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Rhabdias casiraghii n. sp. and R. kibiraensis n. sp. are described from Trioceros ellioti from Burundi and co-infection was observed in one of the host specimens. Distinctive characters between these species are, among others, the mouth and buccal capsule in front view, both of which are round in the former and laterally flattened in the latter species. Both species have a complete set of submedian head papillae (three in each submedian axis) as observed in the fourth stage larva of R. americanus from anurans. This primitive character opposes them to other species parasitic in Chamaeleonidae that have a single papilla per axis. The third species is the first described from the primitive chamaeleonid genus Brookesia; R. brygooi n. sp. from B. superciliaris from Madagascar can be distinguished from other Rhabdias in Chamaeleonidae by the small diameter of its mouth and buccal capsule. In this character, it resembles parasites from anurans. However, its infective larva has a rounded caudal extremity ornated with buds, as described in species of Rhabdias parasitic in Chamaeleonidae.

To date Rhabdias gemellipara is the only species described from Malagasy chameleons, but heterogeneity of the material had been suspected. 11 samples of Rhabdias parasites present in the Paris Natural History Museum collection were examined. The size and shape of the buccal capsule, shape and length of the oesophagus, shape of the apical region of the intestine, extent of the genital tract and structure of the cuticular vesicle led to the distinction of five species. Rhabdias rabetafikae n. sp. parasitises Calumma cucullatum in the northeastern region (Cap Machoual). In the eastern region, R. nasutum n. sp. is parasitic in C. nasutum, and R. brevicorne n. sp. in C. brevicorne. All three species are similar in size to the African species parasitic in chameleons from which they can be distinguished by several characters. The small species, R. gemellipara, type host C. parsonii from the eastern region, was also found in C. brevicorne from the same geographic region. In the central region, Rhabdias sp., equally collected from C. brevicorne, is distinguished from R. gemellipara by a laterally flattened buccal capsule. All Malagasy species are hermaphrodites. Throughout the worm’s life spermatozoids are formed intermittently in a band of cells situated at 1-2 mm from the extremity of the ovaries; they migrate in the ovaries and accumulate in the oviducts.

The lung nematodes of the genus Rhabdias parasitic in chameleons were previously only known from east Africa and Madagascar. Two new species are described from Cameroon: i) Rhabdias okuensis n. sp., type-host Chamaeleo (Trioceros) quadricornis gracilior, from Mont Oku, is frequent; it resembles R. jarki from Burundi, with a short buccal capsule and a long, thin oesophagus, and is distinguished by its large cervical vesicle and cephalic characters (mouth aperture, papillae). The female parasites are hermaphroditic (spermatozoa identified) and they pierce the lung wall and induce lesions, as R. jarki. In the same locality, another chameleon, C. (T.) w. wiedersheimi also harbours R. okuensis, as demonstrated with the 12S rDNA and coxI gene sequences. ii) R. cristati n. sp., type-host C. (T.) cristatus, from Mount Cameroon, is described from one heavily infected specimen; it resembles R. chamaeleonis from East Africa, and is distinguished by the large buccal capsule and the thick apex of the intestine. The free-living phase, studied in R. okuensis, presents characters of other Rhabdias from chameleons: heterogony, development of larvae through matricidal endotoky, infective larval stages with a thick, rounded caudal extremity, exuvium transformed into a thick cuticular sheeth. Each free-living female produces one larva, as in other African Rhabdias, whereas the female of R. gemellipara, a parasite of a Malagasy chameleon, produces two larvae.

