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Compartmentalization of innate immune responses in the central nervous system during cryptococcal meningitis/HIV coinfection

Naranbhai, Viveka,b,c,*; Chang, Christina C.b,d,e,*; Durgiah, Raveshnib; Omarjee, Salehab; Lim, Andrewf; Moosa, Mahomed-Yunus S.g; Elliot, Julian H.d,e; Ndung’u, Thumbib,h,i; Lewin, Sharon R.d,e; French, Martyn A.f; Carr, William H.b,j

doi: 10.1097/QAD.0000000000000200
Basic Science

Objective: The role of innate immunity in the pathogenesis of cryptococcal meningitis is unclear. We hypothesized that natural killer (NK) cell and monocyte responses show central nervous system (CNS) compartment-specific profiles, and are altered by antifungal therapy and combination antiretroviral therapy (cART) during cryptococcal meningitis/HIV coinfection.

Design: Substudy of a prospective cohort study of adults with cryptococcal meningitis/HIV coinfection in Durban, South Africa.

Methods: We used multiparametric flow cytometry to study compartmentalization of subsets, CD69 (a marker of activation), CXCR3 and CX3CR1 expression, and cytokine secretion of NK cells and monocytes in freshly collected blood and cerebrospinal fluid (CSF) at diagnosis (n = 23), completion of antifungal therapy induction (n = 19), and after a further 4 weeks of cART (n = 9).

Results: Relative to blood, CSF was enriched with CD56bright (immunoregulatory) NK cells (P = 0.0004). At enrolment, CXCR3 expression was more frequent among blood CD56bright than either blood CD56dim (P <0.0001) or CSF CD56bright (P = 0.0002) NK cells. Antifungal therapy diminished blood (P <0.05), but not CSF CXCR3pos NK-cell proportions nor CX3CR1pos NK-cell proportions. CD56bright and CD56dim NK cells were more activated in CSF than blood (P <0.0001). Antifungal therapy induction reduced CD56dim NK-cell activation in CSF (P = 0.02). Activation of blood CD56bright and CD56dim NK cells was diminished following cART commencement (P <0.0001, P = 0.03). Immunoregulatory NK cells in CSF tended to secrete higher levels of CXCL10 (P = 0.06) and lower levels of tumor necrosis factor α (P = 0.06) than blood immunoregulatory NK cells. CSF was enriched with nonclassical monocytes (P = 0.001), but antifungal therapy restored proportions of classical monocytes (P = 0.007).

Conclusion: These results highlight CNS activation, trafficking, and function of NK cells and monocytes in cryptococcal meningitis/HIV and implicate immunoregulatory NK cells and proinflammatory monocytes as potential modulators of cryptococcal meningitis pathogenesis during HIV coinfection.

aCentre for the AIDS Programme of Research in South Africa

bHIV Pathogenesis Programme, Nelson R Mandela School of Medicine, University of KwaZulu Natal, Durban, South Africa

cNuffield Department of Medicine, University of Oxford, Oxford, UK

dDepartment of Infectious Diseases, Monash University and Alfred Hospital

eCentre for Biomedical Research, Burnet Institute, Melbourne

fSchool of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia

gDepartment of Infectious Diseases, Nelson R Mandela School of Medicine

hKwaZulu-Natal Research Institute for Tuberculosis and HIV(K-RITH), University of KwaZulu Natal, Durban, South Africa

iMax Planck Institute for Infection Biology, Berlin, Germany

jMedgar Evers College (City University of New York), Brooklyn, New York, USA.

*Vivek Naranbhai and Christina C. Chang contributed equally to the writing of the article.

Correspondence to Vivek Naranbhai, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. E-mail:

Received 12 November, 2013

Revised 6 January, 2014

Accepted 6 January, 2014

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© 2014 Lippincott Williams & Wilkins, Inc.