LABORATORY MODELS IN FILARIASIS: A REVIEW OF FILARIAL LIFE-CYCLE PATTERNS

JOHN F. SCHACHER Division of Infectious and Tropical Diseases, School of Public Health, University of California, Los Angeles, California 90024. U.S.A.

INTRODUCTION Vector variables include order, species and genetic strain; ease of laboratory rearing or While clinical, epidemiological and patho­ maintenance of wild-collected species; ease logical study of filarial disease processes in of feeding, of collecting vectors from hosts man has yielded valuable results, laboratory and finally of recovering filarial larvae from models are pre-requisite to the detailed the vector. Fig. 1 (modified after Wenk, 1967) understanding of the basic physiological, gives an overview of human filarial parasites immunological, pathological, evolutionary, and their location together with some chemotherapeutic and ecological considera­ currently used and some potential laboratory tions underlying various aspects of both models for their study. This diagram does not "normal" and "zoonotic" filariasis. The exhaust the potential models (see Table 1). purpose of the present paper is to discuss actual and potential laboratory models from REVIEW OF LIFE-CYCLE PATTERNS the viewpoint of availability based on life cycle studies. Spiruroid and Filarioid life cycles were reviewed in depth by Chabaud (1954a, b, c), LABORATORY MODELS IN FILARIASIS who at that time listed 29 known filarial cycles, double the number reported earlier by The sine-qua-non of the term, laboratory Williams (1948). The number of reported model, is knowledge of both the life cycle of life cycles was increased to 35 in the review of the chosen agent and of its vector and the Lavoipierre (1958), to 39 in Hawking and ability to duplicate these in the laboratory. Worms (1961), and to 50 by Nelson (1964). The term has several additional implications: Sonin's (1966) summary included previously (1) in a study of host-parasite relations missed and more recent Russian studies to in the final host, the model system must give a total of 59. Macdonald (1971) listed mimic as closely as possible one or more 57 cycles, including Wuchereria lewisi, but features of human infection, and (2) there omitted the Diplotriaenids, which do not must be control over experimental variables have hemophagous vectors. The rapid related to the experimental final host, the growth of knowledge and interest in this agent and the vector. Final-host variables in group is indicated by the recording of 93 life filariasis-models are such things as innate cycles in the present review (Table 1). susceptibility; physiological, immunological and anatomical parameters; age (including DISCUSSION maturation rate and longevity); sex factors Vector - and Tissue - specificity and nutritional status. Agent variables include species or strain, worm burden, site Reordering and analysis of known cycles of inoculation and localization, age and (Table 1) shows several interesting patterns longevity of worms and recovery rates. (or the lack thereof) that merit discussion.

336 Vol. 4 No.3 September 1973 LABORATORY MODELS IN FILARIASIS

L.loa 0. volvulus (o.spp., Wehrdikmansia) 0. streptocercum (0. reconditum, 0. viteae, SKIN, FASCIA D.repens, D. tenuis, Stephanofi Iorio spp.) LYMPH RAOICLES, AFFERENT TRUNKS B. malayi

LYMPH "Timor filaria II (;J)

PERITONEAL M.ozzardi D. perstans (L. carinii, CAVITY spp., D. dracunculoides) CARDINAL (0. armillata, Elaeophora spp.)

VENOUS

ARTERIAL

PLEURAL

carinii)

Fig. I-Diagram to show the site oflocalization of the most important human filarial parasites and (in parentheses) some currently used or potential laboratory models for their study. (Modified after P. Wenk, 1967; Z. Parasitenk, 28: 240-263). .

Vol. 4 No.3 September 1973 337 .... Table 1 00 Synopsis of life cycles in superfamily .

Development Site of Filaria Definitive Host Intennediate Host Larva Reference

Desmidocercitlae Desmidocerca spp. Aves: Ciconiiformes Cepepods(?) ? Nelson, 1964; Chabaud, 1965 Diplotriaenidae Diplotriaenoides tn translucidus Aves: Passeriformes Grasshoppers Hemocele Anderson, 1957, 1962 c:0 D. isahellina Aves: Passeriformes Grasshoppers Hemocele Anderson, 1957, 1962 Serratopiculum tendo Aves: Falconifonnes Locusts, dung-beetles Fat body Bain & Yassiliades, 1969 § Filariidae > Haematobia atripalpis !!l Para/Haria multipapillosa Equidae Fat body Gnedina & Osipov, 1960 > Z ~ ..., (= IQbiato-papillosa) Bovidae Mosquitoes Thoracic muscles Nelson, 1962 ~ S. digitata Bovidae Mosquitoes Thoracic muscles Shoho, 1951; Shoho & Nair, 1960; ;0 Vanna et al., 1971 S. marslwlii Bovidae Mosquitoes Thoracic muscles Kadenatsii, 1956 ~ S. altaica Cervidae Mosquitoes Thoracic muscles Osipov, 1966 ~ S. yehi Cervidae Mosquitoes Thoracic muscles Weinmann, 1972 (pers.comm.) S. equina Equidae Mosquitoes Thoracic muscles Innes & Shoho, 1953; Nelson, 1959 ~ S. sp. (javensis? !" Papillosetaria sp.?) Tragulidae Mosquitoes ? Ramachandran et al., 1963 g: Stephanofilaria stilesi Bovidae Lyperosia titillans Haematobia irritans Fat body? Ivashkin et al., 1963a, b; Hibler, ~ -< 1966 ~ St. assamensis Bovidae Musca conducens Fat body? Srivastava & Dutt, 1963 ~ St. kaeli Bovidae Musca conducens ? Mullin, 1971 St. sp. Bovidae Musca conducens ? Kono & Fukuyoshi, 1967 ~ .... Oswaldofilariinae Conispiculum ~ f/avescens Reptilia: Agamidae Mosquitoes Fat body Pandit et al., 1929 CD Oswaldofilaria Reptilia: g. bacillaris Alligatoridae Mosquitoes Fat body Prod' hon & Bain, 1972 ...(1) ..... IC -0. chlamydosauri Reptilia : Agamidae Mosquitoes Fat body Mackerras, 1953; Johnston & Maw- ....-..J son, 1943

