Transient Transgenic Expression of Gamma Interferon Promotes<i>Legionella pneumophila</i>Clearance in Immunocompetent Hosts

Deng, Jane C.; Tateda, Kazuhiro; Zeng, Xianying; Standiford, Theodore J.

doi:10.1128/iai.69.10.6382-6390.2001

Cited by 67 publications

(54 citation statements)

References 49 publications

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“…NK cell-derived IFN-␥ has been shown to be critical in the resolution of other bacterial infections (51,52). In the context of Lpn infection, a critical role of IFN-␥ has been demonstrated (13,53). We have confirmed and extended this finding by demonstrating a nonredundant role of IFN-␥-producing NK cells in the control of Lpn infection.…”

Section: Discussionsupporting

confidence: 76%

MyD88-Dependent IFN-γ Production by NK Cells Is Key for Control ofLegionella pneumophilaInfection

Spörri

Joller

Albers

et al. 2006

The Journal of Immunology

110

102

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Legionella pneumophila (Lpn) is a ubiquitous Gram-negative bacterium in aquatic systems and an opportunistic intracellular pathogen in immunocompromised humans causing a severe pneumonia known as Legionnaires’ disease. Using a mouse model, we investigated molecular and cellular players in the innate immune response to infection with Lpn. We observed robust levels of inflammatory cytokines in the serum upon intranasal or i.v. infection with live, virulent Lpn, but not with inactivated or avirulent bacteria lacking the Icm/Dot type IV secretion system. Interestingly, Lpn-induced serum cytokines were readily detectable regardless of the capacity of Icm/Dot-proficient Lpn to replicate in host cells and the Lpn permissiveness of the host mice. We found NK cell-derived IFN-γ to be the key cytokine in the resolution of Lpn infection, whereas type I IFNs did not appear to play a major role in our model. Accordingly, NK cell-depleted or IFN-II-R-deficient mice carried severely increased bacterial burdens or failed to control Lpn infection, respectively. Besides the dependence of inflammatory cytokine induction on Lpn virulence, we also demonstrate a strict requirement of MyD88 for this process, suggesting the involvement of TLRs in the recognition of Lpn. However, screening of several TLR-deficient hosts did not reveal a master TLR responsible for the sensing of an Lpn infection, but provided evidence for either redundancy of individual TLRs in Lpn recognition or TLR-independent induction of inflammatory responses.

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Section: Discussionsupporting

confidence: 76%

MyD88-Dependent IFN-γ Production by NK Cells Is Key for Control ofLegionella pneumophilaInfection

Spörri

Joller

Albers

et al. 2006

The Journal of Immunology

110

102

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“…P. aeruginosa challenge in septic WT and IRAK-M -/-mice. Previous work from our laboratory has identified the importance of inflammatory cytokines and chemokines (e.g., TNF-α, IL-12, and the CXC chemokines macrophage inflammatory protein-2 [MIP-2] and IFN-γ-inducible protein 10 [IP-10]) to the innate immune response against bacterial pathogens in the lung (12)(13)(14)(15)(26)(27)(28)(29)(30)(31). We therefore examined…”

Section: Bacterial Clearance Following It P Aeruginosa Administratmentioning

confidence: 99%

“…In macrophages and other immune cells, ligation of TLRs leads to downstream proinflammatory cytokine production. Prior studies from our laboratory have demonstrated that TNF-α and Th1 cytokines, including IFN-γ and IL-12, are critical mediators of innate immunity, particularly against bacterial pathogens in the lung (12)(13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

