than did nonsecreting constructs (P = 0.04).

scholarly journals Survival of Salmonella enterica Serovar Typhimurium within Late Endosomal-Lysosomal Compartments of B Lymphocytes Is Associated with the Inability To Use the Vacuolar Alternative Major Histocompatibility Complex Class I Antigen-Processing Pathway

2005 ◽  
Vol 73 (7) ◽  
pp. 3937-3944 ◽  
Author(s):  
Roberto Rosales-Reyes ◽  
Celia Alpuche-Aranda ◽  
María de la Luz Ramírez-Aguilar ◽  
Angel Denisse Castro-Eguiluz ◽  
Vianney Ortiz-Navarrete
Keyword(s):  
B Lymphocytes ◽  
Salmonella Enterica ◽  
Antigen Processing ◽  
Macrophage Cell ◽  
Mhc I ◽  
Lysosomal Compartment ◽  
Histocompatibility Complex ◽  
Serovar Typhimurium ◽  
Ifn Γ

ABSTRACT Gamma interferon (IFN-γ)-activated macrophages use an alternative processing mechanism to present Salmonella antigens to CD8+ T lymphocytes. This pathway involves processing of antigen in a vacuolar compartment followed by secretion and loading of antigenic peptides to major histocompatibility complex class I (MHC-I) molecules on macrophage cell surface and bystander cells. In this study, we have shown that B lymphocytes are not able to process Salmonella antigens using this alternative pathway. This is due to differences in Salmonella enterica serovar Typhimurium-containing vacuoles (SCV) when comparing late endosomal-lysosomal processing compartments in B lymphocytes to those in macrophages. The IFN-γ-activated IC21 macrophage cell line and A-20 B-cell line were infected with live or dead Salmonella enterica serovar Typhimurium. The SCV in B cells were in a late endosomal-lysosomal compartment, whereas SCV in macrophages were remodeled to a noncharacteristic late endosomal-lysosomal compartment over time. Despite the difference in SCV within macrophages and B lymphocytes, S. enterica serovar Typhimurium survives more efficiently within the IFN-γ-activated B cells than in activated macrophage cell lines. Similar results were found during in vivo acute infection. We determined that a lack of remodeling of late endosomal-lysosomal compartments by live Salmonella infection in B lymphocytes is associated with the inability to use the alternative MHC-I antigen-processing pathway, providing a survival advantage to the bacterium. Our data also suggest that the B lymphocyte late endosome-lysosome environment allows the expression of Salmonella virulence mechanisms favoring B lymphocytes in addition to macrophages and dendritic cells as a reservoir during in vivo infection.

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