Lung-dwelling females of Rhabdias (Rhabdiasidae), and possible migrating ceolomic young females were searched for in 46 chameleons, belonging to seven species. Rhabdias chamaeleonis, the single species identified to date in Africa, was found in Chamaeleo (Trioceros) johnstoni and C. (T.) hoehnelii, and redescribed ; the sizes of the buccal capsule and oesophagus were stable compared to the length of the female parasites, which varied from 6 mm to 22 mm in length. A second species, R. jarki n, sp., was identified from one C. (T.) johnstoni ; it differed from R. chamaeleonis in the shape of anterior region, the longer and slender oesophagus (ratio bulb diameter-body diameter at that level about 1/5 instead of 1/2), the arrangement of the head papillae, the shape of the buccal capsule, and the anatomy of the genital apparatus : one of the ovaries (the anterior or posterior one according to the specimen) had a band of small cells, among larger ovocytes of the synapsis zone, which were likely to generate the spermatozoa present in the oviducts, whereas these two elements were absent from R. chamaeleonis. The parasitic females of R. jarki thus appeared to be hermaphroditic, whereas those of R. chamaeleonis appeared to be parthenogenetic. The free living phase of these Rhabdias species was heterogonic. The infective larva of R. chamaeleonis was 360-590 µm long, unmotile and at third stage inside the maternal cuticle. The free-living male of R. jarki was described. The numerous infective larvae recovered from cultures of unidentified Rhabdias were all in maternal cuticle (one larva/female instead of two as in R. gemellipara from Calumma parsonii, from Madagascar) and two kinds of larvae were identified, R. chamaeleonis and larvae 700-900 µm long provisionally identified to R. jarki. The behaviour of infective larvae and a few successful infections of insects suggest that, in the field, insect transport hosts are involved in transmission and in preventing infective larvae from drying out.

The article presents a study on the lung nematode parasites of the genus Rhabdias including its diversity and biology in the Chamaeleonidae. Fourteen Rhabdias species are said to be discriminated in the Chamaeleonidae. For this study, the researchers collected material from chameleons and a few anurans during field trips or recovered from hosts seized by customs or bought from a dealer. A figure that shows cephalic characters of Rhabdias species from Chamaeleonidae and Anura from Africa and Madagascar is presented. A single acquisition of Rhabdias by ancestral Chamaeleonidae is found.

Filarial parasites are tissue dwelling worms transmitted by hematophagous vectors. Understanding the mechanisms regulating microfilariae (the parasite offspring) development is a prerequisite for controlling transmission in filarial infections. Th2 immune responses are key for building efficient anti-parasite responses but have been shown to also lead to detrimental tissue damage in the presence of microfilariae. Litomosoides sigmodontis , a rodent filaria residing in the pleural cavity was therefore used to characterize pleuropulmonary pathology and associated immune responses in wild-type and Th2 deficient mice. Wild-type and Th2-deficient mice ( Il-4rα -/- /Il-5 -/- ) were infected with L. sigmodontis and parasite outcome was analyzed during the patent phase (when microfilariae are in the general circulation). Pleuropulmonary manifestations were investigated and pleural and bronchoalveolar cells were characterized by RNA analysis, imaging and/or flow cytometry focusing on macrophages. Il-4rα -/- /Il-5 -/- mice were hypermicrofilaremic and showed an enhanced filarial survival but also displayed a drastic reduction of microfilaria-driven pleural cavity pathologies. In parallel, pleural macrophages from Il-4rα -/- /Il-5 -/- mice lacked expression of prototypical alternative activation markers RELMα and Chil3 and showed an altered balance of some markers of the arginine metabolic pathway. In addition, monocytes-derived F4/80 intermediate macrophages from infected Il-4rα -/- /Il-5 -/- mice failed to mature into resident F4/80 high large macrophages. Altogether these data emphasize that the presence of both microfilariae and IL-4R/IL-5 signaling are critical in the development of the pathology and in the phenotype of macrophages. In Il-4rα -/- /Il-5 -/- mice, the balance is in favor of parasite development while limiting the pathology associated with the host immune response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Remion, Gal, Chaouch, Rodrigues, Lhermitte-Vallarino, Alonso, Kohl, Hübner, Fercoq and Martin.)

Filarial diseases, including lymphatic filariasis and onchocerciasis, are considered among the most devastating of all tropical diseases, affecting about 145 million people worldwide. Efforts to control and eliminate onchocerciasis are impeded by a lack of effective treatments that target the adult filarial stage. Herein, we describe the discovery of a series of substituted di(pyridin-2-yl)-1,2,4-thiadiazol-5-amines as novel macrofilaricides for the treatment of human filarial infections.

