Date Published: July 26, 2016
Publisher: Public Library of Science
Author(s): Nancy Van Prooyen, C. Allen Henderson, Davina Hocking Murray, Anita Sil, Bruce S Klein.
Innate immune cells shape the host response to microbial pathogens. Here we elucidate critical differences in the molecular response of macrophages vs. dendritic cells (DCs) to Histoplasma capsulatum, an intracellular fungal pathogen of humans. It has long been known that macrophages are permissive for Histoplasma growth and succumb to infection, whereas DCs restrict fungal growth and survive infection. We used murine macrophages and DCs to identify host pathways that influence fungal proliferation and host-cell viability. Transcriptional profiling experiments revealed that DCs produced a strong Type I interferon (IFN-I) response to infection with Histoplasma yeasts. Toll-like receptors 7 and 9 (TLR7/9), which recognize nucleic acids, were required for IFN-I production and restriction of fungal growth in DCs, but mutation of TLR7/9 had no effect on the outcome of macrophage infection. Moreover, TLR7/9 were essential for the ability of infected DCs to elicit production of the critical cytokine IFNγ from primed CD4+ T cells in vitro, indicating the role of this pathway in T cell activation. In a mouse model of infection, TLR7/9 were required for optimal production of IFN-I and IFNγ, host survival, and restriction of cerebral fungal burden. These data demonstrate the critical role of this pathway in eliciting an appropriate adaptive immune response in the host. Finally, although other fungal pathogens have been shown to elicit IFN-I in mouse models, the specific host cell responsible for producing IFN-I has not been elucidated. We found that CD103+ conventional DCs were the major producer of IFN-I in the lungs of wild-type mice infected with Histoplasma. Mice deficient in this DC subtype displayed reduced IFN-I production in vivo. These data reveal a previously unknown role for CD103+ conventional DCs and uncover the pivotal function of these cells in modulating the host immune response to endemic fungi.
Key functions of the innate immune system include pathogen recognition, effector cytokine production, and orchestration of an adaptive immune response. Type I interferons (IFN-I) are key effector cytokines that are produced by a variety of innate immune cells. In both humans and mice, the IFN-I family is comprised of 13 IFN-α species, a single IFN-β, and other less-studied members (IFN-ω, -ε, -κ) [1, 2]. The initiation of a proper IFN response plays a critical role in antimicrobial clearance by limiting the spread of infection and orchestrating the initial phases of the adaptive immune response. However, the mechanism of detection and IFN production varies greatly depending on the pathogen and site of infection [1, 3]. Much of our information about the IFN-I response comes from viral and bacterial infection models, whereas the mechanism of induction in response to a fungal pathogen remains relatively unexplored .
Endemic fungi such as Histoplasma capsulatum cause severe morbidity and mortality even in immunocompetent individuals  and the general increase in prevalence of fungal infections has stimulated interest in understanding the host response to these ubiquitous primary pathogens . Here we demonstrate that TLR7/9 signaling in BMDCs is required to mount an IFN-I response, restrict intracellular Histoplasma proliferation, and maintain host cell viability. In contrast, BMMs do not induce IFN-I in response to infection with Histoplasma yeasts, and TLR7/9 do not influence the fate of infected macrophages. BMDCs that lack IFNAR are also unable to restrict fungal growth and are killed by Histoplasma, suggesting that IFN-responsive genes are required to control intracellular fungal proliferation. In the mouse model of Histoplasma infection, TLR7/9 are also required for IFN-I production and host survival. Mice lacking TLR7 and TLR9 display defects in production of IFNγ, a key cytokine for Histoplasma control, which likely contributes to their propensity to succumb to disease.