Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from <named-content content-type="genus-species">Cryptococcus gattii</named-content> Independently of T Cells

ABSTRACT Cryptococcus neoformans causes deadly mycosis primarily in AIDS patients, whereas Cryptococcus gattii infects mostly non-HIV patients, even in regions with high burdens of HIV/AIDS and an established environmental presence of C. gattii. As HIV induces type I IFN (t1IFN), we hypothesized tha...

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Autores principales:	Michael J. Davis, Shannon Moyer, Elizabeth S. Hoke, Edward Sionov, Katrin D. Mayer-Barber, Dan L. Barber, Hongyi Cai, Lisa Jenkins, Peter J. Walter, Yun C. Chang, Kyung J. Kwon-Chung
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Cryptococcus gattii Cryptococcus neoformans HIV MDA-5 interferons iron Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ab76c103e8fd408b9740ad489cd574c4
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spelling	oai:doaj.org-article:ab76c103e8fd408b9740ad489cd574c42021-11-15T15:55:24ZPulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from <named-content content-type="genus-species">Cryptococcus gattii</named-content> Independently of T Cells10.1128/mBio.00799-192150-7511https://doaj.org/article/ab76c103e8fd408b9740ad489cd574c42019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00799-19https://doaj.org/toc/2150-7511ABSTRACT Cryptococcus neoformans causes deadly mycosis primarily in AIDS patients, whereas Cryptococcus gattii infects mostly non-HIV patients, even in regions with high burdens of HIV/AIDS and an established environmental presence of C. gattii. As HIV induces type I IFN (t1IFN), we hypothesized that t1IFN would differentially affect the outcome of C. neoformans and C. gattii infections. Exogenous t1IFN induction using stabilized poly(I·C) (pICLC) improved murine outcomes in either cryptococcal infection. In C. neoformans-infected mice, pICLC activity was associated with C. neoformans containment and classical Th1 immunity. In contrast, pICLC activity against C. gattii did not require any immune factors previously associated with C. neoformans immunity: T, B, and NK cells, IFN-γ, and macrophages were all dispensable. Interestingly, C. gattii pICLC activity depended on β-2-microglobulin, which impacts iron levels among other functions. Iron supplementation reversed pICLC activity, suggesting C. gattii pICLC activity requires iron limitation. Also, pICLC induced a set of iron control proteins, some of which were directly inhibitory to cryptococcus in vitro, suggesting t1IFN regulates iron availability in the pulmonary air space fluids. Thus, exogenous induction of t1IFN significantly improves the outcome of murine infection by C. gattii and C. neoformans but by distinct mechanisms; the C. gattii effect was mediated by iron limitation, while the effect on C. neoformans infection was through induction of classical T-cell-dependent immunity. Together this difference in types of T-cell-dependent t1IFN immunity for different Cryptococcus species suggests a possible mechanism by which HIV infection may select against C. gattii but not C. neoformans. IMPORTANCE Cryptococcus neoformans and Cryptococcus gattii cause fatal infection in immunodeficient and immunocompetent individuals. While these fungi are sibling species, C. gattii infects very few AIDS patients, while C. neoformans infection is an AIDS-defining illness, suggesting that the host response to HIV selects C. neoformans over C. gattii. We used a viral mimic molecule (pICLC) to stimulate the immune response, and pICLC treatment improved mouse outcomes from both species. pICLC-induced action against C. neoformans was due to activation of well-defined immune pathways known to deter C. neoformans, whereas these immune pathways were dispensable for pICLC treatment of C. gattii. Since these immune pathways are eventually destroyed by HIV/AIDS, our data help explain why the antiviral immune response in AIDS patients is unable to control C. neoformans infection but is protective against C. gattii. Furthermore, pICLC induced tighter control of iron in the lungs of mice, which inhibited C. gattii, thus suggesting an entirely new mode of nutritional immunity activated by viral signals.Michael J. DavisShannon MoyerElizabeth S. HokeEdward SionovKatrin D. Mayer-BarberDan L. BarberHongyi CaiLisa JenkinsPeter J. WalterYun C. ChangKyung J. Kwon-ChungAmerican Society for MicrobiologyarticleCryptococcus gattiiCryptococcus neoformansHIVMDA-5interferonsironMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cryptococcus gattii Cryptococcus neoformans HIV MDA-5 interferons iron Microbiology QR1-502
spellingShingle	Cryptococcus gattii Cryptococcus neoformans HIV MDA-5 interferons iron Microbiology QR1-502 Michael J. Davis Shannon Moyer Elizabeth S. Hoke Edward Sionov Katrin D. Mayer-Barber Dan L. Barber Hongyi Cai Lisa Jenkins Peter J. Walter Yun C. Chang Kyung J. Kwon-Chung Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from <named-content content-type="genus-species">Cryptococcus gattii</named-content> Independently of T Cells
