Accepted Manuscript

Elucidation of the first definitively identified life cycle for a marine blood fluke (: Spirorchiidae) enables informed control

Thomas H. Cribb, Jose L. Crespo-Picazo, Scott C. Cutmore, Brian A. Stacy, Phoebe A. Chapman, Daniel García-Párraga

PII: S0020-7519(16)30272-7 DOI: http://dx.doi.org/10.1016/j.ijpara.2016.11.002 Reference: PARA 3918

To appear in: International Journal for Parasitology

Received Date: 29 August 2016 Revised Date: 30 October 2016 Accepted Date: 3 November 2016

Please cite this article as: Cribb, T.H., Crespo-Picazo, J.L., Cutmore, S.C., Stacy, B.A., Chapman, P.A., García- Párraga, D., Elucidation of the first definitively identified life cycle for a marine turtle blood fluke (Trematoda: Spirorchiidae) enables informed control, International Journal for Parasitology (2016), doi: http://dx.doi.org/ 10.1016/j.ijpara.2016.11.002

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1 Elucidation of the first definitively identified life cycle for a marine

2 turtle blood fluke (Trematoda: Spirorchiidae) enables informed

3 control

4

5 Thomas H. Cribba,*, Jose L. Crespo-Picazob, Scott C. Cutmorea, Brian A. Stacyc , Phoebe A.

6 Chapmand, Daniel García-Párragab

7

8 aThe University of Queensland, School of Biological Sciences, St Lucia, Queensland, 4072,

9 Australia

10 bFundación Oceanogràfic, Veterinary Services & Research Department, Avanqua

11 Oceanogràfic-Ágora, C/ Eduardo Primo Yúfera 1B, 46013 Valencia, Spain

12 cNational Marine Fisheries Service, Office of Protected Resources and University of Florida,

13 College of Veterinary Medicine, Gainesville, FL, USA

14 dThe University of Queensland, Veterinary Marine Research, Teaching and

15 Investigation Unit, School of Veterinary Science, Gatton, Queensland, 4343, Australia

16 17 * Corresponding author. Tel.: +61 7 3365 2581; fax: +61 7 3365 4699.

18 E-mail address: [email protected] (T.H. Cribb)

19 20 Nucleotide sequence data reported in this paper are available in GenBank under the

21 accession numbers: KX987107-KX987112.

22

1

23 Abstract

24 Blood flukes of the family Spirorchiidae are significant pathogens of both free-

25 ranging and captive marine . Despite a significant proportion of marine turtle mortality

26 being attributable to spirorchiid infections, details of their life cycles remain almost entirely

27 unknown. Here we report on the molecular elucidation of the complete life cycle of a marine

28 spirorchiid, identified as Amphiorchis sp., infecting vermetid gastropods and captive bred

29 neonate Caretta caretta in the Oceanogràfic Aquarium, in Valencia, Spain. Specimens of a

30 vermetid gastropod, cf. rugulosus (Monterosato, 1878), collected from the

31 aquarium filtration system housing diseased C. caretta, were infected with sporocysts and

32 cercariae consistent with the family Spirorchiidae. We generated rDNA sequence data

33 (internal transcribed spacer 2 (ITS2) and partial 28S rDNA) from infections from the

34 vermetid which were identical to sequences generated from eggs from the serosa of the

35 intestine of neonate C. caretta, and an adult spirorchiid from the liver of a C. caretta from

36 Florida, USA. Given the reliability of these markers in the delineation of trematode ,

37 we consider all three stages to represent the same species and tentatively identify it as a

38 species of Amphiorchis Price, 1934. The source of infection at the Oceanogràfic Foundation

39 Rehabilitation Centre, Valencia, Spain, is inferred to be an adult C. caretta from the western

40 Mediterranean being rehabilitated in the same facility. Phylogenetic analysis suggests that

41 this Amphiorchis sp. is closely related to other spirorchiids of marine turtles (species of

42 Carettacola Manter & Larson, 1950, Looss, 1899 and Learedius Price, 1934).

43 We discuss implications of the present findings for the control of spirorchiidiasis in captivity,

44 for the better understanding of epidemiology in wild individuals, and the elucidation of

45 further life cycles.

46 Keywords: Trematoda; Spirorchiidae; Life cycle; ; Conservation; Sea turtles,

47 Transmission

2

48 1. Introduction

49 The Spirorchiidae Stunkard, 1921 is an assemblage of 20 genera of blood flukes

50 which parasitise the circulatory system of freshwater and marine turtles globally (Platt, 2002;

51 Roberts et al., 2016). Spirorchiids have recently come to prominence as they have been

52 widely shown to cause extensive tissue injury and mortality in marine turtles (Glazebrook et

53 al., 1981; Gordon et al., 1998; Flint et al., 2010; Stacy et al., 2010a). As with blood fluke

54 infections in other taxa, disease in turtles results from both inflammation and vascular injury

55 caused by the trematodes and embolized ova, which affect a variety of tissues (Gordon et al.,

56 1998; Stacy et al., 2010a).

