Contribution of interferon-γ in protecting mice during pulmonary and disseminated infection with

Kawakami, Kazuyoshi; Tohyama, Masaki; Teruya, Katsuji; Kudeken, Norifumi; Xie, Qiang-min; Saitô, Atsushi

doi:10.1016/0928-8244(95)00093-3

Cited by 13 publications

(13 citation statements)

References 26 publications

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“…The induction of proinflammatory cytokine signals, including IFN-γ, at the afferent phase is important to the development of the protective immune response against cryptococcal infection (35, 37, 45, 48, 49). In this article, we demonstrate that, albeit without effect on early growth of C. neoformans in the lungs, SRA signaling results in diminished secretion of IFN-γ in the lung at 1 wpi.…”

Section: Discussionmentioning

confidence: 99%

Scavenger Receptor A Modulates the Immune Response to Pulmonary Cryptococcus neoformans Infection

Qiu

Dayrit

Davis

et al. 2013

The Journal of Immunology

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Scavenger receptors represent an important class of pattern recognition receptors shown to mediate both beneficial and detrimental roles in host defense against microbial pathogens. The role of the major macrophage scavenger receptor, scavenger receptor A (SRA), in the immune response against the pathogenic fungus, Cryptococcus neoformans, is unknown. To evaluate the role of SRA in anticryptococcal host defenses, SRA+/+ mice and SRA−/− mice were infected intratracheally with C. neoformans. Results show that infection of SRA−/− mice resulted in a reduction in the pulmonary fungal burden at the efferent phase (3 wk) compared with SRA+/+ mice. Improved fungal clearance in SRA−/− mice was associated with decreased accumulation of eosinophils and greater accumulation of CD4+ T cells and CD11b+ dendritic cells. Additional parameters were consistent with enhanced anti-cryptococcal immunity in the infected SRA−/− mice: 1) increased expression of the costimulatory molecules CD80 and CD86 by lung APCs, 2) decreased expression of Th2 cytokines (IL-4 and IL-13) and IL-10 in lung leukocytes and in cryptococcal Ag-pulsed splenocytes, 3) diminished IgE production in sera, and 4) increased hallmarks of classical pulmonary macrophage activation. These effects were preceded by increased expression of early pro-Th1 genes in pulmonary lymph nodes at the afferent phase (1 wk). Collectively, our data show that SRA can be exploited by C. neoformans to interfere with the early events of the afferent responses that support Th1 immune polarization. This results in amplification of Th2 arm of the immune response and subsequently impaired adaptive control of C. neoformans in the infected lungs.

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Section: Discussionmentioning

confidence: 99%

Scavenger Receptor A Modulates the Immune Response to Pulmonary Cryptococcus neoformans Infection

Qiu

Dayrit

Davis

et al. 2013

The Journal of Immunology

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“…These studies suggested that protection against pulmonary cryptococcosis is mediated by Th1-type cytokines such as IFN-γ, TNF-α, and IL-12 [14], [16], [17], [22], [23], [50]. Additional work supported a protective role for antibody mediated immunity (AMI) against pulmonary cryptococcosis [51], [52].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, recombinant Th1-type cytokines have been investigated for their potential as adjunctive antifungal chemotherapy and to enhance anti-cryptococcal host immune responses [18], [34]–[37]. Specifically, studies with IFN-γ have yielded some promising results as both clinical and experimental studies show that adjunctive therapy in combination with antifungal agents enhances clearance of the organism [17], [36], [38], [39]. Unfortunately, these studies have been unable to demonstrate complete protection against subsequent C. neoformans challenge.…”

Section: Introductionmentioning

confidence: 99%

Insights into the Mechanisms of Protective Immunity against Cryptococcus neoformans Infection Using a Mouse Model of Pulmonary Cryptococcosis