Filarial diseases, including lymphatic filariasis and onchocerciasis, are considered among the most devastating of all tropical diseases, affecting over 86 million people worldwide. To control and more rapidly eliminate onchocerciasis requires treatments that target the adult stage of the parasite. Drug discovery efforts are challenged by the lack of preclinical animal models using the human-pathogenic filariae, requiring the use of surrogate parasites for Onchocerca volvulus for both ex vivo and in vivo evaluation. Herein, we describe a platform utilizing phenotypic ex vivo assays consisting of the free-living nematode Caenorhabditis elegans, microfilariae and adult filariae of the bovine filariae Onchocerca lienalis and Onchocerca gutturosa, respectively, as well as microfilariae and adult filariae of the feline filariae Brugia pahangi, the rodent filariae Litomosoides sigmodontis and the human-pathogenic filariae Brugia malayi to assess activity across various surrogate parasites. Utilization of those surrogate nematodes for phenotypic ex vivo assays in order to assess activity across various parasites led to the successful establishment of a screening cascade and identification of multiple compounds with potential macrofilaricidal activity and desirable physicochemical, MW = 200-400 and low lipophilicity, logP <4, and pharmacokinetic properties, rat and human liver S9 stability of ≥70% remaining at 60 min, and AUC exposures above 3 μM h. This platform demonstrated the successful establishment of a screening cascade which resulted in the discovery of potential novel macrofilaricidal compounds for futher drug discovery lead optimization efforts. This screening cascade identified two distinct chemical series wherein one compound produced a significant 68% reduction of adult Litomosoides sigmodontis in the mouse model. Successful demonstration of efficacy prompted lead optimization medicinal chemistry efforts for this novel series., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Filarial nematodes (superfamily Filarioidea) are responsible for an annual global health burden of ∼6.3 million disability-adjusted life-years, which represents the greatest single component of morbidity attributable to helminths affecting humans. No vaccine exists for the major filarial diseases, lymphatic filariasis and onchocerciasis; in part because research on protective immunity against filariae has been constrained by the inability of the human-parasitic species to complete their lifecycles in laboratory mice. However, the rodent filaria Litomosoides sigmodontis has become a popular experimental model, as BALB/c mice are fully permissive for its development and reproduction. Here, we provide a comprehensive analysis of excretory-secretory products from L. sigmodontis across five lifecycle stages and identifications of host proteins associated with first-stage larvae (microfilariae) in the blood. Applying intensity-based quantification, we determined the abundance of 302 unique excretory-secretory proteins, of which 64.6% were present in quantifiable amounts only from gravid adult female nematodes. This lifecycle stage, together with immature microfilariae, released four proteins that have not previously been evaluated as vaccine candidates: a predicted 28.5 kDa filaria-specific protein, a zonadhesin and SCO-spondin-like protein, a vitellogenin, and a protein containing six metridin-like ShK toxin domains. Female nematodes also released two proteins derived from the obligate Wolbachia symbiont. Notably, excretory-secretory products from all parasite stages contained several uncharacterized members of the transthyretin-like protein family. Furthermore, biotin labeling revealed that redox proteins and enzymes involved in purinergic signaling were enriched on the adult nematode cuticle. Comparison of the L. sigmodontis adult secretome with that of the human-infective filarial nematode Brugia malayi (reported previously in three independent published studies) identified differences that suggest a considerable underlying diversity of potential immunomodulators. The molecules identified in L. sigmodontis excretory-secretory products show promise not only for vaccination against filarial infections, but for the amelioration of allergy and autoimmune diseases., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Filariae are a leading cause of infections which are responsible for serious dermatological, ocular, and vascular lesions. Infective third stage larvae (L3) are transmitted through the bite of a haematophagous vector. Litomosoides sigmodontis is a well-established model of filariasis in the mouse, with the vector being the mite Ornithonyssus bacoti. The aim of the study was to analyse the filarial infection in mites to determine the consequences of filarial infection in the blood-feeding and the reproduction of mites as well as in the regulation of vector-induced inflammation in the mouse skin. Firstly, L3 are unevenly distributed throughout the host population and the majority of the population harbours a moderate infection (1 to 6 L3). Filarial infection does not significantly affect the probing delay for blood feeding. The number of released protonymphs is lower in infected mites but is not correlated with the L3 burden. Finally, induced excreted proteins from infected mites but not from uninfected mites stimulate TNF- α and the neutrophil-chemoattractant KC production by antigen-presenting cells (APCs). Altogether, these results describe the modification of the mite behavior under filarial infection and suggest that the immunomodulatory capacity of the mite may be modified by the presence of the parasite, hindering its defensive ability towards the vertebrate host.