Deng

Cheng

Newstead

et al. 2006

Journal of Clinical Investigation

166

252

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Sepsis results in a state of relative immunosuppression, rendering critically ill patients susceptible to secondary infections and increased mortality. Monocytes isolated from septic patients and experimental animals display a "deactivated" phenotype, characterized by impaired inflammatory and antimicrobial responses, including hyporesponsiveness to LPS. We investigated the role of the LPS/TLR4 axis and its inhibitor, IL-1 receptor-associated kinase-M (IRAK-M), in modulating the immunosuppression of sepsis using a murine model of peritonitis-induced sepsis followed by secondary challenge by intratracheal Pseudomonas aeruginosa. Septic mice demonstrated impaired alveolar macrophage function and increased mortality when challenged with intratracheal Pseudomonas as compared with nonseptic controls. TLR2 and TLR4 expression was unchanged in the lung following sepsis, whereas levels of IRAK-M were upregulated. Macrophages from IRAK-M-deficient septic mice produced higher levels of proinflammatory cytokines ex vivo and greater costimulatory molecule expression in vivo as compared with those of their WT counterparts. Following sepsis and secondary intrapulmonary bacterial challenge, IRAK-M -/-animals had higher survival rates and improved bacterial clearance from lung and blood compared with WT mice. In addition, increased pulmonary chemokine and inflammatory cytokine production was observed in IRAK-M -/-animals, leading to enhanced neutrophil recruitment to airspaces. Collectively, these findings indicate that IRAK-M mediates critical aspects of innate immunity that result in an immunocompromised state during sepsis.

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“…We have previously shown that the i.t. administration of this adenovirus vector results in the intrapulmonary expression of IFN-␥ in a time-and dose-dependent manner, leading to beneficial effects on pulmonary clearance of L. pneumophila (27). IFN-␥, IL-12, TNF-␣, IFN-␥-inducible protein-10 (IP-10), monokine induced by IFN-␥ (Mig), KC, and MIP-2 Abs used in ELISA were obtained from R&D Systems.…”

Section: Reagentsmentioning

confidence: 99%

STAT4 Is a Critical Mediator of Early Innate Immune Responses against Pulmonary Klebsiella Infection

Deng

Zeng

Newstead

et al. 2004

The Journal of Immunology

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Bacterial pneumonia is a leading cause of morbidity and mortality in the U.S. An effective innate immune response is critical for the clearance of bacteria from the lungs. IL-12, a key T1 cytokine in innate immunity, signals through STAT4. Thus, understanding how STAT4 mediates pulmonary immune responses against bacterial pathogens will have important implications for the development of rational immunotherapy targeted at augmenting innate immunity. We intratracheally administered Klebsiella pneumoniae to wild-type BALB/c and STAT4 knockout (STAT4−/−) mice. Compared with wild-type controls, STAT4−/− mice had decreased survival following intratracheal Klebsiella administration, which was associated with a higher lung and blood bacterial burden. STAT4−/− animals also displayed impaired pulmonary IFN-γ production and decreased levels of proinflammatory cytokines, including the ELR− CXC chemokines IFN-γ-inducible protein-10 and monokine induced by IFN-γ. Although total lung leukocyte populations were similar between STAT4−/− and wild-type animals following infection, alveolar macrophages isolated from infected STAT4−/− mice had decreased production of proinflammatory cytokines, including IFN-γ, compared with infected wild-type mice. The intrapulmonary overexpression of IFN-γ concomitant with the systemic administration of IFN-γ partially reversed the immune deficits observed in STAT4−/− mice, resulting in improved bacterial clearance from the blood. Collectively, these studies demonstrate that STAT4 is required for the generation of an effective innate host defense against bacterial pathogens of the lung.

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Transient Transgenic Expression of Gamma Interferon PromotesLegionella pneumophilaClearance in Immunocompetent Hosts

Abstract: Gamma interferon (IFN-␥

Cited by 67 publications

References 49 publications

MyD88-Dependent IFN-γ Production by NK Cells Is Key for Control ofLegionella pneumophilaInfection

MyD88-Dependent IFN-γ Production by NK Cells Is Key for Control ofLegionella pneumophilaInfection

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

STAT4 Is a Critical Mediator of Early Innate Immune Responses against Pulmonary Klebsiella Infection

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