Denis Voronin, PhD
Head, Cellular Microbiology Research Program
Assistant Member, Lindsley F. Kimball Research Institute
Phone: +1 (212) 570-5229 / +1(212) 570-3181
Human lymphatic filariasis and onchocerciasis are two of the most debilitating yet neglected infectious diseases. Combined, they afflict 150 million of “the poorest of the poor” worldwide. Lymphatic filariasis (elephantiasis) is the second leading cause of morbidity, and onchocerciasis (river blindness) – the second leading cause of infectious blindness. Wuchereria bancrofti and Brugia malayi are the causative agents of lymphatic filariasis and Onchocerca volvulus causes onchocerciasis. The filarial parasites have evolved a mutualistic association with the endosymbiotic bacteria, Wolbachia, an association that supports both organisms, none can survive without the other. Wolbachia are crucial for the parasite’s development, fertility, and viability. It has been postulated that the mechanism(s) underlying the obligate interdependence between Wolbachia and filarial parasites relies on the ability of the bacteria and the parasite to share essential metabolites and biosynthetic processes (glycolysis, nucleotide biosynthesis, iron metabolism). These essential roles make Wolbachia a very attractive drug target for anti-filarial drug development. Moreover, investigating the gram-negative bacteria-eukaryotic cells symbiotic interactions may enable the translation of our study outcomes to also better understand bacterial infections in mammalian.
Wolbachia regulates B. malayi genes through manipulation of worm’s microRNAs
Most of what we know about Wolbachia derives from molecular studies performed in insect systems, because 70% of arthropods are parasitized by various Wolbachia strains, and a number of these strains can be cultured in insect cells. This is not the case for the Wolbachia of filarial worms. Noticeably, a recent study showed that to survive in the insect host, pathogenic Wolbachia (wMelPop) manipulate host microRNAs (miRNAs) to control arthropod gene expression. We therefore theorize that although the Wolbachia of filarial worms are mutualistic and not pathogenic as in insects, they could also manipulate host miRNA to control worm gene expression.
Our working hypothesis is the homeostasis of the mutualistic relationship between parasites and Wolbachia requires the coordinated regulation of parasite’s genes through Wolbachia-controlled filarial nematode’s miRNAs. In this project we will focus on 4 Wolbachia-controlled miRNAs and their filarial gene targets and validate the involvement of this specific subset of B. malayi genes in the mutualistic Wolbachia-Brugia association. Any druggable targets could be then tested in vitro and in vivo studies for their ability to affect the fitness of both Wolbachia and the worm.
Activation of autophagy and the elimination of Wolbachia by filarial parasites
Currently, only treatment with antibiotics (doxycycline) that kill endosymbiont has been shown to have macrofilaricidal effects – killing of adult worms. Unfortunately, both the dose of doxycycline and the time-course of treatment needed to be effective in humans are incredibly high and long: ≥100-200 mg/day for 4-6 weeks of treatment. Moreover, the antibiotic cannot be administered to children below the age of 8 and pregnant women, and since doxycycline is a broad spectrum antibiotic, widespread use of it could also promote the development of antibiotic resistant strains of other human pathogenic bacteria. Therefore, in this project we explore a novel approach for the elimination of Wolbachia: a host(parasite)-oriented treatment that induces the host’s innate defense and forces the filarial nematodes to eliminate their endosymbiont. Autophagy is a mechanism of eukaryotic cells that maintains a healthy intracellular environment and protects cells against intracellular invaders (bacteria, virus). We already have shown that Wolbachia load is dependent on the activity of autophagy in insect cells and in filarial nematodes. We will first study the mechanism by which the bacteria manipulate the host’s intracellular defense mechanisms in order to protect themselves and in parallel investigate the ways the parasite controls bacterial population to avoid host fitness cost. Discovering any vulnerable pathways will support such novel strategy to employ a host(parasite)-oriented treatment to eliminate Wolbachia from the filarial worms and consequently affect the survival of the adult parasites
- Emily Schnall, MS, Research Assistant
Education and Training
PhD, Cellular Biology, Institute of Cytology and Genetics, Novosibirsk, Russia.
