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MyD88-dependent signaling drives host survival and early cytokine production during Histoplasma capsulatum infection.

ABSTRACT: The ability of the innate immune system to trigger an adaptive T cell response is critical to resolution of infection with the fungal pathogen Histoplasma capsulatum. However, the signaling pathways and cell types involved in the recognition of and response to this respiratory pathogen remain poorly defined. Here, we show that MyD88, an adaptor protein vital to multiple innate immune pathways, is critically required for the host response to Histoplasma. MyD88-deficient (MyD88-/-) mice are unable to control the fungal burden and are more sensitive to Histoplasma infection than wild-type, Dectin-1-/-, or interleukin 1 receptor-deficient (IL-1R-/-) mice. We found that MyD88 is necessary for the production of key early inflammatory cytokines and the subsequent recruitment of inflammatory monocytes to the lung. In both our in vitro and ex vivo analyses, MyD88 was intrinsically required in dendritic cells and alveolar macrophages for initial cytokine production. Additionally, MyD88-deficient bone marrow-derived dendritic cells fail to efficiently control fungal growth when cocultured with primed splenic T cells. Surprisingly, mice that lack MyD88 only in dendritic cells and alveolar macrophages are competent for early cytokine production and normal survival, indicating the presence of compensatory and redundant MyD88 signaling in other cell types during infection. Ultimately, global MyD88 deficiency prevents proper T cell activation and gamma interferon (IFN-?) production, which are critical for infection resolution. Collectively, this work reveals a central role for MyD88 in coordinating the innate and adaptive immune responses to infection with this ubiquitous fungal pathogen of humans.

SUBMITTER: Coady A

PROVIDER: S-EPMC4363404 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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MyD88-dependent signaling drives host survival and early cytokine production during Histoplasma capsulatum infection.

Coady Alison A Sil Anita A

Infection and immunity 20150112 4

The ability of the innate immune system to trigger an adaptive T cell response is critical to resolution of infection with the fungal pathogen Histoplasma capsulatum. However, the signaling pathways and cell types involved in the recognition of and response to this respiratory pathogen remain poorly defined. Here, we show that MyD88, an adaptor protein vital to multiple innate immune pathways, is critically required for the host response to Histoplasma. MyD88-deficient (MyD88-/-) mice are unable ...[more]

PMID: 25583527

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Project description:Recognition and internalisation of intracellular pathogens by host cells is a multifactorial process, involving both stable and transient interactions. The plasticity of the host cell plasma membrane is fundamental in this infectious process. Here, the participation of macrophage lipid microdomains during adhesion and internalisation of the fungal pathogen Histoplasma capsulatum (Hc) was investigated. An increase in membrane lateral organisation, which is a characteristic of lipid microdomains, was observed during the first steps of Hc-macrophage interaction. Cholesterol enrichment in macrophage membranes around Hc contact regions and reduced levels of Hc-macrophage association after cholesterol removal also suggested the participation of lipid microdomains during Hc-macrophage interaction. Using optical tweezers to study cell-to-cell interactions, we showed that cholesterol depletion increased the time required for Hc adhesion. Additionally, fungal internalisation was significantly reduced under these conditions. Moreover, macrophages treated with the ceramide-glucosyltransferase inhibitor (P4r) and macrophages with altered ganglioside synthesis (from B4galnt1-/- mice) showed a deficient ability to interact with Hc. Coincubation of oligo-GM1 and treatment with Cholera toxin Subunit B, which recognises the ganglioside GM1, also reduced Hc association. Although purified GM1 did not alter Hc binding, treatment with P4 significantly increased the time required for Hc binding to macrophages. The content of CD18 was displaced from lipid microdomains in B4galnt1-/- macrophages. In addition, macrophages with reduced CD18 expression (CD18low ) were associated with Hc at levels similar to wild-type cells. Finally, CD11b and CD18 colocalised with GM1 during Hc-macrophage interaction. Our results indicate that lipid rafts and particularly complex gangliosides that reside in lipid rafts stabilise Hc-macrophage adhesion and mediate efficient internalisation during histoplasmosis.

Project description:Eukaryotic cells, including fungi, release extracellular vesicles (EVs). These lipid bilayered compartments play essential roles in cellular communication and pathogenesis. EV composition is complex and includes proteins, glycans, pigments, and RNA. RNAs with putative roles in pathogenesis have been described in EVs produced by fungi. Here we describe the RNA content in EVs produced by the G186AR and G217B strains of Histoplasma capsulatum, an important human-pathogenic fungal pathogen. A total of 124 mRNAs were identified in both strains. In this set of RNA classes, 93 transcripts were enriched in EVs from the G217B strain, whereas 31 were enriched in EVs produced by the G186AR strain. This result suggests that there are important strain-specific properties in the mRNA composition of fungal EVs. We also identified short fragments (25 to 40 nucleotides in length) that were strain specific, with a greater number identified in EVs produced by the G217B strain. Remarkably, the most highly enriched processes were stress responses and translation. Half of these fragments aligned to the reverse strand of the transcript, suggesting the occurrence of microRNA (miRNA)-like molecules in fungal EVs. We also compared the transcriptome profiles of H. capsulatum with the RNA composition of EVs, and no correlation was observed. Taking the results together, our study provided information about the RNA molecules present in H. capsulatum EVs and about the differences in composition between the strains. In addition, we found no correlation between the most highly expressed transcripts in the cell and their presence in the EVs, reinforcing the idea that the RNAs were directed to the EVs by a regulated mechanism.IMPORTANCE Extracellular vesicles (EVs) play important roles in cellular communication and pathogenesis. The RNA molecules in EVs have been implicated in a variety of processes. EV-associated RNA classes have recently been described in pathogenic fungi; however, only a few reports of studies describing the RNAs in fungal EVs are available. Improved knowledge of EV-associated RNA will contribute to the understanding of their role during infection. In this study, we described the RNA content in EVs produced by two isolates of Histoplasma capsulatum Our results add this important pathogen to the current short list of fungal species with the ability to use EVs for the extracellular release of RNA.

Dataset Information

MyD88-dependent signaling drives host survival and early cytokine production during Histoplasma capsulatum infection.

Publications

MyD88-dependent signaling drives host survival and early cytokine production during Histoplasma capsulatum infection.

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