Wolbachia: It’s a wonderful life
A second focus of the lab is to explore the molecular and cellular interactions between the bacterial endosymbiont Wolbachia and its insect and nematode hosts. Unlike E. coli, which resides in the extracellular environment of our intestines, Wolbachia makes a comfortable living inside the germline cells of its host. Thus, like mitochondria, it is efficiently transmitted to all the offspring of an infected female. Wolbachia, present in the majority of insects species, manipulates host reproduction in extraordinary ways to enhance its own transmission. This includes feminization (the transformation of a male into a fertile female), male-killing (just as it sounds, males are killed leaving more resources for infected females, induction of parthenogenesis), virgin birth (no need to find a male mate) and the most devious of all, Cytoplasmic Incompatibility (CI). CI involves collaborative action of Wolbachia in males and females resulting in the rapid spread of Wolbachia through an uninfected population. Our lab studies the molecular and cellular basis of Wolbachia-host interactions driving its maternal transmission and these female favoring reproductive manipulations. Currently we are exploring the mechanisms how Wolbachia interact with a wide array of host cytoplasmic and nuclear components in order to thrive in a diversity of cell types and cellular environments.
Wolbachia also maintains a symbiotic relationship with pathogenic filarial nematodes, such as Brugia malayi, and is the causative agent of elephantiasis and river blindness — diseases afflicting 150 million people globally. Unlike insects, Wolbachia is an obligate symbiont of filarial nematodes. Consequently, antibiotics that target Wolbachia have proven an effective means of treating these diseases. Our lab employs high throughput cell-based screening platforms in order to identify potent anti-Wolbachia compounds.
Major Questions
1. What is the molecular and cellular basis of CI? CI requires a coordinated action in the maternal and paternal germlines — how is this achieved?
2. How does Wolbachia regulate its interactions with the host cytoskeleton to ensure efficient germline transmission? Wolbachia relies on precisely timed interactions with host plus and minus-end directed motor proteins in order to concentrate at the site of the future germline. What are the Wolbachia effector proteins that mediate these interactions?
3. How is Wolbachia titer in host somatic and germline tissue regulated? Intracellular bacteria must tightly regulate their abundance in the cell: too high and they kill the cell, too low and they are not transmitted to the daughter cells. Our preliminary data suggests Wolbachia maintenance of titer relies on a close linkage with the ER and possibility endosomal organelles. We take advantage of the excellent molecular genetics and cellular reagents available in Drosophila to identify the subcellular interactions regulating Wolbachia intracellular titer.
4. What are the Wolbachia and host factors that mediate the cell-to-cell transmission of this endosymbiont? Wolbachia relies on two distinct strategies to occupy the female germline. Wolbachia in the developing oocyte migrate to and concentrate in the extreme oocyte posterior, the future site of germline formation. A second route requires Wolbachia invading the oocyte from neighboring somatic cells. This requires the ability of Wolbachia to usurp host exocytosis and endocytosis machinery. It also requires Wolbachia tap into host factors, enabling it to target the germline. We use a combination of genetic, biochemical and cellular approaches to identify interactions between Wolbachia and host proteins that drive these events.
5. Employing the Wolbachia/Drosophila system to elucidate the molecular basis of the Behavior Modification Hypothesis. This refers to the observation that many parasites manipulate host behavior in order to promote transmission to uninfected hosts. We find Wolbachia dramatically alters female mating behavior and localizes to relevant regions of the adult brain. These observations combined with sophisticated molecular genetic and biochemical approaches available in Drosophila enable us to provide mechanistic insight into the Behavior Modification Hypothesis.
6. Screens for potent anti-Wolbachia compounds. As Wolbachia is an obligate symbiont of filarial nematodes, targeting Wolbachia has proven an effective treatment against the human diseases caused by these organisms. We have discovered that the FDA approved drug albendazole is extremely effective at killing Wolbachia. This discovery led to a combination albendazole-antibiotic treatment that reduced treatment regime from 6 weeks to 1 week. Most recently we discovered clusters of Wolbachia that are resistant to antibiotic treatment and result in dramatic rebounds in the Wolbachia population following withdrawal of antibiotics. Our ongoing screens have identified promising compounds that target these resistant Wolbachia populations.