Divergent neuroimmune signatures in the cerebrospinal fluid predict differential gender-specific survival among patients with HIV-associated cryptococcal meningitis
IntroductionSurvival among people with HIV-associated cryptococcal meningitis (CM) remains low, particularly among women, despite the currently optimal use of antifungal drugs. Cryptococcus dissemination into the central nervous system [brain, spinal cord, and cerebrospinal fluid (CSF)] elicits the...
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| Format: | Article |
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Frontiers Media S.A.
2023-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1275443/full |
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| author | Samuel Okurut Samuel Okurut David R. Boulware Elizabeth Okafor Joshua Rhein Henry Kajumbula Bernard S. Bagaya Freddie Bwanga Joseph O. Olobo Yukari C. Manabe Yukari C. Manabe David B. Meya David B. Meya David B. Meya Edward N. Janoff Edward N. Janoff |
| author_facet | Samuel Okurut Samuel Okurut David R. Boulware Elizabeth Okafor Joshua Rhein Henry Kajumbula Bernard S. Bagaya Freddie Bwanga Joseph O. Olobo Yukari C. Manabe Yukari C. Manabe David B. Meya David B. Meya David B. Meya Edward N. Janoff Edward N. Janoff |
| author_sort | Samuel Okurut |
| collection | DOAJ |
| description | IntroductionSurvival among people with HIV-associated cryptococcal meningitis (CM) remains low, particularly among women, despite the currently optimal use of antifungal drugs. Cryptococcus dissemination into the central nervous system [brain, spinal cord, and cerebrospinal fluid (CSF)] elicits the local production of cytokines, chemokines, and other biomarkers. However, no consistent diagnostic or prognostic neuroimmune signature is reported to underpin the risk of death or to identify mechanisms to improve treatment and survival. We hypothesized that distinct neuroimmune signatures in the CSF would distinguish survivors from people who died on antifungal treatment and who may benefit from tailored therapy.MethodsWe considered baseline clinical features, CSF cryptococcal fungal burden, and CSF neuroimmune signatures with survival at 18 weeks among 419 consenting adults by “gender” (168 women and 251 men by biological sex defined at birth).ResultsSurvival at 18 weeks was significantly lower among women than among men {47% vs. 59%, respectively; hazard ratio (HR) = 1.4 [95% confidence interval (CI), 1.0 to 1.9; p = 0.023]}. Unsupervised principal component analysis (PCA) demonstrated divergent neuroimmune signatures by gender, survival, and intragender-specific survival. Overall, women had lower levels of programmed death ligand 1, Interleukin (IL) (IL-11RA/IL-1F30, and IL-15 (IL-15) than men (all p < 0.028). Female survivors compared with those who died expressed significant elevations in levels of CCL11 and CXCL10 chemokines (both p = 0.001), as well as increased T helper 1, regulatory, and T helper 17 cytokines (all p < 0.041). In contrast, male survivors expressed lower levels of IL-15 and IL-8 compared with men who died (p < 0.044).ConclusionsSurvivors of both genders demonstrated a significant increase in the levels of immune regulatory IL-10. In conclusion, the lower survival among women with CM was accompanied by distinct differential gender-specific neuroimmune signatures. These female and male intragender-specific survival–associated neuroimmune signatures provide potential targets for interventions to advance therapy to improve the low survival among people with HIV-associated CM. |
| first_indexed | 2024-03-08T23:48:56Z |
| format | Article |
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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-08T23:48:56Z |
| publishDate | 2023-12-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-85c7253969b7452594bd58c0ae40b4792023-12-13T13:45:13ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-12-011410.3389/fimmu.2023.12754431275443Divergent neuroimmune signatures in the cerebrospinal fluid predict differential gender-specific survival among patients with HIV-associated cryptococcal meningitisSamuel Okurut0Samuel Okurut1David R. Boulware2Elizabeth Okafor3Joshua Rhein4Henry Kajumbula5Bernard S. Bagaya6Freddie Bwanga7Joseph O. Olobo8Yukari C. Manabe9Yukari C. Manabe10David B. Meya11David B. Meya12David B. Meya13Edward N. Janoff14Edward N. Janoff15Translation Sciences Laboratory, Research Department, Infectious Diseases Institute, Makerere University, Kampala, UgandaDepartment of Medical Microbiology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, UgandaDivision of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, United StatesDivision of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, United StatesDivision of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, United StatesDepartment of Medical Microbiology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, UgandaDepartment of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, UgandaDepartment of Medical Microbiology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, UgandaDepartment of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, UgandaTranslation