Targeting of <i>Wolbachia endobacteria</i> in <i>Litomosoides sigmodontis</i>: comparison of tetracyclines with chloramphenicol, macrolides and ciprofloxacin

Hoerauf, Achim; Volkmann, Lars; Nissen‐Paehle, Kerstin; Schmetz, Christel; Autenrieth, Ingo B.; Büttner, Dietrich W.; Fleischer, Bernhard

doi:10.1046/j.1365-3156.2000.00544.x

Cited by 90 publications

(55 citation statements)

References 13 publications

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“…Furthermore, microscopic analysis of B. pahangiϩTET female worms revealed mostly empty uteri. Similar results have been observed in vitro and in vivo with TET and doxycycline (4,17,19,20,43). In contrast, females taken from B. pahangiϩIVM gerbils showed levels of in vitro microfilaria production that were similar to those in females taken from B. pahangiϩ0 gerbils, confirming that the activity of IVM was not based upon the interruption of embryogenesis as it was for TET.…”

Section: Discussionsupporting

confidence: 80%

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Removal of Wolbachia from Brugia pahangi Is Closely Linked to Worm Death and Fecundity but Does Not Result in Altered Lymphatic Lesion Formation in Mongolian Gerbils ( Meriones unguiculatus )

Chirgwin¹,

Coleman²,

Porthouse³

et al. 2003

Infect Immun

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Approximately 30 years ago, researchers reported intracellular bacteria in filarial nematodes. These bacteria are relatives of the arthropod symbiont Wolbachia and occur in many filarial nematodes, including Brugia pahangi and Brugia malayi. Wolbachia bacteria have been implicated in a variety of roles, including filaria development and fecundity and the pathogenesis of lymphatic lesions associated with filarial infections. However, the role of the bacteria in worm biology or filarial disease is still not clear. The present experiments support previous data showing that tetracycline eliminates or reduces Wolbachia bacteria in B. pahangi in vivo. The elimination of Wolbachia was closely linked to a reduction in female fecundity and the viability of both sexes, suggesting that the killing of Wolbachia is detrimental to B. pahangi. The gerbils treated with tetracycline showed reduced levels of interleukin-4 (IL-4) and IL-5 mRNA in renal lymph nodes and spleens compared with the levels in B. pahangi-infected gerbils not treated with tetracycline. However, similar findings were noted in B. pahangi-infected gerbils treated with ivermectin, suggesting that the loss of circulating microfilariae, not the reduction of Wolbachia bacteria, was associated with the altered cytokine profile. Despite the change in T-cell cytokines, there was no difference in the sizes of renal lymph nodes isolated from gerbils in each treatment group. Furthermore, the numbers, sizes, or cellular compositions of granulomas examined in the lymphatics or renal lymph nodes did not differ with treatment. These data suggest that Wolbachia may not play a primary role in the formation of lymphatic lesions in gerbils chronically infected with B. pahangi.Lymphatic filariasis is caused primarily by the filarial nematodes Wuchereria bancrofti and Brugia malayi and affects more than 120 million people throughout the tropics and subtropics. The disease presents as a broad range of clinical and subclinical symptoms, including fever, acute and chronic inflammation, lymphatic edema, and elephantiasis. While much research has focused on the disease caused by infection with Brugia or Wuchereria, the mechanism(s) underlying the pathogenesis of lymphatic filariasis has not been clearly defined. In both acute and chronic infections, these mechanisms probably involve a diverse range of inflammatory reactions attributable to the parasite, host inflammatory responses, and opportunistic infections (40).Approximately 30 years ago, several researchers reported intracellular bacteria in filarial nematodes (31, 37, 54). These bacteria have since been identified as relatives of the arthropod symbiont Wolbachia (46). Wolbachia bacteria have now been reported to exist in many filarial nematodes, including B. malayi and Brugia pahangi (3,30,49,55). Interestingly, Wolbachia has recently been proposed to play a role in the induction of the host immune response to filariae (9,44,50,51). Some researchers suggest that lipopolysaccharide (LPS)-like molecules from filarial Wolbachia b...

