Cryptococcal meningitis is a disease that afflicts approximately 1 million human immunodeficiency virus (HIV)–infected individuals annually, with >600 000 deaths, predominantly in the developing world, where antiretroviral therapy is less available [1]. Therapy of cryptococcal meningitis has been poorly effective in resource-limited settings, where 10-week mortality rates have averaged 25%–30%, even when treatment conditions were optimized under experimental protocols [2, 3], and >50% in routine practice, where access to diagnostic tests and medications is difficult [4]. A rational approach to improving these outcomes has sought to understand microbial and host factors that distinguish favorable from adverse outcomes. Recent work on the microbial side of the equation has successfully demonstrated that rates of fungal clearance from the cerebrospinal fluid are an important prognostic marker in cryptococcal meningitis [5, 6]. However, understanding host factors associated with successful outcomes has been more problematic. The majority of our understanding of the host response to Cryptococcus neoformans comes from animal data [7]. Such studies have laid important foundations, such as the role of T-helper 1 (Th1)–type T cell responses [8, 9] and the associated cytokines interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) [10] in the successful activation of macrophages and microbial killing. In contrast, T-helper 2 (Th2) mechanisms, associated with interleukin 4 and interleukin 10, are detrimental [11]. However, translation of these immunological principals into efficacious treatments for human cryptococcal meningitis infections has been difficult, as exemplified by the lack of mortality benefit to immunotherapy with the “protective” cytokine interferon gamma [12], as well as by the “Cryptococcal Optimal ART Timing” (COAT) study, which sought to improve effective immune responses to the fungus but was stopped prematurely because of excess deaths in the early antiviral treatment arm [13]. The outcome of the COAT study was particularly vexing as recent studies have shown benefit of early antiretroviral therapy in other opportunistic infections, including pneumocystis pneumonia [14] and tuberculosis [15–17]. Thus, to explore the human host response in HIV-associated cryptococcal meningitis, Jarvis et al [18], as reported in this issue of the Journal, undertook a detailed study of cryptococcal-specific peripheral CD4 T-cell responses and selected cerebrospinal fluid cytokines in 44 HIV-infected patients with cryptococcal meningitis. Samples were collected at baseline and during follow-up from patients in the trial of interferon gamma therapy, cited above, that was performed in Cape Town, South Africa, between 2007 and 2010 [12]. A partially purified mixture of T-cell–activating cryptococcal mannoproteins was used as the stimulant of peripheral blood cells. Cryptococcal mannoproteins are extensively Omannosylated and facilitate recognition by mannose receptors on antigen-presenting cells, particularly dendritic cells, resulting in efficient antigen uptake and presentation to T cells [19]. These C. neoformans mannoprotein–induced responses were compared with responses to Mycobacterium tuberculosis or cytomegalovirus (CMV), using specific antigens, since over half of the patients were either being treated for tuberculosis or had a history of tuberculosis; CMV exposure is widespread among individuals in Africa, as it is in most regions of the world [20]. These studies demonstrated that C. neoformans–specific CD4 T-cell responses were characterized by the production of CCL3/macrophage inflammatory protein 1α (MIP-1α), IFN-γ, and TNF-α. Interestingly, using a newly developed Received and accepted 23 January 2013; electronically published 14 March 2013. Correspondence: Peter R. Williamson, MD, PhD, 9000 Rockville Pike, Bldg 10, Rm 11N222, MSC 1888, Bethesda, MD 20892 (williamsonpr@mail.nih.gov). The Journal of Infectious Diseases 2013;207:1793–5 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2013. DOI: 10.1093/infdis/jit102
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Apr 25, 2024
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