IFN-gamma at the site of infection determines rate of clearance of infection in cryptococcal meningitis.
In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-gamma, TNF-alpha, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-alpha, IFN-gamma, and IL-6 levels and baseline cryptococcal CFU. Log IFN-gamma, G-CSF, TNF-alpha, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-gamma remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-gamma secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-gamma in the treatment of refractory HIV-associated cryptococcosis.
Siddiqui
Asna A
AA
Department of Infectious Diseases, St. George's Hospital Medical School, London, United Kingdom.
Brouwer
Annemarie E
AE
Wuthiekanun
Vannaporn
V
Jaffar
Shabbar
S
Shattock
Robin
R
Irving
Diane
D
Sheldon
Joanna
J
Chierakul
Wirongrong
W
Peacock
Sharon
S
Day
Nicholas
N
White
Nicholas J
NJ
Harrison
Thomas S
TS
D003455:Cryptococcus neoformans / Q000254:growth & development / Q000276:immunology; D016179:Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis / Q000134:cerebrospinal fluid; D015658:HIV Infections / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000276:immunology / Q000401:mortality; D006801:Humans; D018836:Inflammation Mediators / Q000134:cerebrospinal fluid / Q000378:metabolism; D007371:Interferon-gamma / Q000134:cerebrospinal fluid / Q000378:metabolism*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000134:cerebrospinal fluid; D015850:Interleukin-6 / Q000096:biosynthesis / Q000134:cerebrospinal fluid; D016209:Interleukin-8 / Q000096:biosynthesis / Q000134:cerebrospinal fluid; D016919:Meningitis, Cryptococcal / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000276:immunology* / Q000401:mortality; D015999:Multivariate Analysis; D011379:Prognosis; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000134:cerebrospinal fluid
D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor; D007371:Interferon-gamma