3
ticks, interpreting the pathogenesis of granulocytic ana- plasmosis in diverse hosts and, eventually, understanding the ecology of the disease. References 1 Foley, J. (2000) Human ehrlichiosis: a review of clinical disease and epidemiology for the physician. Inf. Dis. Clin. Pract. 9, 93–98 2 Dumler, J.S. et al. (2005) Human granulocytic anaplasmosis and Anaplasma phagocytophilum. Emerging Inf. Dis. 11, 1828–1834 3 Nuttall, P.A. and Labuda, M. (2004) Tick–host interactions: saliva- activated transmission. Parasitology 129 (Suppl.), S177–S189 4 Brossard, M. and Wikel, S.K. (2004) Tick immunobiology. Parasitology 129 (Suppl.), S161–S176 5 Sukumaran, B. et al. (2006) An Ixodes scapularis protein required for survival of Anaplasma phagocytophilum in tick salivary glands. J. Exp. Med. 203, 1507–1517 6 Telford, S.R. et al. (1996) Perpetuation of the agent of human granulocytic ehrlichiosis in a deer tick–rodent cycle. Proc. Natl. Acad. Sci. U. S. A. 93, 6209–6214 7 Ohashi, N. et al. (2005) Anaplasma phagocytophilum-infected ticks. Japan. Emerging Inf. Dis. 11, 1780–1783 8 Alberdi, M.P. et al. (1998) Natural prevalence of infection with Ehrlichia (Cytoecetes) phagocytophila of Ixodes ricinus ticks in Scotland. Vet. Parasitol. 78, 203–213 9 Das, S. et al. (2000) SALP16, a gene induced in Ixodes scapularis salivary glands during tick feeding. Am. J. Trop. Med. Hyg. 62, 99–105 10 Kurtenbach, K. et al. (2002) Borrelia burgdorferi sensu lato in the vertebrate host. In Lyme Borreliosis: Biology, Epidemiology, and Control (Gray, J. et al., eds), pp. 117–148, CABI Publishing 11 Ramamoorthi, N. et al. (2005) The Lyme disease agent exploits a tick protein to infect the mammalian host. Nature 436, 573–577 12 Chen, S-M. et al. (1994) Identification of a granulocytotrophic Ehrlichia species as the etiologic agent of human disease. J. Clin. Microbiol. 32, 589–595 13 Steere, A.C. et al. (1977) Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three Connecticut communities. Arth. Rheum. 20, 7–17 14 Brown, R.N. et al. (2005) Geographic distribution of tick-borne diseases and their vectors. In Tick-Borne Diseases of Humans (Goodman, J.L. et al., eds), pp. 363–391, ASM Press 1471-4922/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2006.10.003 A niche for Wolbachia Kenneth M. Pfarr and Achim Hoerauf Institute for Medical Microbiology, Immunology and Parasitology, University Clinic Bonn, Sigmund-Freud-Strasse 25, Bonn D-53105, Germany Wolbachia are endosymbionts of arthropods and filarial nematodes. Arthropods infected with these endobac- teria display altered reproductive phenotypes, including cytoplasmic incompatibility and sex-ratio distortion. In nematodes, the endobacteria are essential for embryo- genesis and worm survival. Wolbachia are transmitted vertically from mother to progeny, and Frydman et al. recently showed that, after transfer to uninfected Drosophila, Wolbachia rapidly accumulate in the somatic stem cell niche. From this location, the endobacteria might enter the developing oocytes and infect the progeny. Wolbachia, endosymbionts of arthropods and filarial nematodes The Gram-negative alphaproteobacteria Wolbachia com- prise a genus of endobacteria that infects a range of arthropods and filarial nematodes. It is estimated that 20–80% of all insect species are infected with Wolbachia [1,2]. Most of the filarial nematodes also contain Wolba- chia, including the three major causes of filarial disease in humans: Wuchereria bancrofti, Brugia spp. and Oncho- cerca volvulus [3,4]. However, some filarial worms seem to have lost their endosymbionts during evolution [3–5], indicating that the requirement for Wolbachia by these nematodes can be overcome [6]. In arthropods, these endo- bacteria are responsible for several different phenotypes, including cytoplasmic incompatibility and sex-ratio distor- tion, which are rapidly distributed in the population [7] (Table 1). The endobacteria in nematodes are necessary for the development of embryos and larvae, and the survival of adult worms [8–10]. Wolbachia are transmitted to the next generation ver- tically (i.e. they are transmitted from mother to offspring) [7]. In arthropods, these endobacteria can be experimen- tally transmitted horizontally from infected to uninfected individuals and even between species, and there is evolu- tionary evidence that horizontal transfer has occurred in nature [11,12]. For Wolbachia infections to become fixed in a population, the endobacteria must be transmitted to the next generation through the germline. Until recently, it was unknown how these endobacteria enter the germline. However, Frydman et al. have shown that Wolbachia accumulate in the somatic stem cell niche (SSCN) of the Drosophila germarium, which is the site of egg chamber formation, and they have discussed a role for the SSCN in vertical transmission of these endobacteria [13]. Wolbachia phenotypes Wolbachia infect both arthropods and filarial nematodes but with some differences. In arthropods, these endobac- teria are responsible for cytoplasmic incompatibility, parthenogenesis, feminization of genetic males and male killing, all of which drive the spread of Wolbachia in the arthropod population [7]. In most cases, curing arthropods of their Wolbachia infection using tetracycline does not lead to adverse effects, making Wolbachia infections Corresponding author: Pfarr, K.M. ([email protected]) Available online 20 November 2006. Update TRENDS in Parasitology Vol.23 No.1 5 www.sciencedirect.com