57 Despite their significance as a frequent cause of disease in some marine turtles, lack

58 of knowledge of their life cycles hampers progress in our understanding of the epidemiology

59 of marine spirorchiids. Life cycles are known for five freshwater spirorchiid species, all of

60 which infect pulmonate (heterobranch) gastropods as first intermediate hosts (Wall, 1941a, b,

61 1951; Pieper, 1953; Holliman and Fisher, 1968; Turner and Corkum, 1977). Numerous other

62 putative but unidentified freshwater spirorchiid cercariae are known from both pulmonate and

63 caenogastropod gastropods. In stark contrast, there exists just a single report of a marine

64 turtle spirorchiid life cycle, that of Stacy et al. (2010b) who reported a spirorchiid in a

65 fissurellid (vetigastropod) limpet from Florida, USA. However, this infection was detected by

66 molecular analysis alone; the parasite stages were not observed by microscopy.

67 Caretta caretta (the loggerhead turtle) is considered conservation-dependent globally,

68 including the Mediterranean population (Ullmann and Stachowitsch, 2015). In support of the

69 population, the Oceanogràfic Foundation in Valencia, Spain runs a head-starting program in

70 which cohorts of juvenile C. caretta are incubated and reared from eggs translocated from

71 nearby Mediterranean beaches. The facility also rehabilitates sick, bycaught and injured

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72 juvenile and adult specimens of C. caretta from the nearby Mediterranean coast for eventual

73 reintroduction. Adult and juvenile turtles are always held in separate tanks, but the water

74 passing through the tanks is shared and recirculated. From January 2015 many captive-

75 hatched juvenile turtles began exhibiting debilitation and wasting disease that was

76 characterised by weight loss, malabsorption, anorexia, gastrointestinal stasis and occasionally

77 neurological signs of incoordination or swirling behaviour. Upon necropsy and subsequent

78 histopathology, spirorchiid eggs were found in several tissues and organs, and were

79 especially evident, even macroscopically, within the serosa of the intestine. Individual C.

80 caretta that survived longest in the facility harboured the greatest numbers of eggs. Given

81 that the water supply of the aquarium facility is semi-closed and pretreated, that pre-hatching

82 transmission of spirorchiids is unknown, and the evidence of increasing egg loads in tissues

83 with age despite consecutive deworming treatment (Jacobson et al., 2003), it was concluded

84 that transmission was occurring within the facility. These circumstances created an

85 opportunity to identify the intermediate host within the filtration system. Here we report the

86 elucidation of the intermediate host of the spirorchiid parasite using novel ribosomal data and

87 detail the morphology of the stages associated with it.

88

89 2. Materials and methods

90 2.1. Morphological specimens

91 Examination of the aquarium system for potential intermediate hosts in September

92 2015 revealed the presence of just one gastropod species, a sessile form that was attached to

93 piping delivering and draining water from the turtle holding tanks. We dissected specimens of

94 this gastropod species under a stereomicroscope in a solution of 0.85% saline. When

95 observed, asexual stages and cercariae of trematodes were fixed either in near boiling saline

4

96 and then transferred immediately to 80% alcohol, or directly in cold alcohol for samples for

97 molecular analysis.

98 Specimens for morphological analysis were subsequently washed in fresh water,

99 stained with Mayer’s haematoxylin, destained in a solution of 1.0% HCl and neutralised in

100 0.5% ammonium hydroxide solution. Specimens were then dehydrated through a graded

101 ethanol series, cleared in methyl salicylate and mounted in Canada balsam. Measurements

102 were made using an Olympus SC50 digital camera mounted on an Olympus BX-53

103 compound microscope using cellSens Standard imaging software. Measurements are given in

104 µm and, where length is followed by breadth, the two measurements are separated by ‘×’.

105

106 2.2. Molecular sequencing

107 Total genomic DNA was extracted using phenol/chloroform extraction techniques

108 (Sambrook and Russell, 2001). We amplified the partial D1-D3 fragment of the 28S nuclear

109 rDNA region using the primers LSU5 (5'-TAG GTC GAC CCG CTG AAY TTA AGC A-3';

110 Littlewood, 1994) and 1500R (5'-GCT ATC CTG AGG GAA ACT TCG-3'; Snyder and

111 Tkach, 2001) and the internal transcribed spacer 2 (ITS2) region using the primers 3S (3S: 5'-

112 GGT ACC GGT GGA TCA CGT GGC TAG TG-3'; Morgan and Blair, 1995) and ITS2.2 (5'-

113 CCT GGT TAG TTT CTT TTC CTC CGC-3'; Cribb et al., 1998). The 28S rDNA region has

114 proven informative in phylogenetic analysis of blood flukes and the ITS2 rDNA region has

115 proven effective in species discrimination (Blasco-Costa et al., 2016).