et al. 2009

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Cryptococcus neoformans is an opportunistic fungal pathogen that causes life-threatening pneumonia and meningoencephalitis in immune compromised individuals. Previous studies have shown that immunization of BALB/c mice with an IFN-γ-producing C. neoformans strain, H99γ, results in complete protection against a second pulmonary challenge with an otherwise lethal cryptococcal strain. The current study evaluated local anamnestic cell-mediated immune responses against pulmonary cryptococcosis in mice immunized with C. neoformans strain H99γ compared to mice immunized with heat-killed C. neoformans (HKC.n.). Mice immunized with C. neoformans strain H99γ had significantly reduced pulmonary fungal burden post-secondary challenge compared to mice immunized with HKC.n. Protection against pulmonary cryptococcosis was associated with increased pulmonary granulomatous formation and leukocyte infiltration followed by a rapid resolution of pulmonary inflammation, which protected the lungs from severe allergic bronchopulmonary mycosis (ABPM)-pathology that developed in the lungs of mice immunized with HKC.n. Pulmonary challenge of interleukin (IL)-4 receptor, IL-12p40, IL-12p35, IFN-γ, T cell and B cell deficient mice with C. neoformans strain H99γ demonstrated a requirement for Th1-type T cell-mediated immunity, but not B cell-mediated immunity, for the induction of H99γ-mediated protective immune responses against pulmonary C. neoformans infection. CD4+ T cells, CD11c+ cells, and Gr-1+ cells were increased in both proportion and absolute number in protected mice. In addition, significantly increased production of Th1-type/pro-inflammatory cytokines and chemokines, and conversely, reduced Th2-type cytokine production was observed in the lungs of protected mice. Interestingly, protection was not associated with increased production of cytokines IFN-γ or TNF-α in lungs of protected mice. In conclusion, immunization with C. neoformans strain H99γ results in the development of protective anti-cryptococcal immune responses that may be measured and subsequently used in the development of immune-based therapies to combat pulmonary cryptococcosis.

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“…In immune compromised patients, an initial pulmonary infection of C. neoformans frequently results in a lethal dissemination into the central nervous system (CNS) [3]. To combat CNS dissemination, cell-mediated immune responses, especially Th1 polarization and robust expression of IFN-γ, are required [4], [5], [6], [7], [8], [9], [10]. Studies have demonstrated that Th2 adaptive immune responses are non-protective [5], [11], [12], [13].…”

Section: Introductionmentioning

confidence: 99%

Immune Modulation Mediated by Cryptococcal Laccase Promotes Pulmonary Growth and Brain Dissemination of Virulent Cryptococcus neoformans in Mice

et al. 2012

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C. neoformans is a leading cause of fatal mycosis linked to CNS dissemination. Laccase, encoded by the LAC1 gene, is an important virulence factor implicated in brain dissemination yet little is known about the mechanism(s) accounting for this observation. Here, we investigated whether the presence or absence of laccase altered the local immune response in the lungs by comparing infections with the highly virulent strain, H99 (which expresses laccase) and mutant strain of H99 deficient in laccase (lac1Δ) in a mouse model of pulmonary infection. We found that LAC1 gene deletion decreased the pulmonary fungal burden and abolished CNS dissemination at weeks 2 and 3. Furthermore, LAC1 deletion lead to: 1) diminished pulmonary eosinophilia; 2) increased accumulation of CD4+ and CD8+ T cells; 3) increased Th1 and Th17 cytokines yet decreased Th2 cytokines; and 4) lung macrophage shifting of the lung macrophage phenotype from M2- towards M1-type activation. Next, we used adoptively transferred CD4+ T cells isolated from pulmonary lymph nodes of mice infected with either lac1Δ or H99 to evaluate the role of laccase-induced immunomodulation on CNS dissemination. We found that in comparison to PBS treated mice, adoptively transferred CD4+ T cells isolated from lac1Δ-infected mice decreased CNS dissemination, while those isolated from H99-infected mice increased CNS dissemination. Collectively, our findings reveal that immune modulation away from Th1/Th17 responses and towards Th2 responses represents a novel mechanism through which laccase can contribute to cryptococcal virulence. Furthermore, our data support the hypothesis that laccase-induced changes in polarization of CD4+ T cells contribute to CNS dissemination.

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Contribution of interferon-γ in protecting mice during pulmonary and disseminated infection with

Cited by 13 publications

References 26 publications

Scavenger Receptor A Modulates the Immune Response to Pulmonary Cryptococcus neoformans Infection

Scavenger Receptor A Modulates the Immune Response to Pulmonary Cryptococcus neoformans Infection

Insights into the Mechanisms of Protective Immunity against Cryptococcus neoformans Infection Using a Mouse Model of Pulmonary Cryptococcosis

Immune Modulation Mediated by Cryptococcal Laccase Promotes Pulmonary Growth and Brain Dissemination of Virulent Cryptococcus neoformans in Mice

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