" .l .\ <: Life cycles: filarioidea (Cont'd). ~... Development Site of Z Filaria Definitive Host Intermediate Host Reference ? Larva "'" Vl Onchocercidae (Cont'd) (1) Icosiellinae '0 <> Icosiclla negleeta Amphibia : Anura Ceratopogonids Thoracic muscle g. Psychodids Thoracic muscle Desportes, 1941-42 ..,(1) ...... Dirofilariinae '-0 Man Chrysops spp. Fat body Connal & Connal, 1922; Lavoipier­ -.l re,1958a "'" Loa papion;s Primates: Cercopithecidae Chrysops spp. Fat body Duke, 1964 Pelecitus Aves: ColutnbifOlmes, Mosquitoes Fat body Dissanaike, 1967 (in eeyloncnsis Galliformes Cheong & Omar, 1970) r Foleyella braehyoptera Amphibia: Anura Mosquitoes ;.­ Fat body Causey, 1939; Kotcher, 1941 0; F. doliehoptera Amphibia : Anura Mosquitoes Fat body Causey, 1939; Kotcher, 1941 0 := F. ranae Amphibia: Anura Mosquitoes Fat body Causey, 1939; Kotcher, 1941 ;.­ ....j F. dubois; Amphibia: Anura Mosquitoes Fat body Witenberg & Gerichter, 1944 0 F. fureata Reptilia : Chamaeleontidae Mosquitoes Fat body Brygoo, 1959; Bain, 1969 := F. philistinae Reptilia : Agamidae Mosquitoes Fat body Schacher & Khalil, 1968 >< ~ F. eandezei Reptilia: Chamaeleontidae Mosquitoes Fat body Bain,1970 0 F. jiexieauda Amphibia : Anura Mosquitoes Fat body Crans, 1969; Schacher & Crans, 0 1973; Benach&Crans (pers. comm.) r'" Diro/ilaria imm;tis Canidae, Felidae Mosquitoes Malph. tubules Taylor, 1960; Orihel, 1961 '" D. repens Canidae, Felidae Mosquitoes Malph. tubules Fuelleborn, 1908; Webber & Hawk­ Z ing, 1955 ;::.." D. tenuis Procyonidae Mosquitoes Malph. tubules Pistey, 1956 D. magnilarvatum Primates : Cercopithecidae Mosquitoes Malph. tubules Wharton, 1959 ;xl" D. striata Felidae Mosquitoes Malph. tubules Orihel & Ash, 1964 >:e D. subdermata Rodentia: '" (= spinosa) Erethizontidae Mosquitoes Malph. tubules? Highby, 1939 D. seap;ceps Lagomorpha : Leporidae Mosquitoes Fat body Highby, 1943a, b D. uniformis Lagomorpha : Leporidae Mosquitoes Fat body Bray & Walton, 1961 D. eorynodes Primates: (= aethiops?) Cercopithecidae Mosquitoes Fat body Webber, 1955; Orihel, 1969 D. roemer; Marsupialia : Macropodidae Tabanidae Fat body Spratt, 1970, 1971 (pers. comm.) Macacanema formosana Primates: Cercopithecidae Ceratopogonids Thoracic muscle Bergner & Jachowski, 1968 Onchocercinae Macdonaldius osehei Reptilia : Boidae Argasidae Malph. tubules Frank, 1962, 1964 M. anderson; Reptilia: Helodermatidae Argasidae ? Nelson, 1964 Sauro/ilaria innisfailensis Reptilia: Agamidae Mosquitoes Fat body Mackerras,1962 Cardio/ilaria nilesi Aves : Galliformes Mosquitoes Thoracic muscle Dissanaike & Fernando, 1965 Aproetoides lissum Aves: Galliformes Mosquitoes ? Raghavan & David, 1955 ..., Deraiophoronema evansi '-0 ( = Dipetalonema evansi) Camelidae Mosquitoes Thoracic muscle Kataitseva, 1968 Vol.... Life cycles: filarioidea (Cont'd) . 0

