Conidia but Not Yeast Cells of the Fungal PathogenHistoplasma capsulatumTrigger a Type I Interferon Innate Immune Response in Murine Macrophages

Abstract

Histoplasma capsulatum is the most common cause of fungal respiratory infections and can lead to progressive disseminated infections, particularly in immunocompromised patients. Infection occurs upon inhalation of the aerosolized spores, known as conidia. Once inside the host, conidia are phagocytosed by alveolar macrophages. The conidia subsequently germinate and produce a budding yeast-like form that colonizes host macrophages and can disseminate throughout host organs and tissues. Even though conidia are the predominant infectious particle for H. capsulatum and are the first cell type encountered by the host during infection, very little is known at a molecular level about conidia or about their interaction with cells of the host immune system. We examined the interaction between conidia and host cells in a murine bone-marrow-derived macrophage model of infection. We used whole-genome expression profiling and quantitative reverse transcription-PCR (qRT-PCR) to monitor the macrophage signaling pathways that are modulated during infection with conidia. Our analysis revealed that type I interferon (IFN)-responsive genes and the beta type I IFN (IFN-␤) were induced in macrophages during infection with H. capsulatum conidia but not H. capsulatum yeast cells. Further analysis revealed that the type I IFN signature induced in macrophages in response to conidia is independent of Toll-like receptor (TLR) signaling and the cytosolic RNA sensor MAVS but is dependent on the transcription factor interferon regulatory factor 3 (IRF3). Interestingly, H. capsulatum growth was restricted in mice lacking the type I IFN receptor, indicating that an intact host type I IFN response is required for full virulence of H. capsulatum in mice.

Conventional Dendritic Cells Mount a Type I IFN Response againstCandidaspp. Requiring Novel Phagosomal TLR7-Mediated IFN-β Signaling

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Beneficial innate signaling interference for antibacterial responses by a Toll-like receptor–mediated enhancement of the MKP-IRF3 axis

“…Robust immune responses by APCs are thought to be driven by the cooperation of signaling pathways that emanate from each of the innate receptors (1-5). However, a given innate signaling pathway, essential against some pathogens, may be counterproductive for responses against others (4,(6)(7)(8)(9)(10)(11). Thus, although the main tenet still holds true that innate signaling pathways can engage by cooperation, complementation, and compensation to ensure effective immune responses (12), one may also envisage an additional…”

Comparative Transcriptomics of Infectious Spores from the Fungal Pathogen Histoplasma capsulatum Reveals a Core Set of Transcripts That Specify Infectious and Pathogenic States

“…In previous work, we showed that host macrophages induce different innate immune responses when infected with conidia or yeast cells (4), suggesting that macrophages recognize and respond to an unknown factor(s) that is unique to conidia. Here we describe the development of robust conditions for production and purification of Histoplasma conidia, with the goal of characterizing these cells and comparing their transcriptome to those of yeast and mycelia.…”

“…Bone marrow-derived macrophages (BMDM) from 8-week-old female C57BL/6 mice were obtained as previously described (4,16). BMDM were seeded at 2 ϫ 10 5 cells/well in 24-well dishes in bone marrow-derived macrophage medium and then were incubated overnight at 37°C in 5% CO 2 .…”