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Cytokine and inducible nitric oxide synthase mRNA expression during experimental murine cryptococcal
Claudia M L Maffei1, Laurence F Mirels, Raymond A Sobel
1Department of Cellular and Molecular Biology, School of Medicine of Ribeirão Preto of the University of São Paulo, Ribeirão Preto, São Paulo 14049-900 Brazil.
Abstract:
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.
Insights
The study reveals that cryptococcal meningoencephalitis in mice involves a complex immune response in the central nervous system, with specific cytokines and immune cells appearing at different stages, potentially hindering fungal clearance.
Area of Science:
- Neuroimmunology
- Infectious Diseases
Background:
- Cryptococcal meningoencephalitis is a serious opportunistic infection, particularly in immunocompromised individuals.
- The precise immune mechanisms within the central nervous system (CNS) during cryptococcal infection remain unclear.
Purpose of the Study:
- To characterize the temporal immune response in the CNS during murine cryptococcal meningoencephalitis.
- To identify key cytokines and immune cell infiltrates involved in the host defense against Cryptococcus in the brain.
Main Methods:
- Competitive reverse transcription-PCR was used to quantify mRNA levels of various cytokines and inducible nitric oxide synthase (iNOS).
- Immunohistochemistry was employed to assess the inflammatory response and identify immune cell populations in the CNS.
Main Results:
- Early increases in IL-1 alpha, TNF-alpha, and iNOS transcripts were observed post-infection.
- Later detection of IL-4, IL-6, gamma interferon, IL-1 beta, and IL-10 transcripts indicated a mixed immune response, not a polarized Th1 or Th2 profile.
- Inflammatory infiltrates, including CD4+, CD8+, and CD11b+ cells, were present around abscesses starting around day 10.
Conclusions:
- The observed cytokine profile suggests a complex, non-polarized immune response in the CNS during cryptococcal infection.
- Ineffective anticryptococcal effector functions, potentially due to competing immune mediators, may contribute to persistent Cryptococcus in the CNS.
- These findings provide insights for developing targeted immunomodulatory therapies for cryptococcal meningoencephalitis.