Definitive Host Intermediate Host Development Site of Filaria Larva Reference

Onchocercidae : Onchocercinae (Cont'd) Ackertia marmotae Rodentia: Sciuridae Ixodidae Fat body Ko,1972 Dipetalonema arbuta Rodentia: Erethezontidae Mosquitoes Fat body Highby, 1943a, b D. sp. {=mfrosenawi) Rodentia: Sciuridae Argasidae Muscle Weimhann, 1972 (pers.comm.) D. viteae Rodentia : Cricetidae Argasidae/Ixodidae Muscle Bain,1967 D. setariosa Viverridae Ixodidae Muscle Nelson, 1964 D. grassii Canidae Ixodidae Muscle Grassi & Calandruccio, 1890; Noe & Grassi, 1903 D. manson-bahri Lagomorpha: Leporidae Fleas Fat body Nelson, 1961 en D. reconditum Canidae, Hyaenidae(?) Fleas, Mallophaga Fat body Nelson, 1962b; Pennington & 8 Phelps, 1969 5l D. dracunculoides Canidae, Hyaenidae Hippobosca I:i'" longipennis Fat body Nelson, 1963a o-j D. perstans Man Ceratopogonids Thoracic muscle Sharp, 1928;Hopkins & Nicholas, 1952 ~ D. sprenti Rodentia : Castoridae Mosquitoes Fat body Addison, 1973. ~ D. streptocerca Man Ceratopogonids Thoracic muscle Chardome & Peel, 1949; Duke, 1958 ;-< Mansonella ozzardi Man Ceratopogonids, Buckley, 1934; Cerqueira, 1959 ..., Simuliids := Litomosoides carinii Rodentia: Cricetidae Mites Fat body Williams & Brown, 1946; Bertram, ~ 1957, 1966 Breinlia booliati Rodentia: Muridae Mosquitoes Fat body Singh et al., 1972. 3:: B. sergenti Primates: Lorisidae Mosquitoes Fat body Ho & Kan, 1971 ? Elaeophora schneideri Bovidae, Cervidae Tabanidae Fat body Hibler et al., 1969; "tI c: beaveri Procyonidae Mosquitoes Thoracic muscle Harbut, 1973 (pers.comm.) to B. malayi Man; Primates: Cercopithi­ dae; Felidae; Canidae; Ro- ~ dentia : Cricetidae Mosquitoes Thoracic muscle Brug, 1927; Wharton, 1957 ~ -< B.pahangi Felidae; Canidae; Rodentia: 2- Cricetidae, Muridae et al., Mosquitoes Thoracic muscle Schachcr, 1962 B.patei Canidae; Felidae; Viverridae Mosquitoes Thoracic muscle Laurence & Pester, 1961 .... B. ceylonensis Canidae Mosquitoes Thoracic muscle Jayawardene, 1963 Z B. buckleyi Lagomorpha : Leporidae Mosquitoes Thoracic muscle Dissanaike, 1963 (in Nelson, 1964) ? B. tupaiae Primates : Tupaiidae Mosquitoes Thoracic muscle Orihel, 1967 w Wuchereria bancro/ti Man Mosquitoes Thoracic muscle Manson, 1878 Onchocerca cervicalis Equidae Ceratopogonids Thoracic muscle Steward, 1933; Mellor, 1971 r.Fl (1l O. reticulata Equidae Ceratopogonids Thoracic muscle Moignoux, 195], 1951a, 1952 (in '1:1 Levine, 1968) (t O. gibsoni Bovidae Ceratopogonids Thoracic muscle Buckley, 1938

~(1l O. lienalis Bovidae Simuliidae Thoracic muscle Mikhailuk.1967 .., O. gutferosa Bovidae Simuliidae Thoracic muscle Steward, 1937; Supperer, 1952; Eichler, 1971; Mikhailuk, 1967 -\0..... Vol O.flexuosa Cervidae Simuliidae Thoracic muscle Frank et al., 1968

~ , ", ", ,­

2: .;>. zo ....,

.gtil 8' Life cycles: filarioidea (Cont' d). g. ======cc=====---~- '======-======--==== ~ Filaria Definitive Host Intermediate Host Development Site of Reference \0 Larva -....,-..J Onchocercidae Onchocercinae (Cont'd) O. volvulus Man Simuliidae Thoracic muscle Blacklock, 1927; Bain, 1969 Wehrdikmansia cervipedis Cervidae Simuliidae Thoracic tnuscle Weinmarm, 1972 (pers.comtn.) t'"' Splendidofilariinae ~ Ornithofilaria /allisensis Aves; Anserifortnes Simuliidae Fat body Anderson, 1968 ~ Splendidofilaria cali/ornicus Aves; Gallifonnes Ceratopogonids ? Weinmarm, 1972 (pers.comm.) S. picacardina Aves: Passeriformes Ceratopogonids ? Hibler, 1963 (in Robinson, 1971) ~ Chandlerella quiscali Aves: Passerifortnes Ceratopogonids Thoracic tnuscle Robinson, 1971 C. striatospicula Aves: Passerifortnes Cera topogonids ? Hibler, 1963 (in Robinson, 1971) ~ Lemdaninae : No Life Cycle Information to Date ~ Eufilariinae z ::::l Eufilaria cypse/i Aves: Apodifonnes Mallophaga Fat body Nelson, 1964 t;: E. longicaudata Aves: Passeriformes Ceratopogonids ? Hibler, 1963 (in Robinson, 1971) Saurositus agamae Reptilia: Agamidae Mosquitoes Thoracic muscle Bain, 1969 ~ en~ Onchocercidae Sensu Lata Filaria sp. Sturnus vulgaris (Aves: Sturnidae) Ceratopogonids Thoracic' muscle Robinson, 1961 Filaria sp. Corvus /rugilegus (Aves: Corvidae) Mosquitoes Thoracic muscle Schtefko, 1915 fijiensis Chiroptera : Pteropodidae Mosquitoes Thoracic muscle Symes & Mataika, 1959 Filaria sp. Aves: Galliformes (exp.) Mosquitoes Thoracic muscle Cheong & Omar, 1970