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Section: Discussionsupporting

confidence: 80%

“…16S ribosomal DNA (rDNA) gene by PCR. Primer sequences for the nematode 5S and Wolbachia 16S genes have been previously published for use with Litomosoides sigmodontis (20). Four microliters of gDNA was added to a PCR master mixture and amplified as previously described (12).…”

Section: Gerbils and Parasitesmentioning

confidence: 99%

Removal of Wolbachia from Brugia pahangi Is Closely Linked to Worm Death and Fecundity but Does Not Result in Altered Lymphatic Lesion Formation in Mongolian Gerbils ( Meriones unguiculatus )

Chirgwin¹,

Coleman²,

Porthouse³

et al. 2003

Infect Immun

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“…The presence of complete pathways for nucleotide and heme biosynthesis in Wolbachia and their partial absence in the filarial parasites, coupled with the observation of a loss of viability and reproductive capacity of the filarial organisms following elimination of Wolbachia by antibiotics (42)(43)(44), suggest that the endosymbiont provides crucial signals and pathway components critical for parasite survival. Interestingly, all the members of the heme biosynthetic pathway, except for the ferrochelatase (Wbm0719) and the protoporphyrinogen oxidase, which is absent from the Wolbachia genome, were detected in the present proteomic analysis.…”

Section: Resultsmentioning

confidence: 99%

Stage-specific proteomic expression patterns of the human filarial parasiteBrugia malayiand its endosymbiontWolbachia

Bennuru

Meng

Ribeiro

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

123

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Global proteomic analyses of pathogens have thus far been limited to unicellular organisms (e.g., protozoa and bacteria). Proteomic analyses of most eukaryotic pathogens (e.g., helminths) have been restricted to specific organs, specific stages, or secretomes. We report here a large-scale proteomic characterization of almost all the major mammalian stages of Brugia malayi, a causative agent of lymphatic filariasis, resulting in the identification of more than 62% of the products predicted from the Bm draft genome. The analysis also yielded much of the proteome of Wolbachia, the obligate endosymbiont of Bm that also expressed proteins in a stage-specific manner. Of the 11,610 predicted Bm gene products, 7,103 were definitively identified from adult male, adult female, blood-borne and uterine microfilariae, and infective L3 larvae. Among the 4,956 gene products (42.5%) inferred from the genome as "hypothetical," the present study was able to confirm 2,336 (47.1%) as bona fide proteins. Analysis of protein families and domains coupled with stage-specific expression highlight the important pathways that benefit the parasite during its development in the host. Gene set enrichment analysis identified extracellular matrix proteins and those with immunologic effects as enriched in the microfilarial and L3 stages. Parasite sex-and stage-specific protein expression identified those pathways related to parasite differentiation and demonstrates stage-specific expression by the Bm endosymbiont Wolbachia as well.filaria | nematode D isease associated with infection by Brugia malayi (Bm) and Wuchereria bancrofti, the two major causative organisms of human lymphatic filariasis, is the second leading cause of morbidity/disability worldwide, in large part because of the parasites' ability to alter the structural and functional integrity of the lymphatics, leading to lymphedema and elephantiasis. Invasion, establishment of infection within the host and development are essential processes within the complex parasite life cycle (SI Appendix, Fig. S1), with many of the parasitic stages being targets for therapeutic intervention or vaccines. Each of the filarial life cycle stages has characteristics that are shared and others that are stage-specific.Filarial infections are often characterized by a series of discrete host responses directed at the parasite and its endosymbiont Wolbachia that evolve during the course of infection. Because proteins are usually the effectors of most biological functions, proteomic data enable a more direct understanding of these important processes compared with those inferred from genomic studies. Absolute quantification of genome-wide expressed proteins is not yet within our reach for most eukaryotes. However, spectral counts of massive MS-based data (e.g., observed frequencies of each peptide) allow for relative quantification. Proteomic data also allow for clearer genomic curation by improving annotation and the identification of translational sites, stop codon read-throughs, frame shifts, and predict...

