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Splenic macrophages are required for protective innate immunity against West Nile virus.

ABSTRACT: Although the spleen is a major site for West Nile virus (WNV) replication and spread, relatively little is known about which innate cells in the spleen replicate WNV, control viral dissemination, and/or prime innate and adaptive immune responses. Here we tested if splenic macrophages (M?s) were necessary for control of WNV infection. We selectively depleted splenic M?s, but not draining lymph node M?s, by injecting mice intravenously with clodronate liposomes several days prior to infecting them with WNV. Mice missing splenic M?s succumbed to WNV infection after an increased and accelerated spread of virus to the spleen and the brain. WNV-specific Ab and CTL responses were normal in splenic M?-depleted mice; however, numbers of NK cells and CD4 and CD8 T cells were significantly increased in the brains of infected mice. Splenic M? deficiency led to increased WNV in other splenic innate immune cells including CD11b- DCs, newly formed M?s and monocytes. Unlike other splenic myeloid subsets, splenic M?s express high levels of mRNAs encoding the complement protein C1q, the apoptotic cell clearance protein Mertk, the IL-18 cytokine and the Fc?R1 receptor. Splenic M?-deficient mice may be highly susceptible to WNV infection in part to a deficiency in C1q, Mertk, IL-18 or Caspase 12 expression.

SUBMITTER: Bryan MA

PROVIDER: S-EPMC5800658 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Splenic macrophages are required for protective innate immunity against West Nile virus.

Bryan Marianne A MA Giordano Daniela D Draves Kevin E KE Green Richard R Gale Michael M Clark Edward A EA

PloS one 20180206 2

Although the spleen is a major site for West Nile virus (WNV) replication and spread, relatively little is known about which innate cells in the spleen replicate WNV, control viral dissemination, and/or prime innate and adaptive immune responses. Here we tested if splenic macrophages (MΦs) were necessary for control of WNV infection. We selectively depleted splenic MΦs, but not draining lymph node MΦs, by injecting mice intravenously with clodronate liposomes several days prior to infecting them ...[more]

PMID: 29408905

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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.

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Splenic macrophages are required for protective innate immunity against West Nile virus.

Publications

Splenic macrophages are required for protective innate immunity against West Nile virus.

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