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Of the five accepted Filarioid families­ In family Onchocercidae, five genera have Desmidocercidae, Diplotriaenidae, Filariidae, been studied sufficiently to give a reasonable Setariidae and Onchocercidae-the first. three resolution of patterns: Foleyella, Dirofilaria, are oviparous, with relatively well developed Dipetalonema, Brugia and Onchocerca (Table first-stage larvae. Members of families Se­ 1). Life cycles are known for eight Foleyella tariidae and Onchocercidae produce sheathed spp.. The pattern of development is absolute or unsheathed microfilariform embryos which whether the adults parasitize amphibians or circulate in the blood or are sequestered reptiles-all use mosquito vectors with larval in cutaneous tissue fluids. Desmidocercids development in the fat body. Seven life cycles have thus far been completely ignored, are known for Brugia spp. ; in alI cases, larvae and, if conjectured life cycles were to be develop in the flight muscles of mosquitoes. borne out (Nelson, 1964; Chabaud, 1965), Bimodal patterns are seen in Dirofilaria there would be ample added justification for and Onchocerca. Ten life cycles are known in moving this group to Spiruroidea (as Dirofilaria; mosquitoes have been incrimi­ proposed by Skrjabin, 1949). Cycles in nated as vectors in nine. Of these, five or Diplotriaenidae (Anderson, 1957, 1962; Bain possibly six species have larval development and Vassiliades, 1969) are likewise remniscent in the Malphigian tubules; in the remainder of those in Spiruroidea. Only one cycle is (D. scapiceps, D. uniformis and D. corynodes) , known for family Filariidae, Parafilaria larval morphogenesis occurs in the fat body. multipapillosa, which develops in the fat body Dirofilaria roemeri, a parasite of Macropodids of Haematobia atripalpis (Gnedina and in Australia, develops in the fat body of Osipov, 1960). tabanid flies (Spratt, 1972), possibly indicating that it should not be included in Dirofilaria. Of the most medical and veterinary interest, hence the most intensively. studied, have been Of the seven known cycles in Onchocerca, families Setariidae and Onchocercidae. Some three (0. cervicalis, O. reticulata and o. distinct patterns bearing both on the specifi­ gibsoni) have ceratopogonid vectors; the city of the filaria: vector-type relationship remainder use simuliids. Irrespective of the and on the tissue-specificity of the vector-type or of whether the final host is larva within its vector are becoming clearer in equid, bovid or human, larval development these groups. These evolutionarily contrived occurs in the thoracic muscles of the vector. relationships between vector and agent and It is of interest to note that the closely related their practical and theoretical importance Wehrdikmansia cervipedis of deer also uses have been touched upon in most of the simuliid vectors with larval development in earlier reviews; more information now serves the thoracic muscles (Weinmann, pers. to bring these ideas into sharper focus. comm., 1972).

In family Setariidae, life cycle studies show Analysis of reported life cycles in Dipeta­ J seven species of Setaria to have mosquito lonema confirms what has long been morpho­ intermediate hosts. With one possible excep­ logically evident: there is a complete lack of tion (Table 1), larval development always taxonomic unity in this group (Yeh, 1957). occurs in. the thoracic muscles of the vector. Larval development occurs variously in ticks, Likewise, in Stephanofilaria, the four known fleas, mallophogans, anoplurans, mosquitoes cycles all use m uscid -fly vectors; larval and hippoboscid and ceratopogonid flies and development occurs in the fat body in at least in any site except the Malphigian tubules. two and possible in the others as well. The only semblance of pattern is shown by the

