scholarly journals DNA-Salmonella enterica Serovar Typhimurium Primer-Booster Vaccination Biases towards T Helper 1 Responses and Enhances Protection against Leishmania major Infection in Mice

2004 ◽  
Vol 72 (8) ◽  
pp. 4924-4928 ◽  
Author(s):  
Uta G. Lange ◽  
Pietro Mastroeni ◽  
Jenefer M. Blackwell ◽  
Carmel B. Stober
Keyword(s):  
Salmonella Enterica ◽  
Leishmania Major ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Booster Vaccination ◽  
Interleukin 12 ◽  
T Helper ◽  
T Helper 1 ◽  
Serovar Typhimurium ◽  
Successful Resolution ◽  
Ifn Γ

ABSTRACT Successful resolution of infections by intracellular pathogens requires gamma interferon (IFN-γ). DNA vaccines promote T helper 1 (Th1) responses by triggering interleukin-12 (IL-12) release by dendritic cells (DC) through Toll-like receptor 9 (TLR9). In humans TLR9 is restricted to plasmacytoid DC. Here we show that DNA-Salmonella enterica serovar Typhimurium primer-booster vaccination, which provides alternative ligands to bind TLR4 on myeloid DC, strongly biases towards Th1 responses compared to vaccination with DNA alone. This results in higher immunoglobulin G2a (IgG2a) responses compared to IgG1 responses, higher IFN-γ responses compared to IL-10 CD4+-T-cell responses, and enhanced protection against Leishmania major infection in susceptible BALB/c mice.

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 Selective Expression of an Interleukin-12 Receptor Component by Human T Helper 1 Cells

1997 ◽  
Vol 185 (5) ◽  
pp. 825-832 ◽  
Author(s):  
Lars Rogge ◽  
Luisella Barberis-Maino ◽  
Mauro Biffi ◽  
Nadia Passini ◽  
David H. Presky ◽  
...  
Keyword(s):  
Interleukin 12 ◽  
Type I ◽  
T Helper ◽  
T Helper 1 ◽  
Receptor Component ◽  
Selective Expression ◽  
Ifn Γ ◽  
Activated Monocytes ◽  
Th2 Differentiation

Interleukin-12 (IL-12), a heterodimeric cytokine produced by activated monocytes and dendritic cells, plays a crucial role in regulating interferon (IFN)-γ production and in the generation of IFN–γ–producing T helper 1 (Th1) cells. Here we show that the IL-12 receptor (IL12R) β2 subunit, a recently cloned binding and signal transducing component of the IL-12R, is expressed on human Th1 but not Th2 clones and is induced during differentiation of human naive cells along the Th1 but not the Th2 pathway. IL-12 and type I but not type II interferons induce expression of the IL-12R β2 chain during in vitro T cell differentiation after antigen receptor triggering. The selective expression and regulation of the IL-12R β2 subunit may help to understand the basis of Th1/Th2 differentiation and may provide therapeutic options for altering the Th1/Th2 balance in several immuno-pathological conditions such as autoimmune diseases and allergies.

scholarly journals High Levels of Susceptibility and T Helper 2 Response in MyD88-Deficient Mice Infected with Leishmania major Are Interleukin-4 Dependent

2003 ◽  
Vol 71 (12) ◽  
pp. 7215-7218 ◽  
Author(s):  
Andrea Debus ◽  
Joachim Gläsner ◽  
Martin Röllinghoff ◽  
André Gessner
Keyword(s):  
Knockout Mice ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Interleukin 4 ◽  
Myeloid Differentiation ◽  
Interleukin 12 ◽  
T Helper ◽  
T Helper 1 ◽  
T Helper 2 ◽  
Deficient Mice

ABSTRACT Myeloid differentiation protein 88 (MyD88) is a general adaptor for the signaling cascade through receptors of the Toll/IL-1R family. When infected with Leishmania major parasites, MyD88-deficient mice displayed a dramatically enhanced parasite burden in their tissues similar to that found in susceptible BALB/c mice. In contrast, MyD88 knockout mice did not develop ulcerating lesions despite a lack of interleukin-12 (IL-12) production and a predominant T helper 2 cell response. Blockade of IL-4 produced early (day 1) after infection restored a protective T helper 1 response in MyD88 knockout mice.