116 PCR for both the 28S and ITS2 regions was performed with a total volume of 20 µl

117 consisting of 5 µl of 5x MyTaq Reaction Buffer (Bioline, United Kingdom), 0.75 µl of each

118 primer (10 pmols), 0.25 µl of Taq polymerase (Bioline MyTaq™ DNA Polymerase) and 2 µl

119 of DNA template (approximately 10 ng), made up to 20 µl with Invitrogen™ (United States)

5

120 ultraPURE™ distilled water. Amplification was carried out on an MJ Research (United

121 States) PTC-150 thermocycler. The following profile was used to amplify the 28S region: an

122 initial 95°C denaturation for 4 min, followed by 30 cycles of 95°C denaturation for 1 min,

123 56°C annealing for 1 min, 72°C extension for 2 min, followed by a single cycle of 95°C

124 denaturation for 1 min, 55°C annealing for 45 s and a final 72°C extension for 4 min. The

125 following profile was used to amplify the ITS2 region: an initial single cycle of 95°C

126 denaturation for 3 min, 45°C annealing for 2 min, 72°C extension for 90 s, followed by four

127 cycles of 95°C denaturation for 45 s, 50°C annealing for 45 s, 72°C extension for 90 s,

128 followed by 30 cycles of 95°C denaturation for 20 s, 52°C annealing for 20 s, 72°C extension

129 for 90 s, followed by a final 72°C extension for 5 min. Amplified DNA was purified using a

130 Bioline ISOLATE II PCR and Gel Kit according to the manufacturer’s protocol. Cycle

131 sequencing of purified DNA was carried out using ABI Big Dye™ v.3.1 chemistry following

132 the manufacturer’s recommendations, using the same primers used for PCR amplification as

133 well as the additional 28S primers 300F (5'-CAA GTA CCG TGA GGG AAA GTT G-3';

134 Littlewood et al., 2000), ECD2 (5'-CCT TGG TCC GTG TTT CAA GAC GGG-3';

135 Littlewood et al., 1997) and 1200R (5'-GCA TAG TTC ACC ATC TTT CGG-3'; Lockyer et

136 al., 2003a). Cycle sequencing was carried out at the Australian Genome Research Facility.

137 We extracted DNA from eggs found in the serosa of the small intestine of infected C.

138 caretta using a DNeasy Blood and Tissue kit (Qiagen, Hilden, Germany). The extraction

139 protocol was in accordance with the manufacturer’s instructions, with the exception that 1 g

140 of Silica/Zirconia 0.5 mm beads (Daintree Scientific, Tasmania, Australia) was utilised to

141 disrupt the eggs in a Biospec (United States) Mini-Beadbeater 16 for 3 min prior to

142 extraction, and the final elution was made in 100 µl of elution buffer as opposed to the

143 recommended 200 µl. PCRs for egg extractions were carried out using primers L3F and L2R

144 for 28S, and IF1 and IR1 for ITS2 (Chapman et al., 2015). Reactions and cycling conditions

6

145 were as described by Chapman et al. (2015). PCR products were visualised on a 1% agarose

146 gel and submitted to the Animal Genetics Laboratory (School of Veterinary Science,

147 University of Queensland, Gatton, Australia) for purification and sequencing using the same

148 primers as for PCR.

149 Sequencher™ version 4.5 (GeneCodes Corp., United States) was used to assemble

150 and edit contiguous sequences, and the start and the end of the ITS2 rDNA region were

151 determined by annotation through the ITS2 Database (Koetschan et al., 2012) using the

152 ‘Metazoa’ model.

153

154 2.3. Phylogenetic analysis

155 Partial 28S rDNA sequences generated during this study were aligned with those of

156 species of available on GenBank using MUSCLE version 3.7 (Edgar,

157 2004) with ClustalW sequence weighting and UPGMA clustering for iterations 1 and 2

158 (Table 1). The resultant alignments were refined by eye using MESQUITE (Mesquite: a

159 modular system for evolutionary analysis. Version 2.72 http://mesquiteproject.org) and the

160 ends of each fragment were trimmed to match the shortest sequence in each alignment.

161 Bayesian inference and Maximum Likelihood analyses of the 28S rDNA dataset were

162 conducted to explore distinctions and relationships among these taxa. Bayesian inference

163 analysis was performed using MrBayes version 3.2.6 (Ronquist et al., 2012) and Maximum

164 Likelihood analysis was performed using RAxML version 8.2.8 (Stamatakis, 2014) , run on

165 the CIPRES portal (Miller et al., 2010). The software jModelTest version 2.1.10 (Darriba et

166 al., 2012) was used to estimate the best nucleotide substitution model for the dataset.

