Common strategies to prevent and modulate experimental cerebral malaria in mouse strains with different
Louise M Randall1, Fiona H Amante, Karli A McSweeney
1Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD 4006, Australia.
Abstract:
Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection, predominantly experienced by children and nonimmune adults, which results in significant mortality and long-term sequelae. Previous studies have reported distinct susceptibility gene loci in CBA/CaH (CBA) and C57BL/6 (B6) mice with experimental CM (ECM) caused by infection with Plasmodium berghei ANKA. Here we present an analysis of genome-wide expression profiles in brain tissue taken from B6 and CBA mice with ECM and report significant heterogeneity between the two mouse strains. Upon comparison of the leukocyte composition of ECM brain tissue, microglia were expanded in B6 mice but not CBA mice. Furthermore, circulating levels of gamma interferon, interleukin-10, and interleukin-6 were significantly higher in the serum of B6 mice than in that of CBA mice with ECM. Two therapeutic strategies were applied to B6 and CBA mice, i.e., (i) depletion of regulatory T (Treg) cells prior to infection and (ii) depletion of CD8(+) T cells after the establishment of ECM. Despite the described differences between susceptible mouse strains, depletion of Treg cells before infection attenuated ECM in both B6 and CBA mice. In addition, the depletion of CD8(+) T cells when ECM symptoms are apparent leads to abrogation of ECM in B6 mice and a lack of progression of ECM in CBA mice. These results may have important implications for the development of effective treatments for human CM.
Insights
Cerebral malaria (CM) is a severe Plasmodium falciparum complication. Depleting regulatory T cells before infection and CD8+ T cells during symptoms attenuated experimental CM in mice, offering potential therapeutic insights.
Area of Science:
- Immunology
- Neuroscience
- Infectious Diseases
Background:
- Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection, causing high mortality and long-term sequelae, particularly in children and non-immune adults.
- Distinct genetic loci influence susceptibility to experimental CM (ECM) in different mouse strains, such as CBA/CaH (CBA) and C57BL/6 (B6).
Purpose of the Study:
- To analyze genome-wide expression profiles in brain tissue of B6 and CBA mice with ECM to identify strain-specific differences.
- To investigate the impact of regulatory T (Treg) cell and CD8+ T cell depletion on the course of experimental CM in susceptible mouse strains.
Main Methods:
- Comparative analysis of genome-wide expression profiles in brain tissue from B6 and CBA mice infected with Plasmodium berghei ANKA.
- Assessment of leukocyte composition, focusing on microglia, in ECM brain tissue.
- Measurement of serum cytokine levels (interferon-gamma, interleukin-10, interleukin-6).
- Therapeutic intervention involving depletion of Treg cells before infection and CD8+ T cells after ECM establishment.
Main Results:
- Significant heterogeneity in gene expression profiles was observed between B6 and CBA mice with ECM.
- Microglia were expanded in the brain tissue of B6 mice but not CBA mice.
- Circulating levels of interferon-gamma, interleukin-10, and interleukin-6 were significantly higher in B6 mice compared to CBA mice.
- Depletion of Treg cells prior to infection attenuated ECM in both mouse strains.
- Depletion of CD8+ T cells upon appearance of ECM symptoms abrogated ECM in B6 mice and halted its progression in CBA mice.
Conclusions:
- Experimental CM exhibits significant strain-specific heterogeneity in immune cell infiltration and cytokine profiles.
- Targeting regulatory T cells and CD8+ T cells represents a promising therapeutic strategy for mitigating experimental cerebral malaria.
- These findings hold potential implications for developing effective treatments for human cerebral malaria.
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