The immune events that take place in the central nervous system (CNS) during cryptococcal
infection are incompletely understood. We used competitive reverse transcription-PCR to delineate the time course of the local expression of mRNAs encoding a variety of
cytokines and
inducible nitric oxide synthase (iNOS) during progressive murine cryptococcal
meningoencephalitis and assessed the CNS inflammatory response using immunohistochemistry.
Interleukin 18 (IL-18),
transforming growth factor beta1, and IL-12p(40) mRNAs were constitutively expressed in the brains of infected and uninfected mice;
IL-2 mRNA was not detected at any time. Increased levels of transcripts corresponding to
IL-1 alpha,
tumor necrosis factor alpha (
TNF-alpha), and iNOS were detected as early as day 1 postinfection, with
TNF-alpha rising by approximately 30-fold and iNOS increasing by approximately 5-fold by day 7. Each remained at these levels thereafter.
IL-4,
IL-6, and
gamma interferon transcripts were detected on day 5, and
IL-1 beta and
IL-10 transcripts were detected beginning on day 7. Once detected, each remained at a relatively constant level through 28 days of
infection. This
cytokine profile does not suggest a polarized Th1 or Th2 response. Immunohistochemistry did not reveal inflammatory infiltrates before day 7, despite the presence of cryptococci. Intraparenchymal
abscesses with inflammatory cells in their peripheries were found beginning on day 10. The infiltrates were comprised primarily of cells expressing CD4, CD8, or CD11b; low numbers of cells expressing CD45R/B220 were also present. The persistence of Cryptococcus observed in the CNS may result from an ineffective immune response, perhaps owing to an insufficient anticryptococcal effector function of endogenous glial cells resulting from competing pro- and anti-inflammatory
cytokines. These data detail the immune response in the brain and could be important for the future design of specific
immunomodulatory therapies for this important
opportunistic infection.