title: Anti-filarial activity of antibiotic therapy is due to extensive apoptosis after Wolbachia depletion from filarial nematodes.
abstract: Filarial nematodes maintain a mutualistic relationship with the endosymbiont Wolbachia. Depletion of Wolbachia produces profound defects in nematode development, fertility and viability and thus has great promise as a novel approach for treating filarial diseases. However, little is known concerning the basis for this mutualistic relationship. Here we demonstrate using whole mount confocal microscopy that an immediate response to Wolbachia depletion is extensive apoptosis in the adult germline, and in the somatic cells of the embryos, microfilariae and fourth-stage larvae (L4). Surprisingly, apoptosis occurs in the majority of embryonic cells that had not been infected prior to antibiotic treatment. In addition, no apoptosis occurs in the hypodermal chords, which are populated with large numbers of Wolbachia, although disruption of the hypodermal cytoskeleton occurs following their depletion. Thus, the induction of apoptosis upon Wolbachia depletion is non-cell autonomous and suggests the involvement of factors originating from Wolbachia in the hypodermal chords. The pattern of apoptosis correlates closely with the nematode tissues and processes initially perturbed following depletion of Wolbachia, embryogenesis and long-term sterilization, which are sustained for several months until the premature death of the adult worms. Our observations provide a cellular mechanism to account for the sustained reductions in microfilarial loads and interruption of transmission that occurs prior to macrofilaricidal activity following antibiotic therapy of filarial nematodes.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, Sinsheimer Labs, University of California, Santa Cruz, California, United States of America.
authors.forename: Frederic
authors.initials: F
authors.lastname: Landmann
authors.forename: Denis
authors.initials: D
authors.lastname: Voronin
authors.forename: William
authors.initials: W
authors.lastname: Sullivan
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Taylor
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D017178:Brugia malayi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology*; D053148:Caspase 3 / Q000096:biosynthesis; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D005368:Filariasis / Q000188:drug therapy / Q000469:parasitology*; D005849:Gerbillinae / Q000469:parasitology; D015801:Helminth Proteins / Q000096:biosynthesis; D006801:Humans; D020287:In Situ Nick-End Labeling; D007814:Larva / Q000382:microbiology; D008297:Male; D013559:Symbiosis; D013752:Tetracycline / Q000494:pharmacology; D020577:Wolbachia / Q000187:drug effects* / Q000502:physiology*
chemical_list: D000900:Anti-Bacterial Agents; D015801:Helminth Proteins; D053148:Caspase 3; D013752:Tetracycline; D004318:Doxycycline
references.citation: J Parasitol. 1977 Dec;63(6):992-1000
references.pmid: 592054
references.citation: PLoS Pathog. 2010 Feb 19;6(2):e1000774
references.pmid: 20174550
references.citation: Parasitol Today. 1999 Nov;15(11):437-42
references.pmid: 10511685
references.citation: PLoS Negl Trop Dis. 2009 Jul 14;3(7):e475
references.pmid: 19597542
references.citation: Exp Parasitol. 1999 Apr;91(4):356-61
references.pmid: 10092480
references.citation: Trends Parasitol. 2004 Jun;20(6):280-7
references.pmid: 15147679
references.citation: J Biol Chem. 2009 Aug 14;284(33):22364-22378
references.pmid: 19458089
references.citation: Microbes Infect. 2003 Apr;5(4):261-73
references.pmid: 12706439
references.citation: FEMS Microbiol Lett. 2002 May 21;211(1):1-6
references.pmid: 12052542
references.citation: Adv Parasitol. 2005;60:245-84
references.pmid: 16230105
references.citation: Ann Trop Med Parasitol. 2000 Dec;94(8):801-16
references.pmid: 11214099
references.citation: Symbiosis. 2010 Jul;51(1):55-65
references.pmid: 20730111
references.citation: Mol Biochem Parasitol. 2004 May;135(1):57-67
references.pmid: 15287587
references.citation: J Cell Biol. 1992 Nov;119(3):493-501
references.pmid: 1400587
references.citation: J Clin Invest. 1999 Jan;103(1):11-8
references.pmid: 9884329
references.citation: Am J Trop Med Hyg. 1977 Jul;26(4):663-78
references.pmid: 889009
references.citation: Parasite Immunol. 2007 Feb;29(2):73-9
references.pmid: 17241395
references.citation: Int J Parasitol. 2008 Jul;38(8-9):981-7
references.pmid: 18282572
references.citation: PLoS Negl Trop Dis. 2010 Apr 13;4(4):e660
references.pmid: 20405054
references.citation: Trends Microbiol. 2008 Apr;16(4):173-80
references.pmid: 18353648
references.citation: PLoS Pathog. 2009 Oct;5(10):e1000630
references.pmid: 19851452
references.citation: PLoS Negl Trop Dis. 2010 Jul 27;4(7):e758
references.pmid: 20689574
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):213-5
references.pmid: 17190825
references.citation: J Exp Med. 2004 Oct 4;200(7):905-16
references.pmid: 15452181
references.citation: Cold Spring Harb Symp Quant Biol. 1983;48 Pt 2:443-52
references.pmid: 6586366
references.citation: PLoS Negl Trop Dis. 2009;3(2):e377
references.pmid: 19190745
references.citation: PLoS Pathog. 2009 Apr;5(4):e1000368
references.pmid: 19343208
references.citation: J Immunol. 2004 Oct 15;173(8):5229-37
references.pmid: 15470068
references.citation: Lancet. 2010 Oct 2;376(9747):1175-85
references.pmid: 20739055
references.citation: Parasit Vectors. 2010 Oct 14;3:99
references.pmid: 20946650
references.citation: Nat Rev Microbiol. 2010 Oct;8(10):693-705
references.pmid: 20818415
references.citation: Nat Rev Microbiol. 2010 May;8(5):328-39
references.pmid: 20372158