University of Lyon 1, Lyon, France
Liverpool School of Tropical Medicine, Liverpool, UK
Voronin D, Schnall E, Grote A, Jawahar S, Ali W, Unnasch TR, Ghedin E, Lustigman S. Pyruvate produced by Brugia spp. via glycolysis is essential for maintaining the mutualistic association between the parasite and its endosymbiont, Wolbachia. PLoS Pathog. 2019 Sep;15(9):e1008085. doi: 10.1371/journal.ppat.1008085. eCollection 2019 Sep. PubMed PMID: 31568486; PubMed Central PMCID: PMC6791551.
Kashyap SS, Verma S, Voronin D, Lustigman S, Kulke D, Robertson AP, Martin RJ. Emodepside has sex-dependent immobilizing effects on adult Brugia malayi due to a differentially spliced binding pocket in the RCK1 region of the SLO-1 K channel. PLoS Pathog. 2019 Sep;15(9):e1008041. doi: 10.1371/journal.ppat.1008041. eCollection 2019 Sep. PubMed PMID: 31553770; PubMed Central PMCID: PMC6779273.
Tai W, Voronin D, Chen J, Bao W, Kessler DA, Shaz B, Jiang S, Yazdanbakhsh K, Du L. Transfusion-Transmitted Zika Virus Infection in Pregnant Mice Leads to Broad Tissue Tropism With Severe Placental Damage and Fetal Demise. Front Microbiol. 2019;10:29. doi: 10.3389/fmicb.2019.00029. eCollection 2019. PubMed PMID: 30728813; PubMed Central PMCID: PMC6351479.
Voronin D, Tricoche N, Jawahar S, Shlossman M, Bulman CA, Fischer C, Suderman MT, Sakanari JA, Lustigman S. Development of a preliminary in vitro drug screening assay based on a newly established culturing system for pre-adult fifth-stage Onchocerca volvulus worms. PLoS Negl Trop Dis. 2019 Jan;13(1):e0007108. doi: 10.1371/journal.pntd.0007108. eCollection 2019 Jan. PubMed PMID: 30653499; PubMed Central PMCID: PMC6353222.
Grote A, Voronin D, Ding T, Twaddle A, Unnasch TR, Lustigman S, Ghedin E. (2017) Defining Brugia malayi and Wolbachia symbiosis by stage-specific dual RNA-seq. PLoS Neglected Tropical Diseases. 2017; 11(3):e0005357. PMID: 28358880
Cotton JA, Bennuru S, Grote A, et al. (2016) The genome of Onchocerca volvulus, agent of river blindness. Nature Microbiology. 2016; 2:16216. PMID:27869790.
Taylor MJ, Voronin D, Johnston KL, Ford L. (2013) Wolbachia filarial interactions.Cell Microbiol. (Review). 15(4):520-6. Picture was selected for the cover of the journal.
Voronin D, Cook D, Steven A, Taylor MJ. (2012) Autophagy regulates Wolbachia populations across diverse symbiotic associations. Proc Natl Acad Sci USA (Jun 19), 109(25): E1638-1946
Mavingui P, Moro C, Van Tran V, Wisniewski-Dyé F, Raquin V, Minard G, Tran F, Voronin D, et al. (2012) Whole-Genome sequence of Wolbachia strain wAlbB, an endosymbiont of Tiger mosquito vector Aedes albopictus. J. of Bacteriology 194, 7
Landmann F#, Voronin D#, Sullivan W, Taylor MJ. (2011) Anti-filarial activity of antibiotic therapy is due to extensive apoptosis after Wolbachia depletion from Filarial Nematodes. PLoS Pathog., 7(11):e1002351, # These authors contributed equally to this work
Kremer N, Voronin D, Charif D, Mavingui P, Mollereau B, Vavre F. (2009, Oct) Wolbachia interferes with ferritin expression and iron metabolism in insects.PLoS Pathog., 5(10):e1000630