A niche for Wolbachia

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ticks, interpreting the pathogenesis of granulocytic ana-plasmosis in diverse hosts and, eventually, understandingthe ecology of the disease.

References1 Foley, J. (2000) Human ehrlichiosis: a review of clinical disease and

epidemiology for the physician. Inf. Dis. Clin. Pract. 9, 93–982 Dumler, J.S. et al. (2005) Human granulocytic anaplasmosis and

Anaplasma phagocytophilum. Emerging Inf. Dis. 11, 1828–18343 Nuttall, P.A. and Labuda, M. (2004) Tick–host interactions: saliva-

activated transmission. Parasitology 129 (Suppl.), S177–S1894 Brossard, M. and Wikel, S.K. (2004) Tick immunobiology. Parasitology

129 (Suppl.), S161–S1765 Sukumaran, B. et al. (2006) An Ixodes scapularis protein required

for survival of Anaplasma phagocytophilum in tick salivary glands.J. Exp. Med. 203, 1507–1517

6 Telford, S.R. et al. (1996) Perpetuation of the agent of humangranulocytic ehrlichiosis in a deer tick–rodent cycle. Proc. Natl.Acad. Sci. U. S. A. 93, 6209–6214

7 Ohashi, N. et al. (2005) Anaplasma phagocytophilum-infected ticks.Japan. Emerging Inf. Dis. 11, 1780–1783

Corresponding author: Pfarr, K.M. ([email protected])Available online 20 November 2006.

www.sciencedirect.com

8 Alberdi, M.P. et al. (1998) Natural prevalence of infection withEhrlichia (Cytoecetes) phagocytophila of Ixodes ricinus ticks inScotland. Vet. Parasitol. 78, 203–213

9 Das, S. et al. (2000) SALP16, a gene induced in Ixodes scapularissalivary glands during tick feeding. Am. J. Trop. Med. Hyg. 62, 99–105

10 Kurtenbach, K. et al. (2002) Borrelia burgdorferi sensu lato inthe vertebrate host. In Lyme Borreliosis: Biology, Epidemiology, andControl (Gray, J. et al., eds), pp. 117–148, CABI Publishing

11 Ramamoorthi, N. et al. (2005) The Lyme disease agent exploits a tickprotein to infect the mammalian host. Nature 436, 573–577

12 Chen, S-M. et al. (1994) Identification of a granulocytotrophicEhrlichiaspecies as the etiologic agent of human disease. J. Clin. Microbiol. 32,589–595

13 Steere, A.C. et al. (1977) Lyme arthritis: an epidemic of oligoarticulararthritis in children and adults in three Connecticut communities.Arth. Rheum. 20, 7–17

14 Brown, R.N. et al. (2005) Geographic distribution of tick-borne diseasesand their vectors. In Tick-Borne Diseases of Humans (Goodman, J.L.et al., eds), pp. 363–391, ASM Press

1471-4922/$ – see front matter � 2006 Elsevier Ltd. All rights reserved.

doi:10.1016/j.pt.2006.10.003

A niche for Wolbachia

Kenneth M. Pfarr and Achim Hoerauf

Institute for Medical Microbiology, Immunology and Parasitology, University Clinic Bonn, Sigmund-Freud-Strasse 25,

Bonn D-53105, Germany

Wolbachia are endosymbionts of arthropods and filarialnematodes. Arthropods infected with these endobac-teria display altered reproductive phenotypes, includingcytoplasmic incompatibility and sex-ratio distortion. Innematodes, the endobacteria are essential for embryo-genesis and worm survival. Wolbachia are transmittedvertically from mother to progeny, and Frydman et al.recently showed that, after transfer to uninfectedDrosophila, Wolbachia rapidly accumulate in the somaticstem cell niche. From this location, the endobacteriamight enter the developing oocytes and infect theprogeny.

