Anopheles gambiae APL1 Is a Family of Variable LRR Proteins Required for Rel1-Mediated Protection from the Malaria Parasite, Plasmodium berghei

Michelle M Riehle,Boubacar Coulibaly,Sekou F Traore,Madjou Sacko,Susan M Rottschaefer,Jiannong Xu,Oumou Niare,Brian P Lazzaro,Kenneth D Vernick,Isabelle Morlais

doi:10.1371/journal.pone.0003672

Abstract

BackgroundWe previously identified by genetic mapping an Anopheles gambiae chromosome region with strong influence over the outcome of malaria parasite infection in nature. Candidate gene studies in the genetic interval, including functional tests using the rodent malaria parasite Plasmodium berghei, identified a novel leucine-rich repeat gene, APL1, with functional activity against P. berghei.Principal FindingsManual reannotation now reveals APL1 to be a family of at least 3 independently transcribed genes, APL1A, APL1B, and APL1C. Functional dissection indicates that among the three known APL1 family members, APL1C alone is responsible for host defense against P. berghei. APL1C functions within the Rel1-Cactus immune signaling pathway, which regulates APL1C transcript and protein abundance. Gene silencing of APL1C completely abolishes Rel1-mediated host protection against P. berghei, and thus the presence of APL1C is required for this protection. Further highlighting the influence of this chromosome region, allelic haplotypes at the APL1 locus are genetically associated with and have high explanatory power for the success or failure of P. berghei parasite infection.Conclusions APL1C functions as a required transducer of Rel1-dependent immune signal(s) to efficiently protect mosquitoes from P. berghei infection, and allelic genetic haplotypes of the APL1 locus display distinct levels of susceptibility and resistance to P. berghei.

Highlights

Malaria is a global health problem resulting in over 1 million deaths annually, with disproportionate mortality in African children under the age of five [1]
Gene-specific RNAi assays show that all of the malaria-protective activity we previously reported for A. gambiae APL1 can be attributed exclusively to APL1C
Resequencing of genomic DNA and archived clones from the original A. gambiae sequencing project [13], as well as transcript mapping, revealed that the previous APL1 gene represented the erroneous annotation of a gene family comprised of at least 3 tandem leucine-rich repeat (LRR)-containing genes, here named APL1A, APL1B, and APL1C (Figure 1A)

Summary

Introduction

Malaria is a global health problem resulting in over 1 million deaths annually, with disproportionate mortality in African children under the age of five [1]. More consistent and widespread implementation of existing tools would be beneficial, technical problems such as selection for chemico-resistance in vectors and parasites emphasize the need for a new generation of malaria control tools [3]. One such new approach could be limiting the genetic propensity of vector mosquitoes to serve as competent hosts for parasite development, decreasing or abolishing their ability to transmit the causative agent. Candidate gene studies in the genetic interval, including functional tests using the rodent malaria parasite Plasmodium berghei, identified a novel leucine-rich repeat gene, APL1, with functional activity against P. berghei

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Results

Conclusion