167 Bayesian inference and Maximum Likelihood analyses were conducted using the GTR+I

168 model predicted as the best estimators by the Akaike Information Criterion (AIC) in

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169 jModelTest. Nodal support in the Maximum Likelihood analysis was estimated by

170 performing 100 bootstrap pseudoreplicates. Bayesian inference analysis was run over

171 10,000,000 generations (ngen = 10000000) with two runs each containing four simultaneous

172 Markov Chain Monte Carlo (MCMC) chains (nchains = 4) and every 1000th tree saved

173 (samplefreq = 1000). Bayesian inference analysis used the following parameters: nst = 6,

174 rates = invgamma, ngammacat = 4, and the priors parameters of the combined dataset were

175 set to ratepr = variable. Samples of substitution model parameters, and tree and branch

176 lengths were summarised using the parameters ‘sump burnin = 3000’ and ‘sumt burnin =

177 3000’. These ‘burnin’ parameters were chosen because the log likelihood scores ‘stabilised’

178 well before 3,000,000 replicates in the Bayesian inference analysis.

179

180 3. Results

181 3.1. Morphological analysis

182 The only gastropod found in the holding tanks in the Oceanogràfic Rehabilitation Centre was

183 identified by Dr Rüdiger Bieler of the Chicago Field Museum, Illinois, USA as Thylaeodus

184 cf. rugulosus (Monterosato, 1878) (, Vermetidae) (Fig. 1A). This vermetid

185 species occurs in the western Mediterranean and the central Atlantic (Bieler, 1995). We

186 lodged five voucher specimens in the Chicago Field Museum (FMNH 344699-700).

187 We found infections of spirorchiid sporocysts in 38 of the 45 T. cf. rugulosus

188 individuals dissected (infection prevalence 84%). Large and apparently fully developed

189 ocellate furcocercous cercariae were detected in just three infections; most of the sporocysts

190 had only immature cercariae which could be recognised as such by the presence of eye-spots

191 and developing tails.

192

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193 3.2. Description of intramolluscan stages

194 Sporocysts in digestive gland of T. cf. rugulosus. Body tubular, containing numerous

195 developing cercariae but no more than two close to fully developed. Maximum length

196 observed 1432 µm.

197 Cercaria (Figs. 1B, C) (based on single largest recovered specimen). Body 348 × 101

198 µm. Tegumental spines on body and tail, minute. Dorsal fin-fold not detected. Eye-spots

199 prominent, 159 µm from anterior extremity. Anterior organ 128 × 76 µm; head gland present,

200 prominent. Penetration glands in two groups of three with bodies filling posterior extremity.

201 Ventral sucker 260 µm from anterior extremity, 49 µm long. Tail 974 µm long in total,

202 maximum width 76 µm. Furcae 260 × 37 µm, surrounded by distinct fin-fold terminally.

203 Permanent preparations of cercariae and sporocysts have been lodged in the Queensland

204 Museum, Brisbane, Australia (Nos G 235497- G 235509).

205

206 3.3. Molecular analysis

207 ITS2 and partial 28S rDNA sequences were generated from asexual trematode stages

208 dissected from three individual T. cf. rugulosus and from spirorchiid eggs taken from the

209 serosa of the intestine of a necropsied neonate C. caretta from the Oceanogràfic. Sequences

210 from the intestinal eggs and the stages infecting vermetid gastropods were identical for both

211 markers. The new sequence data were compared with that available from GenBank and with

212 a library of unpublished sequences from marine turtles from off Florida, USA held by one of

213 the authors. No matches were identified from GenBank, but a perfect match (for both

214 markers) was found between samples from Valencia and an adult spirorchiid collected from

215 C. caretta from Florida. The voucher specimen relating to the Florida infection has been

216 deposited in the United States National Museum as no. 1422020. In the combination of

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217 unfused intestinal caeca, two testes with the cirrus-sac and genital pore between, and slender

218 body with the vitelline follicles extending to the caecal extremities, the specimen is consistent

219 with the Amphiorchis Price, 1934. On this basis, we identify the form from the

220 Valencia rehabilitation centre as Amphiorchis sp. We refrain from attempting to identify the

221 specimen relative to the five recognised species of Amphiorchis because its poor condition

222 renders this unreliable.