Wolbachia, endosymbionts of arthropods and filarialnematodesThe Gram-negative alphaproteobacteria Wolbachia com-prise a genus of endobacteria that infects a range ofarthropods and filarial nematodes. It is estimated that20–80% of all insect species are infected with Wolbachia[1,2]. Most of the filarial nematodes also contain Wolba-chia, including the three major causes of filarial disease inhumans: Wuchereria bancrofti, Brugia spp. and Oncho-cerca volvulus [3,4]. However, some filarial worms seemto have lost their endosymbionts during evolution [3–5],indicating that the requirement for Wolbachia by thesenematodes can be overcome [6]. In arthropods, these endo-bacteria are responsible for several different phenotypes,

including cytoplasmic incompatibility and sex-ratio distor-tion, which are rapidly distributed in the population [7](Table 1). The endobacteria in nematodes are necessary forthe development of embryos and larvae, and the survival ofadult worms [8–10].

Wolbachia are transmitted to the next generation ver-tically (i.e. they are transmitted from mother to offspring)[7]. In arthropods, these endobacteria can be experimen-tally transmitted horizontally from infected to uninfectedindividuals and even between species, and there is evolu-tionary evidence that horizontal transfer has occurred innature [11,12]. ForWolbachia infections to become fixed ina population, the endobacteria must be transmitted to thenext generation through the germline. Until recently, itwas unknown how these endobacteria enter the germline.However, Frydman et al. have shown that Wolbachiaaccumulate in the somatic stem cell niche (SSCN) of theDrosophila germarium, which is the site of egg chamberformation, and they have discussed a role for the SSCN invertical transmission of these endobacteria [13].

Wolbachia phenotypesWolbachia infect both arthropods and filarial nematodesbut with some differences. In arthropods, these endobac-teria are responsible for cytoplasmic incompatibility,parthenogenesis, feminization of genetic males and malekilling, all of which drive the spread of Wolbachia in thearthropod population [7]. In most cases, curing arthropodsof their Wolbachia infection using tetracycline does notlead to adverse effects, making Wolbachia infections

Page 2: A niche for Wolbachia

Table 1. Characteristics of Wolbachia infections in different hosts

Host Symbiosis Transmission Phenotype or function Localization Refs

Arthropod Mostly parasitism,

some cases of

mutualism

Vertical and

horizontal (rare)

Cytoplasmic incompatibility, male killing,

parthenogenesis, feminization of genetic males,

oogenesis

Ovaries, testes, embryos,

body cavity

[7,11,12,14,

15]

Nematode Mutualism Vertical only Required for embryogenesis, larval

development, adult survival

Ovaries, embryos,

hypodermis

[3,4,8–10]

6 Update TRENDS in Parasitology Vol.23 No.1

parasitic. However, recent studies have found mutualisticWolbachia infections in the parasitic wasp Asobara tabidaNees [14] and the stone beetle Coccotrypes dactyliperda[15], in which the endobacteria are necessary for embryonicdevelopment.

Wolbachia infections in filarial nematodes are differentfrom those in arthropods in that curing worms usingtetracycline leads to: (i) a block of embryogenesis that ischaracterized by degenerated embryos (no cell structurewithin the eggshell); (ii) female sterility; (iii) larval growthdefects; and (iv) death of adults [8–10]. Thus, the Wolba-chia of filarial nematodes are mutualistic symbionts.Because these endobacteria are required for embryogen-esis and worm survival, antiwolbachial therapy is usedas a treatment for filarial infections on an individualbasis and for cases in which current antifilarial drugsare ineffective [8–10].

Transmission of Wolbachia

Wolbachia of arthropods and nematodes are maintained inthe population by vertical transmission, whereby the endo-bacteria are passed to the next generation through thegermline. The phenotypes that result from Wolbachiainfections in arthropods help to establish the endosym-bionts in the population (Table 1), although not all progenyare infected. By contrast, all embryos, larvae and adultfilarial nematodes contain Wolbachia, which is strongevidence of the requirement for these endobacteria in theseorganisms [8–10].

Interestingly, the Wolbachia of arthropods can be hor-izontally transmitted between individuals and even acrossspecies [11,12,16]. In nature, horizontal transfer is rare butit is theorized that such transmission occurs throughparasitic relationships such as those seen with parasiticwasps [11]. It has been proposed that the presence ofWolbachia in nematodes and arthropods arose from hor-izontal transmission between these phyla in the distantpast (�100 million years ago) [5,17]. Analysis of the twocompleted Wolbachia genomes, from Drosophila [18] andBrugia malayi (a filarial nematode) [19], shows that theendosymbiont of B. malayi has undergone gene reduction,including genes tentatively described as being involved inparasitism [19,20].

Several studies have shown that these endobacteriaaccumulate in the germline stem cells of the Drosophilaoocyte [21,22]. Additionally, Wolbachia use the microtu-bules and dynein of the Drosophila host for localization inthe oocyte [23]. The cellular mechanisms behind verticaland horizontal transmission from the adult female to theoocytes are still unknown.