scholarly journals Tissue Selectivity of Interferon-Stimulated Gene Expression in Mice Infected with Dam+ versus Dam−Salmonella enterica Serovar Typhimurium Strains

2002 ◽  
Vol 70 (10) ◽  
pp. 5579-5588 ◽  
Author(s):  
Ronit Shtrichman ◽  
Douglas M. Heithoff ◽  
Michael J. Mahan ◽  
Charles E. Samuel
Keyword(s):  
Salmonella Enterica ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Class Ii Transactivator ◽  
Mouse Tissues ◽  
Serovar Typhimurium ◽  
Microbial Infections ◽  
Dna Adenine Methylase ◽  
Dependent Protein ◽  
Ifn Γ ◽  
Oxide Synthase

ABSTRACT The host interferon (IFN) system plays an important role in protection against microbial infections. Salmonella enterica serovar Typhimurium is highly virulent in the mouse model, whereas mutants that lack DNA adenine methylase (Dam−) are highly attenuated and elicit fully protective immune responses against murine typhoid fever. We examined the expression of IFN-responsive genes in several mouse tissues following infection with Dam+ or Dam− Salmonella. Infection of mice with Dam+ Salmonella resulted in the induction of host genes known to be indicators of IFN bioactivity and regulated by either IFN-α/β (Mx1) or IFN-γ (class II transactivator protein [CIITA] and inducible nitric oxide synthase [iNOS]) or by both IFN-α/β and IFN-γ (RNA-specific adenosine deaminase [ADAR1] and RNA-dependent protein kinase [PKR]) in a tissue-specific manner compared to uninfected animals. Since the Mx1 promoter is IFN-α/β specific and the Mx1 gene is not inducible directly by IFN-γ, these data suggest a role of IFN-α/β in the host response to Salmonella infection. Mice infected with Dam− Salmonella showed reduced expression of the same set of IFN-stimulated genes (ISGs) as that observed after infection with wild-type Salmonella. The reduced capacity to induce ISGs persisted in Dam−-vaccinated mice after challenge with the virulent (Dam+) strain. Finally, although no Dam− organisms were recovered from the liver or spleen after oral infection of mice, ADAR, PKR, Mx, and CIITA expression levels were elevated in these tissues relative to those in uninfected mice, suggestive of the distant action of a signaling molecule(s) in the activation of ISG expression.

scholarly journals Increased Sensitivity to Salmonella enterica Serovar Typhimurium Infection in Mice Undergoing Withdrawal from Morphine Is Associated with Suppression of Interleukin-12

2005 ◽  
Vol 73 (12) ◽  
pp. 7953-7959 ◽  
Author(s):  
Pu Feng ◽  
Qiana M. Wilson ◽  
Joseph J. Meissler ◽  
Martin W. Adler ◽  
Toby K. Eisenstein
Keyword(s):  
Salmonella Enterica ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Slow Release ◽  
Bacterial Load ◽  
Morphine Withdrawal ◽  
Interleukin 12 ◽  
Bacterial Burden ◽  
Mean Survival Time ◽  
Serovar Typhimurium ◽  
Increased Sensitivity

ABSTRACT We have shown previously that withdrawal from morphine induces immunosuppression in mice. The present study reports the effects of morphine withdrawal on infection with Salmonella enterica serovar Typhimurium. Mice were made dependent on morphine by the implantation of a slow-release morphine pellet for 96 h. Controls received a placebo pellet. Withdrawal was induced by pellet removal. Mice were inoculated intraperitoneally with Salmonella 24 h postwithdrawal. Morphine withdrawal sensitized mice to Salmonella infection, as evidenced by increased mortality, shortened mean survival time, and increased bacterial load in the blood, spleen, and liver. Examination of the levels of a panel of proinflammatory cytokines in sera of infected, morphine-withdrawn mice showed that morphine withdrawal inhibited the elevation of interleukin-12p70 (IL-12p70). The production of IL-12p40 in morphine withdrawal mice was also suppressed. The administration of exogenous IL-12 significantly decreased the bacterial burden in morphine-withdrawn mice. These studies show a correlation between the suppression of IL-12 production and a heightened susceptibility to Salmonella infection in mice undergoing withdrawal from morphine.

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