Mechanisms of microRNA-451 mediated regulation of malaria infection in mice

Chapman, Lesley

Abstract

There are an estimated 300-500 million cases of malaria worldwide each year, with about 3 million annual deaths. Parasite evasion of host defense mechanisms leads to uncontrolled parasite growth, morbidity, and often mortality. Certain genetic traits may delay the progression and severity of malaria disease, such as the sickle cell trait. In a recent study, it was demonstrated that microRNA (miR)-451 is upregulated in erythrocytes from both homozygous and heterozygous carriers of the sickle cell trait, and that miR-451 has a direct role in decreasing intraerythrocytic parasite growth in vitro. Yet, a number of studies have shown that miR-451 may be a key regulator of gene expression related to immune function. Down regulation of miR-451 promotes the release of proinflammatory cytokines from dendritic cells, and NOTCH1 mediated repression of miR-451 promotes T-cell proliferation in a mouse leukemia model. Preliminary studies by our lab using the Plasmodium yoelii (P. yoelii) malaria model have demonstrated that, in contrast to in vitro studies, mice lacking miR-451 have greatly increased parasite clearance compared to wild type (WT) control mice. The goal of this study is to define the underlying genetic and molecular mechanisms that lead to an increased host immune response in miR-451-/- mice during infection. MiR-451 may provide an attractive target for boosting the host response to many types of infection or vaccination.

Public Health Relevance

Approximately 300-500 million cases of malaria are reported worldwide each year, with about 3 million annual deaths. Morbidity and often mortality occur due to parasite evasion of host defense mechanisms. An effective antimalarial therapy that can treat and ultimately eradicate malaria has yet to be discovered due to the parasite's ability to evade host defense mechanisms. Our study will be the first to demonstrate that targeting a specific microRNA, miR- 451, generates a protective CD4+ T-cell mediated immune response against malaria infection. This discovery could provide a new prognostic marker to determine host response against malaria infection, and could also inform the development of novel antimalarial therapies.