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Isolation and Analysis of Brain-sequestered Leukocytes from Plasmodium berghei ANKA-infected Mice
Published on: January 2, 2013
Early cytokine production is associated with protection from murine cerebral malaria
Andrew J Mitchell1, Anna M Hansen, Leia Hee
1University of Sydney, Department of Pathology, Medical Foundation Building, 92-94 Parramatta Rd., Camperdown NSW 2042, Australia.
Abstract:
Cerebral malaria (CM) is an infrequent but serious complication of Plasmodium falciparum infection in humans. Animal and human studies suggest that the pathogenesis of CM is immune mediated, but the precise mechanisms leading to cerebral pathology are unclear. In mice, infection with Plasmodium berghei ANKA results in CM on day 6 postinoculation (p.i.), while infection with the closely related strain P. berghei K173 does not result in CM. Infection with P. berghei K173 was associated with increased plasma gamma interferon (IFN-gamma) at 24 h p.i. and with increased splenic and hepatic mRNAs for a range of cytokines (IFN-gamma, interleukin-10 [IL-10], and IL-12) as well as the immunoregulatory enzyme indoleamine 2,3-dioxygenase. In contrast, P. berghei ANKA infection was associated with an absence of cytokine production at 24 h p.i. but a surge of IFN-gamma production at 3 to 4 days p.i. When mice were coinfected with both ANKA and K173, they produced an early cytokine response, including a burst of IFN-gamma at 24 h p.i., in a manner similar to animals infected with P. berghei K173 alone. These coinfected mice failed to develop CM. In addition, in a low-dose P. berghei K173 infection model, protection from CM was associated with early production of IFN-gamma. Early IFN-gamma production was present in NK-cell-depleted, gammadelta-cell-depleted, and Jalpha281(-/-) (NKT-cell-deficient) mice but absent from beta2-microglobulin mice that had been infected with P. berghei K173. Taken together, the results suggest that the absence of a regulatory pathway involving IFN-gamma and CD8(+) T cells in P. berghei ANKA infection allows the development of cerebral immunopathology.
Insights
Cerebral malaria (CM) pathogenesis involves immune responses. Early gamma interferon (IFN-γ) production, particularly from CD8+ T cells, appears protective against CM development in mouse models.
Area of Science:
- Immunology
- Infectious Diseases
- Neuroscience
Background:
- Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection.
- The exact immune mechanisms driving CM pathology remain unclear.
- Mouse models offer insights into CM pathogenesis, with Plasmodium berghei ANKA causing CM and P. berghei K173 not causing CM.
Purpose of the Study:
- To elucidate the immune mechanisms underlying cerebral malaria (CM) development.
- To investigate the role of early cytokine production in protecting against CM.
- To identify specific immune pathways involved in CM pathogenesis.
Main Methods:
- Comparative analysis of Plasmodium berghei ANKA and P. berghei K173 infections in mice.
- Assessment of cytokine mRNA and protein levels (IFN-γ, IL-10, IL-12) at different time points post-inoculation.
- Evaluation of CM development in coinfected mice and in mice with depleted immune cell populations (NK, gammadelta, NKT, CD8+ T cells).
Main Results:
- P. berghei K173 infection induced early plasma and splenic/hepatic cytokine production, including gamma interferon (IFN-γ).
- P. berghei ANKA infection showed delayed IFN-γ production and absence of early cytokines.
- Coinfection with both strains or early IFN-γ production in P. berghei K173 infection protected mice from CM.
- Absence of early IFN-γ and CD8+ T cell involvement correlated with CM development in P. berghei ANKA infection.
Conclusions:
- Early production of gamma interferon (IFN-γ) is crucial for protection against cerebral malaria (CM).
- The absence of a regulatory pathway involving IFN-γ and CD8+ T cells in P. berghei ANKA infection facilitates cerebral immunopathology.
- Understanding these immune mechanisms can inform strategies for preventing or treating CM.
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