B cell Compartmentalization in Blood and Cerebrospinal Fluid of HIV-Infected Ugandans with Cryptococcal Meningitis

Okurut, Samuel; Meya, David B.; Bwanga, Freddie; Olobo, Joseph; Eller, Michael A.; Cham-Jallow, Fatim; Bohjanen, Paul R.; Pratap, Harsh; Palmer, Brent E.; Hullsiek, Katharine H.; Manabe, Yukari C.; Boulware, David R.; Janoff, Edward N.

doi:10.1101/759092

Cited by 2 publications

(2 citation statements)

References 48 publications

(37 reference statements)

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“…SO -was a Fogarty and GlaxoSmithKline-Trust in Science Africa funded doctoral scholar at Infectious Diseases Institute, Makerere University. Part of the work contributed to the doctoral successful doctoral thesis examination at the Department of Medical Microbiology, School of Biomedical Sciences, College of Health Sciences, Makerere University [42]. AMK -was a member of a data safety monitoring board.…”

Section: Conflict Of Interestmentioning

confidence: 99%

Impact of Cerebrospinal Fluid Leukocyte Infiltration and Neuroimmmune Mediators on Survival with HIV-Associated Cryptococcal Meningitis

Okurut,

Boulware,

Manabe

et al. 2024

Preprint

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IntroductionCryptococcal meningitis remains a prominent cause of death in persons with advanced HIV disease. CSF leukocyte infiltration predicts survival at 18 weeks; however, how CSF immune response relates to CSF leukocyte infiltration is unknown.MethodsWe enrolled 401 adults with HIV-associated cryptococcal meningitis in Uganda who received amphotericin and fluconazole induction therapy. We assessed the association of CSF leukocytes, chemokine, and cytokine responses with 18-week survival.ResultsParticipants with CSF leukocytes ≥50/µL, had higher probability 68% (52/77) of 18-week survival compared with 52% (151/292) 18-week survival in those with ≤50 cells/µL (Hazard Ratio=1.63, 95% confidence intervals 1.14-2.23; p=0.008). Survival was also associated with higher expression of T helper (Th)-1, Th17 cytokines, and immune regulatory elements. CSF levels of Programmed Death-1 Ligand, CXCL10, and Interleukin (IL)-2 independently predicted survival. In multivariate analysis, CSF leukocytes were inversely associated with CSF fungal burden and positively associated with CSF protein, interferon-gamma (IFN-γ), IL-17A, tumor necrosis factor (TNF)-α, and peripheral blood CD4+and CD8+T cells expression.Conclusion18-week survival after diagnosis of cryptococcal meningitis was associated with higher CSF leukocytes at baseline with greater T helper 1 (IFN-γ, IL-2 and TNF-α cytokines), T helper 17 (IL-17A cytokine) and CXCR3+T cell (CXCL10 chemokine) responses. These results highlight the interdependent contribution of soluble and cellular immune responses in predicting survival with HIV-associated cryptococcal meningitis.

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Section: Conflict Of Interestmentioning

confidence: 99%

Impact of Cerebrospinal Fluid Leukocyte Infiltration and Neuroimmmune Mediators on Survival with HIV-Associated Cryptococcal Meningitis

Okurut,

Boulware,

Manabe

et al. 2024

Preprint

Self Cite

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“…Study participants or funders had no role in the design, data curation, or intention to publish. Part of this work was presented in an accepted abstract and poster at the Conference on Retroviruses and Opportunistic Infections (CROI) at Seattle Convention Center, Seattle, Washington, 19-22 February 2023 and was published online on CROI website 96 . SO was a doctoral fellow and the examined thesis abstract was published online by the Makerere University Online Library as a requirement degree award 97 .…”

Section: Conflict Of Interestmentioning

confidence: 99%

Divergent Neuroimmune Signatures in the Cerebrospinal Fluid Predict Differential Gender-Specific Survival Among Patients With HIV-Associated Cryptococcal Meningitis

Okurut

Boulware

Okafor

et al. 2023

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Survival among people with HIV-associated cryptococcal meningitis (CM) remains low, exceptionally among women with the increased threat of death on the current optimal use of antifungal drugs. Cryptococcus dissemination into the central nervous system (CNS) prompts a neuroimmune reaction to activate pathogen-concomitant factors. However, no consistent diagnostic or prognostic immune-mediated signature is reported to underpin the risk of death or mechanism to improve treatment or survival. We theorized that the distinct neuroimmune cytokine or chemokine signatures in the cerebrospinal fluid (CSF), distinguish survivors from people who died on antifungal treatment, who may benefit from tailored therapy. We considered the baseline clinical disease features, cryptococcal microbiologic factors, and CSF neuroimmune modulated signatures among 419 consenting adults by gender (biological sex assigned at birth) (168 females and 251 males) by 18 weeks of survival on antifungal management. Survival at 18 weeks was inferior among females than males (47% vs. 59%; hazard ratio HR=1.4, 95% CI: 1.0 to 1.9, and p=0.023). Unsupervised principal component analysis (PCA) demonstrated the divergent neuroimmune signatures by gender, survival, and intragender-specific survival. Overall, females displayed lower levels of PD-L1, IL-1RA, and IL-15 than males (all p<=0.028). Female survivors compared with those who died, expressed significant fold elevations in levels of CSF (CCL11 - myeloid and CXCL10 - lymphoid chemokine (in both p=0.001), and CSF Th1, Th2, and Th17 cytokines. In contrast, male survivors expressed distinctly lower levels of CSF IL-15 and IL-8 compared with those who died. Survivors of either gender demonstrated a significant increase in the levels of immune regulatory element, IL-10. In the finale, we classified divergent neuroimmune key signatures in CSF by gender, survival, and intragender-specific survival among people with HIV-associated cryptococcal meningitis. These intragender-specific survival-associated neuroimmune signatures suggest the discrete role of gender immune regulating mechanisms as the possible targets for interventions to advance therapy to improve survival among people with HIV-associated cryptococcal meningitis.

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B cell Compartmentalization in Blood and Cerebrospinal Fluid of HIV-Infected Ugandans with Cryptococcal Meningitis

Abstract: 211 words 32

Cited by 2 publications

References 48 publications

Impact of Cerebrospinal Fluid Leukocyte Infiltration and Neuroimmmune Mediators on Survival with HIV-Associated Cryptococcal Meningitis

Impact of Cerebrospinal Fluid Leukocyte Infiltration and Neuroimmmune Mediators on Survival with HIV-Associated Cryptococcal Meningitis

Divergent Neuroimmune Signatures in the Cerebrospinal Fluid Predict Differential Gender-Specific Survival Among Patients With HIV-Associated Cryptococcal Meningitis

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