Litomosoides sigmodontis is a cause of filarial infection in rodents. Once infective larvae overcome the skin barrier, they enter the lymphatic system and then settle in the pleural cavity, causing soft tissue infection. The outcome of infection depends on the parasite's modulatory ability and also on the immune response of the infected host, which is influenced by its genetic background. The goal of this study was to determine whether host factors such as the chemokine axis CXCL12/CXCR4, which notably participates in the control of immune surveillance, can influence the outcome of the infection. We therefore set up comparative analyses of subcutaneous infection by L. sigmodontis in two inbred mouse strains with different outcomes: one susceptible strain (BALB/c) and one resistant strain (C57BL/6). We showed that rapid parasite clearance was associated with a L. sigmodontis-specific CXCL12-dependent cell response in C57BL/6 mice. CXCL12 was produced mainly by pleural mesothelial cells during infection. Conversely, the delayed parasite clearance in BALB/c mice was neither associated with an increase in CXCL12 levels nor with cell influx into the pleural cavity. Remarkably, interfering with the CXCL12/CXCR4 axis in both strains of mice delayed filarial development, as evidenced by the postponement of the fourth molting process. Furthermore, the in vitro growth of stage 4 filariae was favored by the addition of low amounts of CXCL12. The CXCL12/CXCR4 axis thus appears to have a dual effect on the L. sigmodontis life cycle: by acting as a host-cell restriction factor for infection, and as a growth factor for worms.

Despite the small sample size the diversity of Rhabdias Stiles et Hassall, 1905 from anurans in the Afrotropical region was found to be high. Four species were collected from four localities, one in South Africa, two on Cameroonese mountains and one in Madagascar: Rhabdias picardiae sp. n. from the bufonid Amietophrynus gutturalis (Power); Rhabdias ohlerae sp. n. and Rhabdias tanyai sp. n. from the arthroleptids Leptopelis brevirostris (Werner) and Astylosternus rheophilus Amiet, respectively; and Rhabdias vencesi sp. n. from the mantellid Boophis madagascariensis (Peters). Distinctive characters between these species are numerous and obvious, based on body size, shape and size of the buccal capsule, arrangement of head papillae, and shape and size of the oesophagus and intestinal apex. Molecular data based on 500 bp of 12S rDNA and 600 bp of coxl of three of the four species are presented. Rhabdias vencesi resembles Rhabdias madagascariensis Chabaud, Brygoo et Petter, 1961 from an African ptychadenid introduced on Madagascar, but differs in body size and head morphology. The remaining new species are clearly distinct from those previously known from Afrotropical anurans. Outside the Afrotropics, some Rhabdias species present characters similar to those observed in the new species, but they all differ in various other characters. No clear correlation was seen between Rhabdias species and families of anuran hosts in this region. However, the narrow buccal capsule seen in Rhabdias species from Afrotropical lissamphibians opposes them to the majority of Rhabdias parasitic in chamaeleonids. Furthermore, the infective larva of R. vencesi has a conical pointed tail, while those of Rhabdias from chameleons have a rounded tail tip ornated with a few buds.

Rhabdias rhampholeonis n. sp. from Rhampholeon (Rh.) spectrum, Cameroon, and Rhabdias mariauxi n. sp. from Rieppeleon brevicaudatus, Tanzania, are the first lung worms from leaf chameleons. The new species are similar to the majority of species parasitic in chamaeleonids by having a long (>or=10 mm) and thick body (>or=500 microm), long oesophagus (>or=800 microm), wide buccal capsule (>or=40 microm) and low buccal ratio (<0.5). They most closely resemble Rhabdias chamaeleonis and Rhabdias cristati parasitic in Trioceros spp. from East Africa and Cameroon, respectively. Main distinctive characters are a buccal capsule composed of two segments and the head shape. The dorso-ventrally flattened buccal capsule of R. mariauxi n. sp. is unique in Rhabdias parasitising Chamaeleonidae. Sequences of the 12S rDNA and mitochondrial cytochrome c oxidase subunit 1 (coxI) genes were obtained and compared to those of Rhabdias okuensis, the only sequences published for chamaeleonid lung worms. The smallest nucleotide interspecific distances were found between R. mariauxi n. sp. and the former species of Trioceros from Cameroon. Hermaphroditism in females in the lungs, and R. mariauxi n. sp. free-living stages are like in other species from Chamaeleonidae, but the number of infective larvae produced per free-living female (one or two) was not fixed.