Dataset Information

Detrimental Influence of Alveolar Macrophages on Protective Humoral Immunity during Francisella tularensis SchuS4 Pulmonary Infection.

ABSTRACT: Opsonizing antibody is a critical component of the host protective immune response against many respiratory pathogens. However, the role of antibodies in protection against pulmonary infection with highly virulent Francisella tularensis strain SchuS4 is unclear, and the mechanism that allows F. tularensis to evade antibody-mediated bacterial clearance is not fully understood. We have now found that depletion of alveolar macrophages reveals an otherwise cryptic protective effect of opsonizing antibody. While antibody opsonization alone failed to confer any survival benefit against SchuS4 lung infection, significant protection was observed when mice were depleted of alveolar macrophages prior to infection. Blood immune signature analyses and bacterial burden measurements indicated that the treatment regimen blocked establishment of productive, systemic infection. In addition, protection was found to be dependent upon neutrophils. The results show for the first time a protective effect of opsonizing antibodies against highly virulent F. tularensis SchuS4 pulmonary infection through depletion of alveolar macrophages, the primary bacterial reservoir, and prevention of systemic dissemination. These findings have important implications for the potential use of therapeutic antibodies against intracellular pathogens that may escape clearance by residing within mucosal macrophages.

SUBMITTER: Steiner DJ

PROVIDER: S-EPMC5865038 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Detrimental Influence of Alveolar Macrophages on Protective Humoral Immunity during Francisella tularensis SchuS4 Pulmonary Infection.

Steiner Donald J DJ Furuya Yoichi Y Metzger Dennis W DW

Infection and immunity 20180322 4

Opsonizing antibody is a critical component of the host protective immune response against many respiratory pathogens. However, the role of antibodies in protection against pulmonary infection with highly virulent <i>Francisella tularensis</i> strain SchuS4 is unclear, and the mechanism that allows <i>F. tularensis</i> to evade antibody-mediated bacterial clearance is not fully understood. We have now found that depletion of alveolar macrophages reveals an otherwise cryptic protective effect of ...[more]

PMID: 29311236

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Project description:Invasive fungal infections, including Pneumocystis Pneumonia (PcP), remain frequent life-threatening conditions of patients with adaptive immune defects. While innate immunity helps control pathogen growth early during infection, it is typically not sufficient for complete protection against Pneumocystis and other human fungal pathogens. Alveolar macrophages (AM) possess pattern recognition molecules capable of recognizing antigenic and structural determinants of Pneumocystis. However, this pathogen effectively evades innate immunity to infect both immunocompetent and immunosuppressed hosts, albeit with differing outcomes. During our studies of mouse models of PcP, the FVB/N strain was identified as unique because of its ability to mount a protective innate immune response against Pneumocystis infection. In contrast to other immunocompetent strains, which become transiently infected prior to the onset of adaptive immunity, FVB/N mice rapidly eradicated Pneumocystis before an adaptive immune response was triggered. Furthermore, FVB/N mice remained highly resistant to infection even in the absence of functional T cells. The effector mechanism of innate protection required the action of functional alveolar macrophages, and the adoptive transfer of resistant FVB/N AMs, but not susceptible CB.17 AMs, conferred protection to immunodeficient mice. Macrophage IFN? receptor signaling was not required for innate resistance, and FVB/N macrophages were found to display markers of alternative activation. IFN? reprogrammed resistant FVB/N macrophages to a permissive M1 biased phenotype through a mechanism that required direct activation of the macrophage IFN?R. These results demonstrate that appropriately programmed macrophages provide protective innate immunity against this opportunistic fungal pathogen, and suggest that modulating macrophage function may represent a feasible therapeutic strategy to enhance antifungal host defense. The identification of resistant and susceptible macrophages provides a novel platform to study not only the mechanisms of macrophage-mediated antifungal defense, but also the mechanisms by which Pneumocystis evades innate immunity.

Dataset Information

Detrimental Influence of Alveolar Macrophages on Protective Humoral Immunity during Francisella tularensis SchuS4 Pulmonary Infection.

Publications

Detrimental Influence of Alveolar Macrophages on Protective Humoral Immunity during Francisella tularensis SchuS4 Pulmonary Infection.

Similar Datasets

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