342 Vol. 4 No.3 September 1973 LABORATORY MODELS IN FILARIASIS four species transmitted by ticks, all of which show we are dealing with more than one develop in the muscles (Table 1). . parasite (Schacher and Geddawi, 1969). There are five recent instances in which a Judging from life-cycle patterns within the given filarial life cycle has been reported to group, I would estimate the potential diagnostic violate the one-filaria: one-vector-type thesis. error to be of at least generic magnitude. Mansonella ozzardi has been stated to develop both in Culicoides furens (Buckley, 1934) CURRENT LABORATORY MODELS and in Simulium (Cerqueira, 1959). Nelson (1962, 1964) and Pennington and Phelps An overview of the literature with regard (1969) reported development of Dipetalonema to the "goodness of fit" of some currently reconditum from dogs in fleas, Mallophaga used laboratory models (Fig. 1) shows that and (in the latter paper) in sucking lice. with the exception of Loa papionis and Loa Colluzi (1964) screened a broad group of loa in chimpanzees and baboons (Duke, 1957, potential vectors for in 1964) and Brugia spp. in cats, dogs and lower Italy. In addition to confirming the accepted primates (Schacher and Sahyoun, 1967; mosquito vector, he reported development of Schacher et al., 1970, 1973; Schacher and third-stage larvae in Haematopota variegata Sulahian, 1972), none of the currently most (Tabanidae) 11 days post-infection. Wuchere­ used models mimic the corresponding condi­ ria bancrofti and (Manson, tions in man with enough precision to permit 1878; Brug, 1927) have long been known to direct and general clinical and pathological develop in the flight muscles of mosquitoes; extrapolation. Burton's (1960, 1963) reports of development in Cimex were not confirmed either by Cutaneous Forms Wharton and Omar (1962) or by Nelson While both Dirofilaria repens and Di­ (1963). Ogunba (1972) recently reported petalonema viteae live in subcutaneous Loa loa to develop in Mansonia africana; as tissues, neither demonstrates the migratory yet, there have been no published confirma­ propensities and allergenic properties of Loa tion attempts. Similarly, in the older loa; neither forms nodules or has microfilariae literature, the 0 bservations of Wellman (1907) in the skin or eyes like or on Dipetalonema perstans in Ornithodoros Dipetalonema streptocercum. Onchocerca spp. moubata and of Yao et al., (1938) and from horses and cattle have provided Langeron (1938) on W. bancrofti in Phlebo­ some advances and much stimulation (Nelson tomus require confirmation, negation or 1970), but other than the chimpanzee (Duke, explanation. If they could be confirmed, 1962), no practical final host has been observations such as these might point the discovered or proposed fOf the laboratory way to the establishment of otherwise study of onchocerciasis. The crucial point to impracticeable laboratory models. Such mo­ be overcome in formuation of an onchocer­ dels might be "abnormal" in the strict ciasis-model has always been the refusal of sense, but as soft ticks, fleas or mosquitoes Simulium to mate in the laboratory; the recent are more amenable to colonization and reports by Wenk and Raybould (1972, 1972a) laboratory usage than ceratopogonids, simu­ of the controlled breeding of S. damnosum Liids or tabanids, this approach would provide remain to be exploited. Reports ofOnchocerca a great impetus toward the study of presently in spider-monkeys (Caballero and Barrera, unattackable problems. The taxonomic and 1958) and in pigs (Ramanujachari and Alwar, epidemiologic significance of reports of two 1953; Ramachandran and Eng, 1967) should vector-types for the same filaria is that it may be followed up; the availability of miniature

Vol. 4 No.3 September 1973 343 SOUTHEAST ASIAN J. TRap. MED. PUB. HLTH. swine-breeds and the similarities between purpose models could be conveniently esta­ porcine and human skin (Montagna, 1966; blished are for in vitro (Taylor and Baker, Weinstein, 1966) might here be combined to 1968) and "in vivo" (Yoeli et al., 1958; Singh good advantage. It is entirely possible that and Mammen, 1964) cultivation of filariae much effort has been dissipated seeking an and in the formulation and evaluation of Onchocerca species per se, when what was field epidemiological methods. really required was a filaria whose microfila­ Preliminary studies clarifying Onchocerca riae were confined to the skin. At least two field-epidemiology have made use of the Ixodid-tick-borne forms fit this criterion: model of O. flexuosa of red deer and Prosimu­ Dipetalonema grassi in dogs and Ackertia lium nigripes/Odagmia ornata (Frank et al., marmotae in woodchucks (Table 1). Surveys 1968). Similar studies might be established utilizing skin-snips rather than blood films using O. gutterosa, o. lienalis or Wehrdikman­ might turn up other useful leads. sia cervipedis (Table 1) for other simuliid­ transmitted forms. The studies of Nelson and Lymphatic Filariae his co-workers (Nelson, 1970) should be Three Brugia spp. are currently available expanded for those Onchocerca spp. with to model various aspects of the pathophy­ ceratopogonid vectors; information gained siology, immunology and chemotherapy of from this model might secondarily help to W. bancrofti and B. malayi infections. devise new techniques for the field study of Introduction of the selected Liverpool strain D. perstans, D. streptocerca and M. ozzardi of aegypti as a laboratory vector epidemiology. While much has been learned (Macdonald, 1962a, b) and the jird as a final about the epidemiology and control of host (Ash and Riley, 1970a, b) have expedited Wuchereria and Brugia by the study of man new avenues (particularly for chemotherapy) and relevant vectors in endemic foci (Edeson, and reduced costs in some types of studies. 1972), there have been few attempts at longitudinal studies, and none which Cavity-Dwelling Forms embodied controlled experimentation were While Litomosoides carmll may in some possible. Some studies on field transmission ways mimic D. perstans and Mansonella of mosquito-borne filariae have been perfor­ ozzardi, our current knowledge of these forms med using D. immitis in dogs (Otto, 1972). in man is too meager to judge the correctness A more controllable (and cheaper) test model of fit of any laboratory model. might be set up using Foleyella in frogs SPECIAL-PURPOSE MODELS (Crans, 1969). Many basic questions regarding filarial Models can be formulated which do not disease in man can only be approached by have the requirement that they mimic one or the use of laboratory models. The present another of the human filariases. These models paper only attempts to point out some of the have definite value for the study of important possibilities based on review of current -pathogens such as D. immitis (Bradley knowledge of life cycles and a short evalua­ and Pacheco, 1972), for the clarification of tion of models presently in use. immune response mechanisms and immuno­ logic methodology (D. immitis, L. carinii, D. SUMMARY viteae, Brugia spp.), and for the study of vector (susceptibility) genetics and vector­ Laboratory models in filariasis are dis­ parasite relations (Brugia, Dirofilaria, Foleyel­ cussed in general terms and some prerequisites la spp.). Two areas where further special- to their establishment are defined.

