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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2019-06-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00799-19 |
| _version_ | 1818932581691817984 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-20T04:34:46Z |
| format | Article |
| id | doaj.art-ab76c103e8fd408b9740ad489cd574c4 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-20T04:34:46Z |
| publishDate | 2019-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-ab76c103e8fd408b9740ad489cd574c42022-12-21T19:53:18ZengAmerican Society for MicrobiologymBio2150-75112019-06-0110310.1128/mBio.00799-19Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from <named-content content-type="genus-species">Cryptococcus gattii</named-content> Independently of T CellsMichael J. Davis0Shannon Moyer1Elizabeth S. Hoke2Edward Sionov3Katrin D. Mayer-Barber4Dan L. Barber5Hongyi Cai6Lisa Jenkins7Peter J. Walter8Yun C. Chang9Kyung J. Kwon-Chung10Molecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USAMolecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USAMolecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USAMolecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USAInflammation & Innate Immunity Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USAT-Lymphocyte Biology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USAClinical Mass Spectrometry Core, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, Maryland, USATransport Biochemistry Section, Laboratory of Cell Biology, National Cancer Institute (NCI), Bethesda, Maryland, USAClinical Mass Spectrometry Core, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, Maryland, USAMolecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USAMolecular Microbiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USAABSTRACT 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.https://journals.asm.org/doi/10.1128/mBio.00799-19Cryptococcus gattiiCryptococcus neoformansHIVMDA-5interferonsiron |
| spellingShingle | 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 mBio Cryptococcus gattii Cryptococcus neoformans HIV MDA-5 interferons iron |
| 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_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_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_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 |
| topic | Cryptococcus gattii Cryptococcus neoformans HIV MDA-5 interferons iron |
| url | https://journals.asm.org/doi/10.1128/mBio.00799-19 |
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