Development of Plasmodium parasites in the Anopheles mosquito is required for successful malaria parasite transmission. Although the greatest burden of disease occurs in Sub-Saharan Africa (SSA), malaria morbidity and mortality extends far beyond the African continent. Across the geographical distribution of known anopheline vectors of Plasmodium, morbidity and mortality are caused by both Plasmodium falciparum and Plasmodium vivax. In fact, P. vivax has the widest geographic distribution with 2.5 billion people at risk of the disease, and between 80 - 300 million clinical cases every year, including severe disease and death. Despite this tremendous public health burden, P. vivax research has received far less attention and support than efforts centered on P. falciparum. There is a recent heightened re-emphasis on studies aimed at elucidating the transmission biology of P. vivax. Unfortunately, little molecular and genome-scale information exists for vectors of P. vivax, which in some endemic regions outside of SSA are also vectors of P. falciparum. Moreover, although the molecular functions of the genome of the """"""""model"""""""" African P. falciparum vector, Anopheles gambiae is relatively well studied, the substantial evolutionary divergence observed within anophelines limits its utility as the reference for the entire lineage, especially with respect to several P. vivax vectors. One of the major vectors of P. vivax and P. falciparum, and a potentially great emerging model system to understand the transmission biology of human Plasmodia through mosquitoes, is Anopheles farauti 1 (FAR1/AF1) and related species complex members in the Western Pacific. To better understand malaria transmission biology, it is imperative to more thoroughly examine the interaction between the parasite and mosquito tissues, particularly the mosquito midgut. In this project our overarching question is """"""""What are the molecular determinants mediating Plasmodium ookinete-Anopheles midgut interactions?"""""""" Thus, we will perform comparative transcriptomic and proteomic analyses of mosquito midgut lumen expressed immune- related genes from the model (gambiae), the recently sequenced """"""""emerging model"""""""" anopheline vector (FAR1) colony and wild-type farauti (AF1) mosquitoes, as well as the non-model but related species (An. punctulatus, AP). Our focus will be on the subset of immune-related genes that are differentially expressed as both transcript and protein in response to blood feeding and Plasmodium invasion. We will first focus on FAR1 infections with laboratory P. falciparum and complement these studies with subsequent P. vivax membrane feeding assays with FAR1/AF1/AP. It should be noted that the transcriptome assembly and proteomics analysis of the FAR1/AF1 mosquito midgut described in this project will not only strongly complement and enhance the vector-biology community's recent FAR1 sequencing effort and genome annotation for this species but will also greatly contribute to bringing our knowledge on vivax-anopheles interactions on par with that of falciparum-gambiae, thus allowing the two study systems to """"""""reciprocally illuminate"""""""" one another.

Public Health Relevance

Substantial evolutionary divergence observed within anopheline mosquitoes limits the utility of a single sequenced genome to serve as the reference genome for the entire lineage. Simply because a genome has been sequenced and annotated does not imply that our knowledge about tissue-specific transcriptomes and proteomes is substantial, let alone complete;however, tissue-specific functional data is vital for understandin the functional genome of an organism, and for enhancing the quality of the sequenced genome and its annotation. Therefore, we will use our novel, seamlessly integrated RNASeq transcriptomics to proteomics data analysis platform to compare the midgut transcriptomes and proteomes of the model African malaria vector (Anopheles gambiae) with the recently sequenced emerging model (Anopheles farauti) and non-model (Anopheles punctulatus) vectors, both of which transmit falciparum and vivax malaria in the Western Pacific.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Vector Biology Study Section (VB)
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Costero-Saint Denis, Adriana
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Johns Hopkins University
Schools of Public Health
United States
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