Immunopathogenesis of Onchocerca volvulus keratitis (river blindness): a novel role for TLR4 and endosymbiotic Wolbachia bacteria

Abstract

Infection with the parasitic nematode Onchocerca volvulus is associated with inflammation of the skin and cornea that can lead to blindness. Corneal damage is thought to occur as a result of the host inflammatory responses to degenerating microfilariae in the eye. We have utilized a murine model of corneal inflammation (keratitis) to investigate the immune and inflammatory responses associated with river blindness. Soluble extracts of O. volvulus, a filarial species that contains the endosymbiont bacteria Wolbachia or Acanthocheilonema viteae (a nematode not naturally infected with the bacteria) were injected into mouse corneas. Inflammatory responses and corneal changes were measured. We demonstrated a major role for endosymbiont Wolbachia bacteria and Toll-like receptor 4 (TLR4) in the pathogenesis of ocular onchocerciasis.

References

Who , Onchocerciasis (River Blindness). Fact Sheet, 1990; No. 95.

Duke BO , The population dynamics of Onchocerca volvulus in the human host. Trop Med Parasitol 1993; 44: 61-68.

Hall LR , Pearlman E. Pathogenesis of onchocercal keratitis (river blindness). Clin Microbiol Rev 1999; 12: 445-453.

Ottesen EA Immune responsiveness and the pathogenesis of human onchocerciasis. J Infect Dis 1995; 171: 659-671.

Taylor MJ , Hoerauf A.

Wolbachia bacteria of filarial nematodes. Parasitol

Today 1999; 15: 437-442.

Stouthamer R. , Breeuwer JA , Hurst GD Wolbachia pipientis: microbial manipulator of arthropod reproduction. Annu Rev Microbiol 1999; 53: 71-102.

Bandi C. , Anderson TJ , Genchi C. , Blaxter ML Phylogeny of Wolbachia in filarial nematodes. Proc R Soc Lond B Biol Sci 1998; 265: 2407-2413.

Taylor MJ , Bilo K. , Cross HF , Archer JP , Underwood AP 16S rDNA phylogeny and ultrastructural characterization of Wolbachia intracellular bacteria of the filarial nematodes Brugia malayi, B. pahangi, and Wuchereria bancrofti. Exp Parasitol 1999; 91: 356-361.

McGarry HF , Pfarr K. , Egerton G. et al. Evidence against Wolbachia symbiosis in Loa loa. Filaria J 2003; 2: 9.

10.

Buttner DW , Wanji S. , Bazzocchi C. , Bain O. , Fischer P. Obligatory symbiotic Wolbachia endobacteria are absent from Loa loa. Filaria J 2003; 2: 10.

11.

Grobusch MP , Kombila M. , Autenrieth I. , Mehlhorn H. , Kremsner PG No evidence of Wolbachia endosymbiosis with Loa loa and Mansonella perstans . Parasitol Res 2003.

12.

Lo N. , Casiraghi M. , Salati M. , Salati E. , Bazzocchi C. , Bandi C. How many Wolbachia supergroups exist? Mol Biol Evol 2002; 19: 341-346.

13.

Taylor MJ Wolbachia in the inflammatory pathogenesis of human filariasis. Ann N Y Acad Sci 2003; 990: 444-449.

14.

Bandi C. , Trees AJ , Brattig NW Wolbachia in filarial nematodes: evolutionary aspects and implications for the pathogenesis and treatment of filarial diseases. Vet Parasitol 2001; 98: 215-238.

15.

Casiraghi M. , Anderson TJ , Bandi C. , Bazzocchi C. , Genchi C. A phylogenetic analysis of filarial nematodes: comparison with the phylogeny of Wolbachia endosymbionts. Parasitology 2001 ; 122: 93-103.

16.

Kramer H. , Passeri B. , Corona S. , Simoncini L. , Casiraghi M. Immunohistochemical/immunogold detection and distribution of the endosymbiont Wolbachia of Dirofilaria immitis and Brugia pahangi using a polyclonal antiserum raised against WSP (Wolbachia surface protein). Parasitol Res 2003; 89: 381-386.

17.

Peixoto CA , Silva LF , Teixeira KM , Rocha A. Ultrastructural characterization of intracellular bacteria of Wuchereria bancrofti . Trans R Soc Trop Med Hyg 2001; 95: 566-568.

