Harnessing Wolbachia-Induced Conditional Infertility for Control of the Malaria Mosquito

Project Summary:
Wolbachia endosymbionts hold strong potential for the control of vector-borne infections. Indeed, these bacteria
are currently used to control dengue virus transmission by Aedes aegypti, where they combine the ability to
spread through populations via Cytoplasmic Incompatibility (CI) with efficient blocking of arboviral infections. For
decades, however, scientists have been puzzled by the apparent lack of both natural and artificial Wolbachia
infections in Anopheles, the vectors of human malaria, with only a handful of examples reported. Wolbachia are
genetically intractable, making functional study of both their reproductive manipulations and this host tropism
difficult. However, my previous work suggests that a Wolbachia-derived CI-inducing factor, CifB, causes severe
abnormalities in females (rescued by a different gene, cifA), that may in part prevent Wolbachia from establishing
natural infections in Anopheles mosquitoes. I will elucidate the mechanisms regulating Wolbachia infections in
Anopheles, while gaining general mechanistic insight into CI in insects. Using a combination of genetics, cell
biology, molecular, genomic and bioinformatics approaches to address key questions related to Wolbachia
toxicity and rescue across different insects, these studies will push the field of insect-endosymbiont interactions
into new areas of inquiry and will also generate tools for the generation of Wolbachia-based strategies for the
control of malaria-transmitting Anopheles populations.
I will conduct the K99 phase of this award as a post-doctoral researcher in Dr. Flaminia Catteruccia’s group at
the Harvard T.H. Chan School of Public Health. The laboratory is exceptionally well-equipped to establish
transgenic insects and is one of the only vector biology labs with a robotic micro-injector and a COPAS Biosorter
in addition to a world-class Plasmodium infection facility. Dr. Catteruccia is supported by the Howard Hughes
Medical Institute, which allows flexibility of research funds which can be drawn upon for this project, and
facilitates access to state-of-the-art equipment, facilitating expansive research in vector biology. In addition to
Dr. Catteruccia’s expertise in mosquito reproduction, mosquito transgenesis, and host-parasite interactions, I will
be supported by Dr. Zhiyong Xi, an expert at the forefront of Wolbachia-based vector control implementation in
Aedes mosquitoes, and in establishing Wolbachia infections in Anopheles. Further, I will collaborate with Dr.
John Beckmann, a molecular biologist and biochemist with expertise working with Wolbachia’s CI-inducing
factors, and Dr. Lauren Childs, a mathematical modeling specialist. Additional mentors will include local
researchers Dr. Daniel Neafsey, who has vast experience with functional genomics in Wolbachia, Anopheles,
and Plasmodium, and Dr. Paul Garrity whose group excels at genetic engineering of various Dipterans. This
combination of expertise will train me to have a unique perspective and skillset to apply to research questions
related to tripartite interactions between Wolbachia, Anopheles and Plasmodium, with which I will be well-
positioned to establish an independent laboratory with a distinct set of research capabilities and questions.

Grant Number: 7K99AI185151-02
NIH Institute/Center: NIH
Principal Investigator: Kelsey Adams