description	ABSTRACT Cryptococcus neoformans causes deadly mycosis primarily in AIDS patients, whereas Cryptococcus gattii infects mostly non-HIV patients, even in regions with high burdens of HIV/AIDS and an established environmental presence of C. gattii. As HIV induces type I IFN (t1IFN), we hypothesized that t1IFN would differentially affect the outcome of C. neoformans and C. gattii infections. Exogenous t1IFN induction using stabilized poly(I·C) (pICLC) improved murine outcomes in either cryptococcal infection. In C. neoformans-infected mice, pICLC activity was associated with C. neoformans containment and classical Th1 immunity. In contrast, pICLC activity against C. gattii did not require any immune factors previously associated with C. neoformans immunity: T, B, and NK cells, IFN-γ, and macrophages were all dispensable. Interestingly, C. gattii pICLC activity depended on β-2-microglobulin, which impacts iron levels among other functions. Iron supplementation reversed pICLC activity, suggesting C. gattii pICLC activity requires iron limitation. Also, pICLC induced a set of iron control proteins, some of which were directly inhibitory to cryptococcus in vitro, suggesting t1IFN regulates iron availability in the pulmonary air space fluids. Thus, exogenous induction of t1IFN significantly improves the outcome of murine infection by C. gattii and C. neoformans but by distinct mechanisms; the C. gattii effect was mediated by iron limitation, while the effect on C. neoformans infection was through induction of classical T-cell-dependent immunity. Together this difference in types of T-cell-dependent t1IFN immunity for different Cryptococcus species suggests a possible mechanism by which HIV infection may select against C. gattii but not C. neoformans. IMPORTANCE Cryptococcus neoformans and Cryptococcus gattii cause fatal infection in immunodeficient and immunocompetent individuals. While these fungi are sibling species, C. gattii infects very few AIDS patients, while C. neoformans infection is an AIDS-defining illness, suggesting that the host response to HIV selects C. neoformans over C. gattii. We used a viral mimic molecule (pICLC) to stimulate the immune response, and pICLC treatment improved mouse outcomes from both species. pICLC-induced action against C. neoformans was due to activation of well-defined immune pathways known to deter C. neoformans, whereas these immune pathways were dispensable for pICLC treatment of C. gattii. Since these immune pathways are eventually destroyed by HIV/AIDS, our data help explain why the antiviral immune response in AIDS patients is unable to control C. neoformans infection but is protective against C. gattii. Furthermore, pICLC induced tighter control of iron in the lungs of mice, which inhibited C. gattii, thus suggesting an entirely new mode of nutritional immunity activated by viral signals.
format	article
author	Michael J. Davis Shannon Moyer Elizabeth S. Hoke Edward Sionov Katrin D. Mayer-Barber Dan L. Barber Hongyi Cai Lisa Jenkins Peter J. Walter Yun C. Chang Kyung J. Kwon-Chung
author_facet	Michael J. Davis Shannon Moyer Elizabeth S. Hoke Edward Sionov Katrin D. Mayer-Barber Dan L. Barber Hongyi Cai Lisa Jenkins Peter J. Walter Yun C. Chang Kyung J. Kwon-Chung
author_sort	Michael J. Davis
title	Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from <named-content content-type="genus-species">Cryptococcus gattii</named-content> Independently of T Cells
title_short	Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from <named-content content-type="genus-species">Cryptococcus gattii</named-content> Independently of T Cells
title_full	Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from <named-content content-type="genus-species">Cryptococcus gattii</named-content> Independently of T Cells
title_fullStr	Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from <named-content content-type="genus-species">Cryptococcus gattii</named-content> Independently of T Cells
title_full_unstemmed	Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from <named-content content-type="genus-species">Cryptococcus gattii</named-content> Independently of T Cells
title_sort	pulmonary iron limitation induced by exogenous type i ifn protects mice from <named-content content-type="genus-species">cryptococcus gattii</named-content> independently of t cells
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/ab76c103e8fd408b9740ad489cd574c4
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Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from <named-content content-type="genus-species">Cryptococcus gattii</named-content> Independently of T Cells

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