Malaria has consistently ranked as one of the world's top infectious causes of mortality over the lastcentury. The lack of an effective vaccine reflects a deficiency in our understanding of protective immunity tomalaria. This is in large part due to the complex nature of the immune response, which requires both adaptiveand innate immune components for successful control and clearance of parasites. Two fundamental questions regarding innate immunity to malaria remain unanswered. First, how areparasites recognized by the immune system? TLR2 and TLR9 have been identified as sensors for malariainfection, but their relevance in vivo remains in question due to the mild phenotypes of infection in Tlr2-/-andTlr9-/- mice. We have determined that TLR9 is indeed a sensor of early parasite infection in vivo, but thatadditional unidentified pathways for immune activation exist. These pathways are likely to provide somedegree of functional redundancy with TLR9 signaling, which may explain the mildness of the defects observedin Tlr9-/- mice. We also observe that the TLR9 signaling in response to malaria infection is not mediated by thecanonical IRF7-dependent pathway. We propose to delineate the components of this unusual TLR9 signalingpathway and to identify the unknown pathway that is redundant with TLR9. Second, it is established that a branch of the innate immune system is critical for control of parasitereplication, but the mechanism is not known. Candidates have been proposed, but no study has directly andcomprehensively examined the components of the innate immune system that contribute to parasite control.We propose to obtain this information through a systematic and exhaustive in vivo approach, followed bycharacterization of the leukocyte populations that are determined to be essential for control of the infection. The role of innate immune mechanisms in malaria control is underappreciated, which has likelycontributed to our lack of an effective malaria vaccine. This work will address fundamental questions ofmalaria immunity and lay the groundwork for more informed vaccine design.
The body's ability to recognize infectious pathogens is a key step in the ability to fight an infection. The goal of this work is to discover the mechanisms for immunological recognition and control of malaria infection. The work would benefit public health by increasing our general knowledge of immunity and by discovering principles which will have relevance to other infectious diseases.
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