344 Vol. 4 No.3 September 1973 LABORATORY MODELS IN FILARIASIS

The life cycles of 93 filarioids from man and ASH, L.R. and RILEY, J. M., (1970a). Deve­ lower vertebrates are reviewed; some follow a lopment of Brugia pahangi in the jird, defined pattern with regard to the vector-type Meriones unguiculatus, with notes on and the tissue specificity of larval stages. The infections in other rodents. J. Parasit., taxonomic significance of biological specificity 56: 962. and reported exceptions to the "one-filaria: ASH, L.R. and RILEY, J.M., (1970b). one-vector-type" thesis are pointed out, and Development of subperiodic Brugia possible llses of these exceptions (if they can malay; in the jird, Meriones unguiculatus, be confirmed) are discussed. with notes on infections in other rodents. Some actual and potential laboratory J. Parasit., 56 : 969. models for specific types of filarial disease are BAIN, 0., (1967). Biologie larvaire et meca­ discussed; further possibilities are evaluated nisme de transmission de la filaire based on life-cycle review. Dipetalonema viteae. Ann. Parasit. Hum. Comp., 42: 211. ACKNOWLEDGEMENTS BAIN, 0., (1969). Cycle d'une Filaire d' Agame, Saurositus agamae hamoni n. ssp. This investigation was supported in part (Eufilariinae) chez Anopheles stephensi. by the United States-Japan Cooperative C.R. Acad. Sci. Paris., 268 : 2439. Medical Science Program administered by BAIN, O. and VASSILIADES, G., (1969). the NIAID, NIH, DHEW, Grant 2R 22 AI­ Cycle evolutif d'un Dicheilonematinae, 07770. The author wishes to thank Dr. John Serratospiculum tendo, Filaire parasite Belkin for translation of some Russian du faucon. Ann. Parasit. Hum. Comp., references, Prof. Dr. Peter Wenk for permis­ 44: 595. sion to modify his diagram and Mrs. Elisabeth Sayegh for bibliographic and BERGNER, J.F. and JACHOWSKI, L.A., (1968). stenographic assistance. The filarial parasite Macacanema formo­ sana from the Taiwan monkey and its REFERENCES* development in various arthropods. Formosan Sci., 22 : 1. ADDISON, E.M., (1973). Life cycle of Dipeta­ BRADLEY, R.E. and PACHECO, G., EDS., lonema sprenti Anderson (Nematoda: (1972). Canine Heartworm Disease: Filarioidea) of beaver (Castor cana­ The Current Knowledge, Univ. Fla. Press, denSis) Canad. J. Zool., 51: 403. Gainesville; 148 pp. ANDERSON, R.C., (1957). The life cycle of BRUG, S.L., (1927). Een nieuwe Filaria-soort Dipetalonematid (Filarioidea, (Filaria malayi) , parasiteerende bij den Dipetalonematidae): The problem of mensch. Geneesk. Tijdschr. Nederl. their evolution. J. Helminth., 31: 203. -Indie, 67: 750. ANDERSON, R.c., (1962). On the development BUCKLEY, J.J.C., (1934). On the development, morphology, and experimental transmis­ in Culicoides jitrens Poey, of Filaria sion of Diplotriaena barusinica (Filario­ (= Mansonella) ozzardi Manson, 1897. idea: Diplotriaenidae). Canad. J. Zool., J. Helminth., 12 : 99. 40: 1175. BURTON, G.J., (1960). A preliminary note *Note: Only references cited in text or not included concerning development of larval stages in the earlier reviews by Lavoipierre, Haw­ of Brugia malay; and Wuchereria ban­ king and Worms, Nelson or Sonin (q.v.) are included here. crofti in the bedbug in coastal filarial

