: This is a competing continuation proposal for the four-year project #AI42361, previously entitled, """"""""Genetics of An. gambiae susceptibility to Plasmodium."""""""" Since its inception, this project has comprised the first systematic examination of mechanisms of mosquito immunity and resistance to Plasmodium in nature. Understanding the biology of these interactions could permit development of novel strategies to inhibit parasite transmission. In the last project period, we carried out a field-based genetic analysis of the major human malaria vector, Anopheles gambiae. This work for the first time identified genes in An. gambiae that reduce the natural transmission of P. falciparum. We mapped two loci for parasite resistance, Pfin1 and Pfin2. Resistant homozygotes at the Pfin1 locus had a mean of 0.17 oocysts per mosquito, while susceptible homozygotes had 50.6. We found an apparent high natural frequency of resistance alleles, which suggests that malaria parasites (or a similar pathogen) exert a significant selective pressure on vector populations. Here, we present new integrated Aims that build directly upon the previous work to study the genetics and genomics of mosquito immunity and parasite resistance in the context of the natural malaria transmission system. We will: 1) Screen a natural population of An. gambiae by genome-wide scanning at 10 cM resolution for loci that control resistance to P. falciparum in the natural transmission system in Mali, West Africa. 2) Map natural resistance loci identified in Aim 1 at high genetic resolution to isolate a tractable number of candidate resistance genes. 3) Filter the candidate resistance genes by sequence analysis, transcriptional profiling, and physiological studies, and positionally clone at least one resistance trait gone. The proposed continuation project will be the first genetic screen in a mosquito field population for genes conferring resistance to malaria parasites. We will determine the number, frequencies, and genomic organization of parasite-resistance traits, at 10 cM genetic resolution. We will maintain mosquito families segregating chosen traits and we may select stable lines, we will map the traits, describe the cellular mechanism, and we will positionally clone one or more underlying genes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042361-08
Application #
7008861
Study Section
Special Emphasis Panel (ZRG1-TMP (99))
Program Officer
Costero, Adriana
Project Start
1998-08-05
Project End
2008-02-29
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
8
Fiscal Year
2006
Total Cost
$575,957
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Redmond, Seth N; Eiglmeier, Karin; Mitri, Christian et al. (2015) Association mapping by pooled sequencing identifies TOLL 11 as a protective factor against Plasmodium falciparum in Anopheles gambiae. BMC Genomics 16:779
Rottschaefer, Susan M; Crawford, Jacob E; Riehle, Michelle M et al. (2015) Population genetics of Anopheles coluzzii immune pathways and genes. G3 (Bethesda) 5:329-39
Jiang, Xiaofang; Peery, Ashley; Hall, A Brantley et al. (2014) Genome analysis of a major urban malaria vector mosquito, Anopheles stephensi. Genome Biol 15:459
Xu, Jiannong; Hillyer, Julian F; Coulibaly, Boubacar et al. (2013) Wild Anopheles funestus mosquito genotypes are permissive for infection with the rodent malaria parasite, Plasmodium berghei. PLoS One 8:e61181
Holm, Inge; Lavazec, Catherine; Garnier, Thierry et al. (2012) Diverged alleles of the Anopheles gambiae leucine-rich repeat gene APL1A display distinct protective profiles against Plasmodium falciparum. PLoS One 7:e52684
Crawford, Jacob E; Bischoff, Emmanuel; Garnier, Thierry et al. (2012) Evidence for population-specific positive selection on immune genes of Anopheles gambiae. G3 (Bethesda) 2:1505-19
Mitri, Christian; Vernick, Kenneth D (2012) Anopheles gambiae pathogen susceptibility: the intersection of genetics, immunity and ecology. Curr Opin Microbiol 15:285-91
Riehle, Michelle M; Guelbeogo, Wamdaogo M; Gneme, Awa et al. (2011) A cryptic subgroup of Anopheles gambiae is highly susceptible to human malaria parasites. Science 331:596-8
Mitri, Christian; Jacques, Jean-Claude; Thiery, Isabelle et al. (2009) Fine pathogen discrimination within the APL1 gene family protects Anopheles gambiae against human and rodent malaria species. PLoS Pathog 5:e1000576
Riehle, Michelle M; Xu, Jiannong; Lazzaro, Brian P et al. (2008) Anopheles gambiae APL1 is a family of variable LRR proteins required for Rel1-mediated protection from the malaria parasite, Plasmodium berghei. PLoS One 3:e3672

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