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Published on: December 4, 2015
Cerebral Malaria Is Regulated by Host-Mediated Changes in Plasmodium Gene Expression
Clare K Cimperman1, Mirna Pena1, Sohret M Gokcek2,3,4
1Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, Maryland, USA.
Abstract:
Cerebral malaria (CM), the deadliest complication of Plasmodium infection, is a complex and unpredictable disease. However, our understanding of the host and parasite factors that cause CM is limited. Using a mouse model of CM, experimental CM (ECM), we performed a three-way comparison between ECM-susceptible C57BL/6 mice infected with ECM-causing Plasmodium ANKA parasites [ANKA(C57BL/6)], ECM-resistant BALB/c mice infected with Plasmodium ANKA [ANKA(BALB/c)], and C57BL/6 mice infected with Plasmodium NK65 that does not cause ECM [NK65(C57BL/6)]. All ANKA(C57BL/6) mice developed CM. In contrast, in ANKA(BALB/c) and NK65(C57BL/6), infections do not result in CM and proceed similarly in terms of parasite growth, disease course, and host immune response. However, parasite gene expression in ANKA(BALB/c) was remarkably different than that in ANKA(C57BL/6) but similar to the gene expression in NK65(C57BL/6). Thus, Plasmodium ANKA has an ECM-specific gene expression profile that is activated only in susceptible hosts, providing evidence that the host has a critical influence on the outcome of infection. IMPORTANCE Hundreds of thousands of lives are lost each year due to the brain damage caused by malaria disease. The overwhelming majority of these deaths occur in young children living in sub-Saharan Africa. Thus far, there are no vaccines against this deadly disease, and we still do not know why fatal brain damage occurs in some children while others have milder, self-limiting disease progression. Our research provides an important clue to this problem. Here, we showed that the genetic background of the host has an important role in determining the course and the outcome of the disease. Our research also identified parasite molecules that can potentially be targeted in vaccination and therapy approaches.
Insights
Host genetics critically influence cerebral malaria (CM) outcomes. Plasmodium ANKA parasites activate specific gene expression in susceptible mice, revealing host-parasite interactions crucial for CM development and potential therapeutic targets.
Area of Science:
- Immunology
- Infectious Diseases
- Genetics
Background:
- Cerebral malaria (CM) is a severe complication of Plasmodium infection, causing significant mortality, particularly in young children.
- The unpredictable nature of CM and limited understanding of host and parasite factors contributing to its pathogenesis hinder effective treatment and prevention.
- Existing knowledge gaps exist regarding why some individuals develop severe CM while others experience milder disease.
Purpose of the Study:
- To investigate the influence of host genetic background on the development of experimental cerebral malaria (ECM).
- To compare parasite gene expression profiles in susceptible versus resistant hosts during ECM.
- To identify potential parasite-derived targets for novel therapeutic and vaccination strategies against CM.
Main Methods:
- Utilized a mouse model of experimental cerebral malaria (ECM).
- Conducted a three-way comparison involving ECM-susceptible C57BL/6 mice infected with Plasmodium ANKA, ECM-resistant BALB/c mice infected with Plasmodium ANKA, and C57BL/6 mice infected with non-ECM-causing Plasmodium NK65.
- Analyzed parasite gene expression profiles in different host genetic backgrounds.
Main Results:
- All susceptible C57BL/6 mice infected with Plasmodium ANKA developed ECM.
- In contrast, Plasmodium ANKA infection in resistant BALB/c mice and Plasmodium NK65 infection in C57BL/6 mice did not result in ECM.
- Parasite gene expression in ANKA-infected BALB/c mice differed significantly from ANKA-infected C57BL/6 mice, but was similar to NK65-infected C57BL/6 mice, indicating ECM-specific parasite gene activation in susceptible hosts.
Conclusions:
- The host genetic background plays a critical role in determining the outcome of Plasmodium infection and the development of cerebral malaria.
- Plasmodium ANKA exhibits an ECM-specific gene expression profile that is activated only in susceptible host environments.
- These findings highlight host-parasite interactions and identify potential parasite molecules for targeted interventions against CM.