223 Preliminary Bayesian inference and Maximum Likelihood analysis of the partial 28S

224 rDNA alignment of a wide range of Schistosomatoidea produced a topology (essentially

225 identical in both analyses) in which species of marine genera of Aporocotylidae formed a

226 well-supported clade sister to all spirorchiids and schistosomatids. The Spirorchiidae was

227 paraphyletic, forming one clade of freshwater spirorchiids and a second strongly supported

228 clade of four marine spirorchiids (including the current form, Amphiorchis sp.). The clade of

229 marine spirorchiids was sister to schistosomatids. These results are broadly consistent with

230 previous analyses (Snyder, 2004; Orelis-Ribeiro et al., 2014; Pinto et al., 2015) and are

231 therefore not reproduced here. In light of these preliminary results we realigned and analysed

232 a reduced data set comprising just sequences of marine spirorchiids (including Amphiorchis

233 sp.), using a range of schistosomatids as the outgroup. Maximum Likelihood and Bayesian

234 inference analyses of this reduced dataset resulted in phylograms with identical topologies

235 (Fig. 2), in which the marine spirorchiids formed a well-supported clade to the exclusion of

236 the schistosomatids. Within the marine spirorchiid clade, Carettacola hawaiiensis Dailey,

237 Fast & Balazs, 1991 was basal to the remaining taxa and Amphiorchis sp. was sister to

238 Hapalotrema pambanensis Mehrotra, 1973 (senior syn. of Hapalotrema mehrai Rao, 1976

239 according to Chapman et al. (2015)) and Learedius learedi Price, 1934.

240

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241 4. Discussion

242 The genetic match between sequences derived from infections from the vermetid

243 gastropod T. cf. rugulosus, from eggs from the intestine of neonate C. caretta at the

244 Oceanogràfic, and from adult worms from C. caretta from Florida allows us to conclude that

245 the life cycle of this species has been demonstrated.

246 The voucher specimen from C. caretta from Florida is consistent with the genus

247 Amphiorchis, but is too poorly preserved to allow reliable identification to species. Notably,

248 no species of Amphiorchis is known from C. caretta; all five described Amphiorchis spp. are

249 reported from either Chelonia mydas or Eretmochelys imbricata (Price, 1934; Oguro, 1938;

250 Simha, 1970; Fischthal and Acholonu, 1976; Gupta and Mehrotra, 1981; Werneck and Silva,

251 2013). The present form may thus prove to be a new species. Our phylogenetic analyses

252 suggest that the present Amphiorchis sp. is closely related to species of Hapalotrema Looss,

253 1899, Learedius Price, 1934 and Carettacola Manter & Larson, 1950. These four genera are

254 morphologically similar, and recent molecular analysis by Chapman et al. (2015) found that

255 the single species of Learedius nested within Hapalotrema. Further molecular

256 characterization of species of these genera is needed.

257 Despite the absence of previous reports of species of Amphiorchis from C. caretta,

258 this species hosts a rich fauna of spirorchiids from five genera (Luhman, 1935; Manter and

259 Larson, 1950; Jacobson et al., 2006; Stacy et al., 2010a; Chen et al., 2012). Strikingly, as far

260 as we can detect, spirorchiids have not previously been reported from C. caretta nor other

261 turtle species from the Mediterranean despite several surveys (e.g. Manfredi et al., 1998;

262 Gracan et al., 2012). However, it is likely this population does harbour spirorchiids, given

263 that the ultimate source of the infection of Amphiorchis sp. in the neonate turtles housed at

264 the Oceanogràfic rescue centre is inferred to have been mature turtles taken from the western

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265 Mediterranean. Caretta caretta from the western Mediterranean are part of a trans-Atlantic

266 population, genetically distinguishable from the eastern Mediterranean population (e.g.

267 Carreras et al., 2011). Possibly there is a distinction in the parasites of these populations,

268 which might explain the absence of spirorchiids in previous reports of parasites of some

269 Mediterranean C. caretta.

270 Our studies provide direct evidence that marine spirorchiids can be transmitted in

271 closed-system aquaria. Notably, the Amphiorchis specimens collected from Florida, which

272 were genetically identical to the specimens from Valencia, was also from a captive juvenile

273 C. caretta. This individual had been raised in an aquarium from hatching and was believed to

274 have acquired fatal spirorchiidiasis in captivity (unpublished observations). Glazebrook and

275 Campbell (1990) reported spirorchiids in hatchling-raised individuals of both C. mydas and

276 E. imbricatus in Queensland, Australia. Furthermore, the study of Stacy et al. (2010b) was

277 based on material from a Cayman Island turtle farm where transmission of L. learedi occurs

278 (Greiner et al., 1980). Given the threatened status of many marine turtles and the frequent

279 rearing of young turtles and rehabilitation of older turtles in aquarium facilities, our work

280 demonstrates the need for vigilance to ensure that pathogenic spirorchiid infections are not

281 transmitted within these systems. Elimination of vermetids is now one clear approach to the

282 control of spirorchiidiasis in turtle hatchery and rehabilitation centres. Notably, many

283 vermetids produce non-planktonic “crawl-away juveniles” (e.g. Calvo et al., 1998), and this

284 reproductive habit may make them especially liable to multiply in marine aquaria.