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Ho, B.-c. and KAN, S.-P., (1971). Evidence Isolation and Maintenance of Parasites of the intn;cellular development of in vivo. Taylor, A.E.R. & Muller, R., Breinlia sergenti (Dipetalonematidae) in Eds.; Oxford and Edinburgh, Blackwell. the fat cells of mosquito. l. Parasit., 123. 57: 1145. MANSON, P., (1878). On the development KATAITSEVA, F.V., (1968). Life cycle of of Filaria sanguinis hominis and on the Dipetalontma evansi. Doklad. A cad. mosquito considered as a nurse. J. Nauk SSSR, 180: 1262. (In Russian) Linn. Soc. Zool., London; 14: 304. Ko, R.C., (1972). The transmission of MIKHAILYUK, A.P., (1967). Biology of Ackertia marmotae Webster, 1967 Onchocerca gutturosa and O. lienalis in (Nematoda: Onchocercidae) of ground­ the forest-steppe zone of the Ukrainian hogs (Marmota monax) by Ixodes cookei. SSR. Veterinariya, Kiev; 11 : 62. Canad. l. Zool., 50: 437. MONTAGNA, W., (1966). The microscopic KONO, I. and FUKUYOSHI, S., (1967). anatomy of the skin of swine and man. Leucoderma of the muzzle of cattle In: Swine in Biomedical Research. induced by a new species of Stephanofila­ Bustad, L.K. et al., Eds.; Richland, ria. II. lap. l. Vet. Sci., 29: 301. Wash., Pacific Northwest Laboratory, 285. LANGERON, M., (1938). Notulae zoologicae. I. Evolution de microfilaires nocturnes MULLIN, S.W., (1971). A preliminary report chez les phJebotomes. Ann. Parasit. on the life cycle of Stephanofilaria Hum. Comp., 16: 477. kaeli. Southeast Asian l. Trop. Med. Pub. Hlth., 2: 84. LAVOIPIERRE, M.M.J., (1958). Studies on the host-parasite relationships of filarial NELSON, G.S., (1962). Dipetalonema reCOll­ nematodes and their arthropod hosts. ditum (Grassi, 1889) from the dog with II. The arthropod as a host to the a note on its development in the flea, nematode: a brief appraisal of our Ctenocephalides felis and the louse, present knowledge, based on a study of Heterodoxlls spin iget. J. Helminth., the more important literature from 1878 36: 297. to 1957. Ann. Trop. Med. Parasit., 52 :326. NELSON, G.S., (1963). Are bedbugs vectors of filariasis? Trans. Roy. Soc. Trop. Med. LEVINE, N.D., (1968). Nematode Parasites of Hyg., 57: 149. Domestic and of Man. Burgess: Minneapolis; 600 pp. NELSON, G.S., (1964). Factors influencing the development and behaviour of filarial MACDONALD, W.W., (1962a). The selection nematodes in their arthropodan hosts. of a strain of Aedes aegypti susceptible In: Host-parasite Relationships in Inver­ to infection with semi-periodic Brugia tebrate Hosts. (2nd Symposium Brit. malayi. Ann. Trop. Med. Parasit., Soc. Parasit.) Taylor, A.E.R., Ed.; 56: 368. Blackwell, Oxford. 75. MACDONALD, W.W., (1962b). The genetic NELSON, G.S., (1970). Onchocerciasis. In: basis of susceptibility to infection with Advances in Parasitology. Dawes, B., semi-periodic Brugia malay; in Aedes Ed.; London and New York, Academic aegypti. Ann. Trop. Med. Parasit., Press. Vol. 8: 173. 56: 373. OGUNBA, E.O., (1972). The development of MACDONALD, W.W., (1971). The main­ Loa loa (Guyot) in Mansonia africana tenance of vectors of filariasis. In: (Theobald). l. Med. Entom., 9: 159.

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ORIHEL, T.C. and ASH, L.R., (1964). Occur­ topogonidae) as a host for Chandlerella rence of Dirofilaria striata in the bobcat qu;scali (von Linstow, 1904) comb.n. (Lynx rufus) in Louisiana with observa­ (Filarioidea :Onchocercidae). J. Parasit., tions on its larval development. J. 57: 772. Parasit., 50: 590. SCHACHER, J.F. and CRANS, W.J., (1973). ORIHEL, T.C., (1967). Development of Bru­ Foleyella flexicauda sp. n. (Nematoda: gia tupaiae in the intermediate and Filarioi4ea) from Rana catesbeiana in J. \ . definitive hosts. Parasit., 53: 376. New Jersey with a review of the genus ,,\ ORIHEL, T.C., (1969). Dirofilaria corynodes and erection of two new sub-genera. ( (von Linstow, 1899): Morphology and J. Parasit., 59: 685. life history. J. Parasit., 55: 94. SCHACHER, J.F. and GEDDAWI, M.K., (1969). OTTO, G.F., (1972). Epizootiology of canine An analysis of speciation and evolution heartworm disease. In: Canine Heart­ in Wuchereria bancrofti by the study of worm Disease: The Current Knowledge. nuclear constancy (eutely) in microfila­ Bradley, R.E. and Pacheco, G., Eds.; riae. Ann. Trop. Med. Parasit., 63: 67. Univ. Fla. Press, Gainesville. 1. SCHACHER, J.F. and KHALIL, G.M., (1968). PENNINGTON, N.B. and PHELPS, c.A., (1969). Development of Foleyella philistinae Canine filariasis on Okinawa, Ryukyu Schacher & Khalil, 1967 (Nematoda: Islands. J. Med. Entom., 6: 59. Filarioidea), in Culex pipiens molestus PROD'HON, J. and BAIN,O.,(1972). Developpe­ with notes on pathology in the arthropod. ment larvaire chez Anopheles stephensi J. Parasit., 54: 869. d'Oswaldofilaria bacillaris, filaire de SCHACHER, J.F. and SAHYOUN, P.F., (1967). Caiman sudamericaine, et redescription A chronological study of the histopatho­ des adultes. Ann. Parasit. Hum. Comp., logy of filarial disease in cats and dogs 47: 745. caused by Brugia pahangi (Buckley & RAMACHANDRAN, C.P. and ENG, T.B., (1967). Edeson, 1956). Trans. Roy. Soc. Trop. Microfilariae of the genus Onchocerca Med. Hyg., 61: 234. from the skin snips of a domestic pig in SCHACHER, J.F. and SULAHIAN, A., (1972). Malaya. Malay. Vet. J., 4 : 159. Lymphatic drainage patterns and experi­ RAMACHANDRAN, c.P., WHARTON, R.H., mental filariasis in dogs. Ann. Trop. DUNN, F.L. and KERSHAW, W.E., (1963). Med. Parasit., 66: 209. Aedes (Finlaya) togoi Theobald, a useful SCHACHER, J.F., EDESON, J.F.B., SULAHIAN, laboratory vector in studies of filariasis. A. and RIZK, G., (1970). Direct lym­ :.. Ann. Trop. Med. Parasit., 57: 442. phangiography in dogs infected with RAMANUJACHARI, G. and ALWAR, V.S., Brugia pahangi (Buckley & Edeson, 1956) (1953). Indian pig (Sus scrofa domestica) Trans. Roy. Soc. Trop. Med. Hyg., 64: 23. as a host for Onchocerca sp. and Entero­ SINGH, D. and MAMMEN, M.L., (1964). bius vermicularis. Indian Vet. J., 29: 329. Preliminary studies on the development ROBINSON, E.J., JR., (1961). Early develop­ of micro filariae of Dirofilaria immitis in ment of an avian filarial worm in the the haemocoel of Aedes aegypti. Bull. gnat, Culicoides crepuscularis. J. Parasit., Indian Soc. Mal. Comm. Dis., 1: 49. 47: 808. SINGH, M., Ho, B.-C. and LIM, L.B., (1972). ROBINSON, E.J., JR., (1971). Culicoides cre­ Preliminary results on experimental puscularis (Malloch) (Diptera: Cera­ transmission of a new filarial parasite,