18.

Townson S. , Hutton D. , Siemienska J. et al. Antibiotics and Wolbachia in filarial nematodes: antifilarial activity of rifampicin, oxytetracycline and chloramphenicol against Onchocerca gutturosa, Onchocerca lienalis and Brugia pahangi. Ann Trop Med Parasitol 2000; 94: 801-816.

19.

Smith HL , Rajan TV

Tetracycline inhibits development of the infective-stage larvae of filarial nematodes in vitro. Exp

Parasitol 2000; 95: 265-270.

20.

Cross HF , Haarbrink M. , Egerton G. , Yazdanbakhsh M. , Taylor MJ Severe reactions to filarial chemotherapy and release of Wolbachia endosymbionts into blood. Lancet 2001; 358: 1873-1875.

21.

Hoerauf A. , Nisson-Pahle K. , Schmetz V. et al. Tetracycline therapy targets intracellular bacteria in the filarial nematode Litomosoides sigmodontis and results in filarial infertility. J Clin Invest 1999; 103: 11-18.

22.

Rao RU , Moussa H. , Weil GJ

Brugia malayi: effects of antibacterial agents on larval viability and development in vitro. Exp

Parasitol 2002; 101: 77-81.

23.

Taylor MJ , Cross HF , Bilo K. Inflammatory responses induced by the filarial nematode Brugia malayi are mediated by lipopolysaccharide-like activity from endosymbiotic Wolbachia bacteria. J Exp Med 2000; 191: 1429-1436.

24.

Saint Andre A , Blackwell NM , Hall LR et al. The role of endosymbiotic Wolbachia bacteria in the pathogenesis of river blindness. Science 2002; 295: 1892-1895.

25.

Brattig NW , Buttner DW , Hoerauf A. Neutrophil accumulation around Onchocerca worms and chemotaxis of neutrophils are dependent on Wolbachia endobacteria. Microbes Infect 2001; 3: 439-446.

26.

Kenyon K. (ed) Morphology and Pathologic Responses of the Cornea to Disease, 2nd edn. Boston, MA: Little, Brown and Company.

27.

Abiose A. Onchocercal eye disease and the impact of Mectizan treatment. Ann Trop Med Parasitol 1998; 92 (Suppl 1): S11-S22.

28.

Hall LR , Lass JH , Diaconu E. , Strine ER , Pearlman E. An essential role for antibody in neutrophil and eosinophil recruitment to the cornea: B cell-deficient (microMT) mice fail to develop Th2-dependent, helminth-mediated keratitis. J Immunol 1999 ; 163: 4970-4975.

29.

Hall LR Diaconu E, Patel R, Pearlman E. CXC chemokine receptor 2 but not C-C chemokine receptor 1 expression is essential for neutrophil recruitment to the cornea in helminth-mediated keratitis (river blindness). J Immunol 2001; 166: 4035-4041.

30.

Kaifi JT , Diaconu E. , Pearlman E. Distinct roles for PECAM-1, ICAM-1, and VCAM-1 in recruitment of neutrophils and eosinophils to the cornea in ocular onchocerciasis (river blindness). J Immunol 2001; 166: 6795-6801.

31.

Pearlman E. , Hall LR Immune mechanisms in Onchocerca volvulus-mediated corneal disease (river blindness). Parasite Immunol 2000; 22: 625-631.

32.

Hoerauf A. , Mand S. , Adjei O. , Fleischer B. , Buttner DW Depletion of Wolbachia endobacteria in Onchocerca volvulus by doxycycline and microfilaridermia after ivermectin treatment. Lancet 2001; 357: 1415-1416.

33.

Poltorak A. , He X. , Smirnova I. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998; 282: 2085-2088.

34.

Song PI , Abraham TA , Park Y. et al. The expression of functional LPS receptor proteins CD14 and Toll-like receptor 4 in human corneal cells. Invest Ophthalmol Vis Sci 2001; 42: 2867-2877.

35.

Hoerauf A. , Mand S. , Fischer K. et al. Doxycycline as a novel strategy against bancroftian filariasis - depletion of Wolbachia endosymbionts from Wuchereria bancrofti and stop of microfilaria production. Med Microbiol Immunol 2003; 5: 5.