285 We do not know whether T. cf. rugulosus is the only host for the present Amphiorchis

286 sp., however, given the general pattern of specificity of trematodes for molluscan

287 intermediate hosts (Cribb et al., 2001), it seems unlikely that the host range is wider than a

288 range of vermetids. As far as we can determine, no spirorchiid has been reported from more

289 than a single gastropod family. A potentially parallel system may be exemplified by an

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290 aporocotylid (fish blood fluke), Cardicola forsteri Cribb, Daintith & Munday, 2000. The tuna

291 hosts of this species are highly mobile marine that, similar to marine turtles, travel

292 large distances. This trematode infects different polychaete intermediate hosts in Australia

293 and Japan (Cribb et al., 2011; Shirakashi et al., 2016). Thus, further examination of vermetids

294 in other geographical locations may well expand the intermediate host range of this

295 Amphiorchis sp..

296 There is extensive literature relating to the life cycles of spirorchiids, but almost all of

297 it relates to freshwater species. A series of classical and often highly detailed experiment-

298 based studies characterised life cycles for five freshwater species from North America –

299 Spirorchis artericola (Ward, 1921), Spirorchis elephantis (Cort, 1918), Spirorchis parvus

300 (Stunkard, 1923), Spirorchis scripta Stunkard, 1923 and Vasotrema robustum (Stunkard,

301 1928) by Wall (1941a, b, 1951), Pieper (1953), Holliman and Fisher (1968), and Turner and

302 Corkum (1977). All these species infect (“”: ). The

303 cercariae of these species are morphologically similar and were recognised by Wall (1941b)

304 as a distinct group among furcocercous cercariae, united by a range of features including

305 being large, distomate, and having a distinctive arrangement of eye-spots. No complete new

306 life cycle has been described for a spirorchiid for many years. However, five further

307 spirorchiid cercariae have recently been characterised as such by molecular analyses (Brant et

308 al., 2006; Kraus et al., 2014; Pinto et al., 2015). Table 2 summarises the reports of these and

309 the five classically elucidated cycles. There are also descriptions of several other cercariae

310 likely to be spirorchiids (e.g. Nasir and Diaz, 1973; Bayssade-Dufour et al., 1989). The status

311 of these species as spirorchiids cannot be considered certain (in the absence of experimental

312 or molecular data) and they do not modify our understanding of the apparent intermediate

313 host range of the Spirorchiidae. Before the present study, the only report of marine

314 spirorchiid asexual stages was that by Stacy et al. (2010b), who generated sequences

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315 consistent with the marine spirorchiid L. learedi from samples from the tissues of a fissurellid

316 limpet, nodosa, collected from a marine turtle mariculture facility. Notably, the

317 approach did not lead to observation of the parasitic stages and vermetids were not among the

318 potential host taxa examined. The details of this report are included in Table 2.

319 The limited material available for examination in the present study did not allow the

320 detailed observations on the anatomy of the intramolluscan stages made by earlier studies

321 (e.g. Wall, 1941a, b, 1951). However, the present specimens are broadly consistent with

322 previously described spirorchiid cercariae. All typical features of previously described

323 spirorchiid cercariae were present – substantial size, well-developed eye-spots and ventral

324 sucker, penetration glands occupying space posterior to eye-spots, and a well-developed head

325 organ. We did not detect a dorsal finfold or “cuticular crest” in the present form. In this, it

326 resembles the cercariae of S. artericola, S. elegans, S. elephantis and S. scripta which lack

327 finfolds, rather than those of V. robustum and S. parvus which have them. Overall, it appears

328 that the morphology of spirorchiid cercariae is conservative.

329 The new data reported here makes the distribution of intermediate hosts of

330 spirorchiids especially striking. Freshwater species overwhelmingly infect planorbids

331 (: “Pulmonata”), with just a single species known from an ampullariid

332 (Caenogastropoda) from South America. The two reported marine infections are from

333 gastropods from separate subclasses, a caenogastropod (present study) and a vetigastropod

334 (Stacy et al., 2010b). Although understanding of the deep branches of gastropod evolution

335 remains unstable (e.g. Aktipis and Giribet, 2010), it is clear that the Heterobranchia,

336 Caenogastropoda and represent deeply distinct and ancient lineages within

337 the . It is surprising that L. learedi and the present form (Amphiorchis sp.), which

338 are evidently closely related, have intermediate hosts that are deeply phylogenetically distant.

339 Such a host distribution implies dramatic host-switching. However, there is a precedent for

14

340 such a contrast in that African and Asian species of Schistosoma Weinland, 1858, which

341 represent distinct clades in the same genus (Lockyer et al., 2003b), infect gastropods as

342 phylogenetically distinct as caenogastropods and vetigastropods.