Wolbachia accumulate in the SSCNWolbachia colonization of the SSCN in the Drosophilagermarium was studied using microinjection of the endo-

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bacteria into uninfected Drosophila females [13]. Micro-scopy was used to track fluorescent dyes and antibodiesagainst proteins from Wolbachia and Drosophila. Fifteendays after their injection into the abdominal cavity ofuninfected Drosophila females, the Wolbachia had colo-nized the germarium, with a preference for the SSCN.

By characterizing the distribution of Wolbachia in thisregion, the authors were able to show that the SSCN hadtwo times the number ofWolbachia in the cells adjacent toit and three times the number in all other regions of thegermarium. The SSCN is a region of the germarium thatall germ cells contact and it contains two or three stemcells. These stem cells produce the follicle cells that remainin contact with the germ cells throughout their develop-ment into oocytes. Although direct infection has not beenobserved, Wolbachia in the SSCN are ideally located toinfect the germline directly because the germ cells passthrough the SSCN, or indirectly through the follicle cellsthat develop from the somatic stem cells in the SSCN.

The SSCN was colonized by Wolbachia not only aftermicroinjection but also in an experiment in which unin-fected germaria were transplanted into infected Droso-phila females. The germaria of these females wereinfected with Wolbachia from the abdominal cavity, andthe endobacteria accumulated in the SSCN of the trans-planted germaria. The targeting of the SSCN byWolbachiaafter inoculation mimics what could have occurred duringevolution: for example, a horizontal infection from a para-sitic wasp [11]. In such an infection, the numbers ofWolbachia would be limited. In order for the endobacteriato become established in the new host species, Wolbachiawould need to infect a tissue that: (i) had a cell type thatdivided slowly so that the endobacteria could accumulate;and (ii) would come into contact with the germline. Thus,endobacteria in the SSCNwould be ideally placed to multi-ply in the host and to establish the infection in the nextgeneration.

Concluding remarksThe study by Frydman et al. shows that Wolbachiaaccumulate in the SSCN after horizontal transmissionto a new host. More importantly, examination of femaleflies that were infected by vertical transmission showedthat Wolbachia were concentrated in the SSCN. TheSSCN might, therefore, be the location from whichWolbachia enter the germline after vertical transmissionbecause germline cells posterior to the SSCN are infectedwith endobacteria.

The colonization of the SSCN by Wolbachia highlightsthe complexity of the Wolbachia–host interaction. In thework by Frydman et al., the SSCN was colonized soonafter microinjection of the endobacteria into the abdomenof uninfected Drosophila females or following the trans-plantation of uninfected germaria into infected females.

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Update TRENDS in Parasitology Vol.23 No.1 7

In both experiments, the Wolbachia crossed three differ-ent tissues to access the SSCN: the peritoneal sheathmembrane around the ovary, the muscle epithelium ofeach ovariole and the somatic cells surrounding thegermline cells. Such movement must require interactionsbetween Wolbachia and the host cells to facilitate move-ment within and between cells and cell types, and toidentify when the endobacteria have reached their desti-nation, the SSCN.

Despite the differences in phenotype that Wolbachia ofarthropods and nematodes cause, both types are verticallytransmitted through the germline from one generation tothe next [7]. The accumulation of endobacteria in a regionof the ovary such as the SSCN might be evolutionarilyconserved in all Wolbachia. Favoring such a hypothesis isthe fact that, in filarial species that are infected withWolbachia, almost every oocyte contains endosymbionts,and embryos develop only when they are infected withWolbachia [4,8,9]. This indicates that the endobacteria aretransmitted to the oocytes early during oogenesis.Although nematodes do not have an SSCN, the distal cellof the Caenorhabditis elegans gonad [the distal tip cell(DTC)] forms a stem cell niche in which the germline cellsdivide [24,25]. The DTC is in contact with germ cells and isrequired to maintain the germ cell population. In filarialworms, the DTC, or a similar structure, could function as arepository forWolbachia that are transmitted to the divid-ing germ cells, ensuring transmission to the developingoocytes.

The tropism of Wolbachia towards a stem cell niche, ifevolutionarily conserved, might be exploitable to estab-lish Wolbachia of filariae in C. elegans. Because Wolba-chia of filariae are hypothesized to have lost the genesthat are necessary for invading cells [20], microinjectionof Wolbachia directly into the DTC of C. elegans mightenable the endobacteria to survive if the intracellularinteractions that are needed for endobacterial growthare conserved. Alternatively, microinjection of theseWolbachia into the SSCN could provide a useful toolfor studying both parasitic and mutualistic symbiosis inWolbachia.

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doi:10.1016/j.pt.2006.11.002