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“…The presence of intracytoplasmic bacteria in O. volvulus was first described by Kozek in 1977, who found Rickettsia-like bacteria in hypodermal lateral cords of male and female worms, in female reproductive organs, and in the first-stage larvae (microfilariae) (15). The bacteria appear to have an essential role in embryogenesis in these nematodes, as antibiotic treatment of infected individuals or experimental animals inhibits production of microfilariae (11)(12)(13).…”

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confidence: 97%

Wolbachia-Induced Neutrophil Activation in a Mouse Model of Ocular Onchocerciasis (River Blindness)

et al. 2004

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Endosymbiotic Wolbachia bacteria are abundant in the filarial nematodes that cause onchocerciasis (river blindness), including the larvae (microfilariae) that migrate into the cornea. Using a mouse model of ocular onchocerciasis, we recently demonstrated that it is these endosymbiotic bacteria rather than the nematodes per se that induce neutrophil infiltration to the corneal stroma and loss of corneal clarity (Saint Andre et al., Science 295:1892-1895, 2002). To better understand the role of Wolbachia organisms in the pathogenesis of this disease, we examined the fate of these bacteria in the cornea by immunoelectron microscopy. Microfilariae harboring Wolbachia organisms were injected into mouse corneas, and bacteria were detected with antibody to Wolbachia surface protein. Within 18 h of injection, neutrophils completely surrounded the nematodes and were in close proximity to Wolbachia organisms. Wolbachia surface protein labeling was also prominent in neutrophil phagosomes, indicating neutrophil ingestion of Wolbachia organisms. Furthermore, the presence of numerous electron-dense granules around the phagosomes indicated that neutrophils were activated. To determine if Wolbachia organisms directly activate neutrophils, peritoneal neutrophils were incubated with either parasite extracts containing Wolbachia organisms, parasite extracts depleted of Wolbachia organisms (by antibiotic treatment of worms), or Wolbachia organisms isolated from filarial nematodes. After 18 h of incubation, we found that isolated Wolbachia organisms stimulated production of tumor necrosis factor alpha and CXC chemokines macrophage inflammatory protein 2 and KC by neutrophils in a dose-dependent manner. Similarly, these cytokines were induced by filarial extracts containing Wolbachia organisms but not by Wolbachia-depleted extracts. Taken together, these findings indicate that neutrophil activation is an important mechanism by which Wolbachia organisms contribute to the pathogenesis of ocular onchocerciasis.Wolbachia organisms infect filarial nematodes of importance to human health, including Wuchereria bancrofti and Brugia malayi, which cause lymphatic filariasis, and Onchocerca volvulus, which causes river blindness (10). The presence of intracytoplasmic bacteria in O. volvulus was first described by Kozek in 1977, who found Rickettsia-like bacteria in hypodermal lateral cords of male and female worms, in female reproductive organs, and in the first-stage larvae (microfilariae) (15). The bacteria appear to have an essential role in embryogenesis in these nematodes, as antibiotic treatment of infected individuals or experimental animals inhibits production of microfilariae (11-13).Using a murine model of ocular onchocerciasis, we recently demonstrated that O. volvulus extracts containing Wolbachia organisms induce pronounced corneal inflammation (characterized by neutrophil infiltration and development of corneal haze) when injected into the corneal stroma, whereas parasite extracts depleted of Wolbachia organisms by antibiotics do ...

show abstract

Targeting of Wolbachia endobacteria in Litomosoides sigmodontis: comparison of tetracyclines with chloramphenicol, macrolides and ciprofloxacin

Cited by 90 publications

References 13 publications

Removal of Wolbachia from Brugia pahangi Is Closely Linked to Worm Death and Fecundity but Does Not Result in Altered Lymphatic Lesion Formation in Mongolian Gerbils ( Meriones unguiculatus )

Removal of Wolbachia from Brugia pahangi Is Closely Linked to Worm Death and Fecundity but Does Not Result in Altered Lymphatic Lesion Formation in Mongolian Gerbils ( Meriones unguiculatus )

Stage-specific proteomic expression patterns of the human filarial parasiteBrugia malayiand its endosymbiontWolbachia

Wolbachia-Induced Neutrophil Activation in a Mouse Model of Ocular Onchocerciasis (River Blindness)

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