343 The identification of a vermetid as an intermediate host for marine spirorchiids has

344 clear implications for the search for further intermediate hosts of marine spirorchiids. Stacy et

345 al. (2010b) observed that this search is challenging due to the immense range of potential

346 hosts and because infections might be rare or localised. We consider that it now makes sense

347 to focus future studies on fissurellid limpets and vermetids. In this context, we note that both

348 families of gastropods have been surveyed for trematode infections previously and shown to

349 be infected. Fissurellids are known to be infected by a hemiuroid and an opecoelid (Cable,

350 1956, 1963). Vermetids are known to be infected by an echinostomatid, a hemiurid, a

351 mesometrid, a microphallid and a possible opecoelid (Prévôt, 1969, 1971a, b; Jousson and

352 Bartoli, 1999). Despite these reports, we suspect that the nature of these gastropod families,

353 especially the particularly unconventional Vermetidae, has led to them being less studied than

354 many other groups of gastropods. In some parts of the world, vermetids occur in such large

355 numbers that they comprise reef-building organisms (Shier, 1969; Safriel, 1975). Should the

356 vermetid species involved prove to be intermediate hosts for spirorchiids, then such localities

357 may be especially important in spirorchiid transmission.

358 The sessile habit of the Vermetidae raises the intriguing possibility that they could

359 attach to the carapaces of turtles so that the intermediate hosts of spirorchiids are carried

360 around with the turtles; this idea was suggested by Frazier et al. (1985) before any marine

361 spirorchiid life cycle was known. There is extensive literature on the epibiotic fauna of turtle

362 carapaces (e.g. Frazier et al., 1985; Kitsos et al., 2005; Pfaller et al., 2008; Domenech et al.,

363 2015). However, apart from a few references to unidentified ‘tubeworms’ by Frazier et al.

364 (1985), which might refer to several kinds of animals, we have not detected any reports of

15

365 Vermetidae on turtles. Vermetids are easily confused with some groups of polychaetes

366 (especially Serpulidae) to the extent that some species of the two groups were described in

367 the wrong phylum. We think that vermetids may well occur on turtles, and such infestation is

368 worthy of a specific search.

369 The present study is just the second to report information on marine spirorchiid life

370 cycles, following that of Stacy et al. (2010b), and the first evidence of sporocysts and

371 cercariae formation in a marine intermediate host. The intermediate hosts identified in the

372 two studies represent completely unrelated gastropods. Additionally, this is the first known

373 report of spirorchiid infection in sea turtles in the Mediterranean Sea. Thus, despite recent

374 progress, we do not yet have a broad understanding of the transmission of marine

375 spirorchiids. Increased knowledge is bound to prove valuable in explaining the epidemiology

376 of spirorchiids over the complex life cycles of their hosts, which incorporate pelagic, inshore

377 and migratory phases. Also, as seen here, improved life cycle knowledge can enhance the

378 well-being of captive turtle populations.

379

380 Acknowledgements

381 We thank Dr Rüdiger Bieler of the Chicago Field Museum, USA for his help with the

382 identification of the vermetid gastropod. We also thank all professionals, students and

383 volunteers at the Oceanogràfic [Spain] and Fundación Oceanografic [Spain], especially at the

384 ARCA Rehabilitation Centre [Spain], for their many efforts and complete dedication to the

385 best animal care. In particular, we are grateful to the Conselleria de Agricultura, Medio

386 Ambiente, Cambio Climático y Desarrollo Rural of the Valencia Community Regional

387 Government, Spain, especially to Juan Jiménez, Juan Antonio Gómez y Juan Eymar who

388 made this project possible with their invaluable support. We thank the ‘Institut Cavanilles de

16

389 Biodiversitat i Biologia Evolutiva,’ University of Valencia, Spain for their collaboration and

390 Fundación Bios CV, [Spain] for their advice on the head starting program. This research did

391 not receive any specific grant from funding agencies in the public, commercial or not-for-

392 profit sectors.

393

394

17

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602

26

603 Captions to figures

604 Fig. 1. Life cycle of Amphiorchis sp. (A) Thylaeodus cf. rugulosus (Vermetidae), the

605 intermediate host of Amphiorchis sp ex Caretta caretta. Scale bar = 3 mm. (B) Whole

606 cercaria of Amphiorchis sp. ex T. cf. rugulosus. Scale bar = 100 µm. (C) Cercarial body of

607 Amphiorchis sp. Scale bar = 50 µm.

608

609 Fig. 2. Relationships of marine Spirorchiidae, with Schistosomatidae as outgroup, based on

610 Maximum Likelihood and Bayesian inference analysis of the partial 28S rDNA dataset.

611 GenBank accession numbers are indicated in parentheses. Nodal support values for each node

612 are indicated as posterior probabilities (Bayesian inference) above the node and bootstrap

613 support (Maximum Likelihood) below the node. Support values < 70 are not shown.