Sciences Laboratory, Research Department, Infectious Diseases Institute, Makerere University, Kampala, UgandaDivision of Infectious Diseases, Department of Medicine, John Hopkins University School of Medicine, Baltimore, MD, United StatesTranslation Sciences Laboratory, Research Department, Infectious Diseases Institute, Makerere University, Kampala, UgandaDivision of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, United StatesDepartment of Medicine, School of Medicine, College of Health Sciences, Makerere University, Kampala, UgandaMucosal and Vaccine Research Program Colorado, Department of Medicine, Division of Infectious Diseases, University of Colorado Denver, Aurora, CO, United StatesDepartment of Medicine and Infectious Disease, Denver Veterans Affairs Medical Center, Denver, CO, United StatesIntroductionSurvival among people with HIV-associated cryptococcal meningitis (CM) remains low, particularly among women, despite the currently optimal use of antifungal drugs. Cryptococcus dissemination into the central nervous system [brain, spinal cord, and cerebrospinal fluid (CSF)] elicits the local production of cytokines, chemokines, and other biomarkers. However, no consistent diagnostic or prognostic neuroimmune signature is reported to underpin the risk of death or to identify mechanisms to improve treatment and survival. We hypothesized that distinct neuroimmune signatures in the CSF would distinguish survivors from people who died on antifungal treatment and who may benefit from tailored therapy.MethodsWe considered baseline clinical features, CSF cryptococcal fungal burden, and CSF neuroimmune signatures with survival at 18 weeks among 419 consenting adults by “gender” (168 women and 251 men by biological sex defined at birth).ResultsSurvival at 18 weeks was significantly lower among women than among men {47% vs. 59%, respectively; hazard ratio (HR) = 1.4 [95% confidence interval (CI), 1.0 to 1.9; p = 0.023]}. Unsupervised principal component analysis (PCA) demonstrated divergent neuroimmune signatures by gender, survival, and intragender-specific survival. Overall, women had lower levels of programmed death ligand 1, Interleukin (IL) (IL-11RA/IL-1F30, and IL-15 (IL-15) than men (all p < 0.028). Female survivors compared with those who died expressed significant elevations in levels of CCL11 and CXCL10 chemokines (both p = 0.001), as well as increased T helper 1, regulatory, and T helper 17 cytokines (all p < 0.041). In contrast, male survivors expressed lower levels of IL-15 and IL-8 compared with men who died (p < 0.044).ConclusionsSurvivors of both genders demonstrated a significant increase in the levels of immune regulatory IL-10. In conclusion, the lower survival among women with CM was accompanied by distinct differential gender-specific neuroimmune signatures. These female and male intragender-specific survival–associated neuroimmune signatures provide potential targets for interventions to advance therapy to improve the low survival among people with HIV-associated CM.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1275443/fullcryptococcal meningitiscerebrospinal fluid (CSF)neuroimmune responseschemokine CXCL10cytokine IL-15CCL11/Eotaxin |
| spellingShingle | Samuel Okurut Samuel Okurut David R. Boulware Elizabeth Okafor Joshua Rhein Henry Kajumbula Bernard S. Bagaya Freddie Bwanga Joseph O. Olobo Yukari C. Manabe Yukari C. Manabe David B. Meya David B. Meya David B. Meya Edward N. Janoff Edward N. Janoff Divergent neuroimmune signatures in the cerebrospinal fluid predict differential gender-specific survival among patients with HIV-associated cryptococcal meningitis Frontiers in Immunology cryptococcal meningitis cerebrospinal fluid (CSF) neuroimmune responses chemokine CXCL10 cytokine IL-15 CCL11/Eotaxin |
| title | Divergent neuroimmune signatures in the cerebrospinal fluid predict differential gender-specific survival among patients with HIV-associated cryptococcal meningitis |
| title_full | Divergent neuroimmune signatures in the cerebrospinal fluid predict differential gender-specific survival among patients with HIV-associated cryptococcal meningitis |
| title_fullStr | Divergent neuroimmune signatures in the cerebrospinal fluid predict differential gender-specific survival among patients with HIV-associated cryptococcal meningitis |
| title_full_unstemmed | Divergent neuroimmune signatures in the cerebrospinal fluid predict differential gender-specific survival among patients with HIV-associated cryptococcal meningitis |
| title_short | Divergent neuroimmune signatures in the cerebrospinal fluid predict differential gender-specific survival among patients with HIV-associated cryptococcal meningitis |
| title_sort | divergent neuroimmune signatures in the cerebrospinal fluid predict differential gender specific survival among patients with hiv associated cryptococcal meningitis |
| topic | cryptococcal meningitis cerebrospinal fluid (CSF) neuroimmune responses chemokine CXCL10 cytokine IL-15 CCL11/Eotaxin |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1275443/full |
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