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


METHODS
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 CD56(bright) (immunoregulatory) NK cells (P = 0.0004). At enrolment, CXCR3 expression was more frequent among blood CD56(bright) than either blood CD56(dim) (P < 0.0001) or CSF CD56(bright) (P = 0.0002) NK cells. Antifungal therapy diminished blood (P < 0.05), but not CSF CXCR3(pos) NK-cell proportions nor CX3CR1(pos) NK-cell proportions. CD56(bright) and CD56(dim) NK cells were more activated in CSF than blood (P < 0.0001). Antifungal therapy induction reduced CD56(dim) NK-cell activation in CSF (P = 0.02). Activation of blood CD56(bright) and CD56(dim) 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).


CONCLUSIONS
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.
Vivek
V
Naranbhai
Christina C
CC
Chang
Raveshni
R
Durgiah
Saleha
S
Omarjee
Andrew
A
Lim
Mahomed-Yunus S
MY
Moosa
Julian H
JH
Elliot
Thumbi
T
Ndung'u
Sharon R
SR
Lewin
Martyn A
MA
French
William H
WH
Carr
D000328:Adult; D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D001773:Blood Cells; D002490:Central Nervous System / Q000276:immunology*; D002555:Cerebrospinal Fluid / Q000166:cytology; D015331:Cohort Studies; D060085:Coinfection / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000737:chemistry / Q000276:immunology; D037181:Lectins, C-Type / Q000032:analysis; D008297:Male; D016919:Meningitis, Cryptococcal / Q000276:immunology*; D008875:Middle Aged; D009000:Monocytes / Q000737:chemistry / Q000276:immunology; D011446:Prospective Studies; D054367:Receptors, CXCR3 / Q000032:analysis; D023062:Receptors, Interleukin-8A / Q000032:analysis; D013019:South Africa; D055815:Young Adult; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016207:Cytokines; D037181:Lectins, C-Type; D054367:Receptors, CXCR3; D023062:Receptors, Interleukin-8A; D000099192:CD69 Antigens; C515187:CXCR3 protein, human