614 Sequences generated in this study are in bold.

615

616

617

618

619

27

620

621

622 Fig. 1

623

624

28

625

626

627

628

629 Fig. 2

630

29

631 Table 1 28S rDNA sequences from GenBank analysed in this study.

Species Host Locality GenBank Accession # Reference

Spirorchiidae

Carettacola hawaiiensis Chelonia mydas Hawaii, Pacific Ocean AY604709 Snyder (2004)

Hapalotrema mehrai Chelonia mydas Hawaii, Pacific Ocean AY604708 Snyder (2004)

Learedius learedi Chelonia mydas Hawaii, Pacific Ocean AY604707 Snyder (2004)

Schistosomatidae

Austrobilharzia variglandis Larus delawarensis Delaware, USA AY157250 Lockyer et al. (2003b)

Bivitellobilharzia nairi Rhinoceros unicornis Nepal JQ975005 Devkota et al. (2014)

Dendritobilharzia pulverulenta Gallus gallus New Mexico, USA AY157241 Lockyer et al. (2003b)

Heterobilharzia americana Mesocricetus auratus Louisiana, USA AY157246 Lockyer et al. (2003b)

Ornithobilharzia canaliculata Larus delawarensis Texas, USA AY157248 Lockyer et al. (2003b)

Schistosoma japonicum Mus musculus Philippines Z46504 Littlewood and Johnston (1995)

Schistosoma mansoni Mus musculus Puerto Rico Z46503 Littlewood and Johnston (1995)

Schistosomatium douthitti Mesocricetus auratus Indiana, USA AY157247 Lockyer et al. (2003b)

30

632 Table 2. Hosts of spirorchiid intermediate hosts demonstrated as such either experimentally or by molecular analysis.

Species Host Family Superfamily Higher taxon Basis Reference Freshwater Spirorchis elephantis Helisoma trivolvis Planorbidae Planorboidea SCl Heterobranchia Experimental Wall (1941a) Spirorchis parvus Helisoma trivolvis Planorbidae Planorboidea SCl Heterobranchia Experimental Wall (1941b) Vasotrema robustum Physa spp Physidae Planorboidea SCl Heterobranchia Experimental Wall (1951) Spirorchis artericola Helisoma trivolvis Planorbidae Planorboidea SCl Heterobranchia Experimental Pieper (1953) Spirorchis elegans Helisoma anceps Planorbidae Planorboidea SCl Heterobranchia Experimental Goodchild and Kirk

(1960) dilatatus Planorbidae Planorboidea SCl Heterobranchia Experimental Goodchild and Kirk (1960) Spirorchis scripta Helisoma anceps Planorbidae Planorboidea SCl Heterobranchia Experimental Holliman and Fisher (1968) Ferrissia fragilis Planorbidae Planorboidea SCl Heterobranchia Experimental Turner and Corkum (1977) W1120 Biomphalaria Planorbidae Planorboidea SCl Heterobranchia Mol. + Morphology Brant et al. (2006) sudanica Spirorchiidae sp. 1 Biomphalaria spp Planorbidae Planorboidea SCl Heterobranchia Mol. + Morphology Pinto et al. (2015) Spirorchiidae sp. 2 Biomphalaria Planorbidae Planorboidea SCl Heterobranchia Mol. + Morphology Pinto et al. (2015) glabrata Spirorchiidae sp. 3 Pomacea sp. Ampullariidae Ampullarioidea SCl Caenogastropoda Mol. + Morphology Pinto et al. (2015) Marine Learedius learedi Fissurella nodosa Fissurelloidea SCl Vetigastropoda Mol. only Stacy et al. (2010b) Amphiorchis sp. Thylaeodus cf. Vermetidae SCl Caenogastropoda Mol. + Morphology Present study rugulosus

31

633 Mol., molecular studies.

634

635

32

636 Highlights 637

638 • Spirorchiidae blood flukes are significant pathogens of marine turtles but their life

639 cycles remain almost entirely unknown.

640 • We show that Amphiorchis sp. of Caretta caretta infects a vermetid gastropod,

641 Thylaeodus cf. rugulosus.

642 • We matched DNA from infections from the vermetid, eggs from neonate C. caretta,

643 and an adult spirorchiid from C. caretta.

644 • The Amphiorchis sp. is closely related to marine turtle spirorchiid of the genera

645 Carettacola, Hapalotrema and Learedius.

646 • The findings enable control of spirorchiidiasis in captivity and better understanding of

647 epidemiology in wild individuals.

648 649

650

651

33

652

653

654

655 Graphical abstract

656

657

34