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Breinlia booliati sp. n. Singh and Ho, containing embryos of Filaria perstans 1972 from Malayan wild rats to labora­ (Manson). Brit. Med J.. , 2: 142. tory albino rat. Southeast Asian J. WENK, P., (1967). Der Invasionsweg der Trop. Med. Pub. Hlth., 3: 622. metazyklischen Larven von Litomosoides SKRJABlN, K.T., (1949). Key to Parasitic Ne­ carinii Chandler, 1931 (Filariidae). Z. matodes. Vol.l - Spirurata and Filariata. Parasitenk., 28: 240. Moscow and Leningrad Izdatelstvo, WENK, P. and RAYBOULD, J.N., (1972). Nauk SSSR. 495 pp. (In Russian; Mating, blood-feeding and oviposition translated ed., 1968.) of the "Kibwezi" form of Simulium ~ SONIN, M.D., (1966). Filariata ofAnimals and damnosum Theobald (Diptera:Simulii­ the Diseases They Cause. In: Principles dae) in the laboratory. WHOjONCHOj of Nematodology. Vol. 17: Skrjabin, 72.88; WHOjVBCj 72.351. 1-13. K.I., Ed.; Moscow, Ed. Nauka, 360pp.. WENK, P. and RAYBOULD, J.N., (I972a). (In Russian). Mating, blood-feeding and oviposition SPRATT, D.M., (1970). The Synonymy of of Simulium damosum Theobald in the Agamojilaria tabanicola and Dirojilaria laboratory. Bull. w.H.O., 47 : 627. roemeri. J. Parasit., 56: 622. WHARTON, R.H. and OMAR, A.H.B., (1962). Failure of Wuchereria bancrofti and SPRATT, D.M., (1972). Aspects of the life­ Brugia malayi to develop in the tropical history of Dirojilaria roemeri in naturally bedbug, Cimex hemipterus. Ann. Trop. and experimentally infected kangaroos, Med. Parasit., 56: 188. wallaroos and wallabies. Internat. J. Parasit., 2: 139. WILLIAMS, R.W., (1948). Studies on the life cycle of Litomosoides carinii, fila rid TAYLOR, A.E.R. and BAKER, J.R., Ens., parasite of the cotton rat, Sigmodon (1968). The Cultivation of Parasites hispidus litoralis. J. Parasit., 34: 24. in vitro. Oxford and Edinburgh, Black­ well; 377 pp. YAO, Y.T., Wu, C.C. and JUNG SUN, c., (1938). Further study on the develop­ VARMA, A.K., SAHAI, B.N., SINGH, S.P., ment of microfilaria of Wuchereria LAKRA, P. and SHRIVASTAVA, V.K., bancrofti in sandflies. In : Far Eastern (1971). On Setaria digitata, its specific Association of Tropical Medicine-10th characters, incidence and development Congress Hanoi, Comptes Rendus in Aedes vittatus and Armigeres obturbans (Transactions). 755. in India with a note on its ectopic YEH, L.-S., (1957). On a filarial parasite, occurrence. Z. Parasitenk., 36: 62. Deraiophoronema freitaslenti n. sp., from WEINSTEIN, G.D., (1966). Comparison of the giant anteater, Myrmecophaga tridac­ turnover time and of keratinous protein tyla from British Guyana, and a fractions in swine and human epidermis. proposed re-classification of Dipetalone­ In: Swine in Biomedical Research. ma and related genera. Parasitology, Bustad, L.K. et al., Eds.; Richland, 47: 196. Wash., Pacific Northwest Laboratory. YOELI, M., ALGER, N. and MOST, H., (1958). 287. Studies on filariasis. I. The behavior of WELLMAN, F.C., (1907). Preliminary note on micro filariae of Dirojilaria immitis in the some bodies found in ticks- Ornithodo­ wax moth larva (Galleria melonella). ros moubata (Murray) - fed on blood- Exp. Parasit., 7: 531.

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