Abstract
BackgroundMalaria, caused by Plasmodium sp. parasites, is a leading cause of global morbidity and mortality. Cerebral malaria, characterized by neurological symptoms, is a life-threatening complication of malaria affecting over 500,000 young children in Africa every year. Because of the prevalence and severity of cerebral malaria, a better understanding of the underlying molecular mechanisms of its pathology is desirable and could inform future development of therapeutics. This study sought to clarify the role of Toll-like receptors (TLRs) in promoting immunopathology associated with cerebral malaria, with a particular focus on the understudied TLR7.MethodsUsing the Plasmodium berghei ANKA mouse model of experimental cerebral malaria, C57BL/6 mice deficient in various TLRs were infected, and their resistance to cerebral malaria and immune activation through cytokine production were measured.ResultsLoss of TLR7 conferred partial protection against fatal experimental cerebral malaria. Additionally, loss of TLR signalling dysregulated the cytokine profile, resulting in a shift in the cytokine balance towards those with more anti-inflammatory properties.ConclusionThis work identifies signalling through TLR7 as a source of pathology in experimental cerebral malaria.
Highlights
Malaria, caused by Plasmodium sp. parasites, is a leading cause of global morbidity and mortality
The current findings demonstrate that the absence of TLR7 during experimental cerebral malaria shifts the balance of cytokines towards an anti-inflammatory state and confers protection from cerebral malaria lethality
Given the reduced levels of inflammatory cytokines observed in Tlr7-/- mice in response to several Plasmodium sp. in a previous work [41], it was hypothesized that TLR7 might play a role in the pathology of P. berghei cerebral malaria that was previously undetected
Summary
Malaria, caused by Plasmodium sp. parasites, is a leading cause of global morbidity and mortality. Malaria, caused by protozoan parasites of the genus Plasmodium, is a major source of global morbidity and mortality, resulting in an estimated 154–289 million infections and 660,000 deaths in 2010 [1]. Of children who survive cerebral malaria, approximately 15% exhibit neurological sequelae, from which a proportion of children experience permanent neurological impairment [3,4]. This severe form of malaria represents only a modest proportion of cases, the overall high incidence of malaria results in an estimated 575,000 cases of cerebral malaria occurring annually in Africa [5]. The large number of cases, compounded by the severity of cerebral malaria, makes a better understanding of the underlying molecular mechanisms, and therapeutics based thereon, desirable
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