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Naive B cells reduce fungal dissemination in Cryptococcus neoformans infected Rag1-/- mice.

ABSTRACT: IgM and B-1 cell deficient mice exhibit early C. neoformans dissemination from lungs to brain, but a definitive role for B cells in conferring resistance to C. neoformans dissemination has not been established. To address this question, we developed an intranasal (i.n.) C. neoformans infection model in B and T cell deficient Rag1-/- mice and found they also exhibit earlier fungal dissemination and higher brain CFU than wild-type C57Bl/6 (wild-type) mice. To probe the effect of B cells on fungal dissemination, Rag1-/- mice were given splenic (intravenously) or peritoneal (intraperitoneally) B cells from wild-type mice and infected i.n. with C. neoformans 7 d later. Mice that received B cells had lung histopathology resembling wild type mice 14 d post-infection, and B-1, not B-2 or T cells in their lungs, and serum and lung IgM and IgG 21 d post-infection. Lung CFU were comparable in wild-type, Rag1-/-, and Rag1-/- mice that received B cells 21 d post-infection, but brain CFU were significantly lower in mice that received B cells than Rag1-/- mice that did not. To determine if natural antibody can promote immunity in our model, we measured alveolar macrophage phagocytosis of C. neoformans in Rag1-/- mice treated with naive wild-type IgM-sufficient or sIgM-/- IgM-deficient sera before infection. Compared to IgM-deficient sera, IgM-sufficient sera significantly increased phagocytosis. Our data establish B cells are able to reduce early C. neoformans dissemination in mice and suggest natural IgM may be a key mediator of early antifungal immunity in the lungs.

SUBMITTER: Dufaud C

PROVIDER: S-EPMC5955176 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Naïve B cells reduce fungal dissemination in Cryptococcus neoformans infected Rag1<sup>-/-</sup> mice.

Dufaud Chad C Rivera Johanna J Rohatgi Soma S Pirofski Liise-Anne LA

Virulence 20171004 1

IgM and B-1 cell deficient mice exhibit early C. neoformans dissemination from lungs to brain, but a definitive role for B cells in conferring resistance to C. neoformans dissemination has not been established. To address this question, we developed an intranasal (i.n.) C. neoformans infection model in B and T cell deficient Rag1<sup>-/-</sup> mice and found they also exhibit earlier fungal dissemination and higher brain CFU than wild-type C57Bl/6 (wild-type) mice. To probe the effect of B cells ...[more]

PMID: 28837391

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Project description:Cryptococcus neoformans, an opportunistic yeast pathogen, relies on a complex network of stress response pathways that allow for proliferation in the host. In Saccharomyces cerevisiae, stress responses are regulated by integral membrane proteins containing a transient receptor potential (TRP) domain, including the flavin carrier protein 1 (Flc1), which regulates calcium homeostasis and flavin transport. Here, we report that deletion of C. neoformans FLC1 results in cytosolic calcium elevation and increased nuclear content of calcineurin-dependent transcription factor Crz1, which is associated with an aberrant cell wall chitin overaccumulation observed in the flc1Δ mutant. Absence of Flc1 or inhibition of calcineurin with cyclosporine A prevents vacuolar fusion under conditions of combined osmotic and temperature stress, which is reversed in the flc1Δ mutant by the inhibition of TORC1 kinase with rapamycin. Flc1-deficient yeasts exhibit compromised vacuolar fusion under starvation conditions, including conditions that stimulate formation of carbohydrate capsule. Consequently, the flc1Δ mutant fails to proliferate under low nutrient conditions and displays a defect in capsule formation. Consistent with the previously uncharacterized role of Flc1 in vacuolar biogenesis, we find that Flc1 localizes to the vacuole. The flc1Δ mutant presents a survival defect in J774A.1 macrophage cell-line and profound virulence attenuation in both the Galleria mellonella and mouse pulmonary infection models, demonstrating that Flc1 is essential for pathogenicity. Thus, cryptococcal Flc1 functions in calcium homeostasis and links calcineurin and TOR signaling with vacuolar biogenesis to promote survival under conditions associated with vacuolar fusion required for this pathogen's fitness and virulence. IMPORTANCE Cryptococcosis is a highly lethal infection with limited drug choices, most of which are highly toxic or complicated by emerging antifungal resistance. There is a great need for new drug targets that are unique to the fungus. Here, we identify such a potential target, the Flc1 protein, which we show is crucial for C. neoformans stress response and virulence. Importantly, homologues of Flc1 exist in other fungal pathogens, such as Candida albicans and Aspergillus fumigatus, and are poorly conserved in humans, which could translate into wider spectrum therapy associated with minimal toxicity. Thus, Flc1 could be an "Achille's heel" of C. neoformans to be leveraged therapeutically in cryptococcosis and possibly other fungal infections.

Dataset Information

Naive B cells reduce fungal dissemination in Cryptococcus neoformans infected Rag1-/- mice.

Publications

Naïve B cells reduce fungal dissemination in Cryptococcus neoformans infected Rag1<sup>-/-</sup> mice.

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