Behaviour of filariae: morphological and anatomical signatures of their life style within the arthropod and vertebrate hosts
© Bain and Babayan; licensee BioMed Central Ltd. 2003
Received: 13 February 2003
Accepted: 15 December 2003
Published: 15 December 2003
This paper attempts to pinpoint the most original morphological anatomical features of the biology of filariae per se and those which are or could be important for triggering regulatory processes in the arthropod vector and uncontrolled pathogenic processes in the vertebrate hosts. The following stages are considered: the motile egg or newly-hatched larva, the microfilaria, in the lymphatic or blood vessels of its vertebrate host; the larva, its migrations and its intrasyncitial development in the hematophagous arthropod subverted as vector; its transfer to the vertebrate host, migratory properties through the lymphatic system, maturation, mating and, finally, egg laying in the tissues they reach. This synthesis is based on parasite morphological features and their functional interpretation, histological features in the different niches the filariae reach, and on quantitative analyses of filarial development at its different phases, as well as on the rare and valuable observations of living parasites in situ. Data have been drawn from various species of Onchocercidae from amphibians, reptiles, birds and mammals. These comparative analyses have revealed the major constraints to which the filariae, including those parasitizing humans, have been subjected during their evolution from their ancestors, the oviparous and heteroxenic spirurids. Emphasis is placed on mechanical events: resistance of the microfilariae to the currents in the blood or lymph vessels, regulatory processes induced in the vector mesenteron by the movements of the ingested microfilariae, transient disruption by the microfilarial cephalic hook of the vectors' tissues and cell membranes during microfilarial translocation, attachment of males to females during mating by means of 'non-slip' systems, etc. Like other nematodes, filariae are equipped with sensory organs and a locomotor system, composed of the muscles and of the original osmoregulatory-excretory cell. Any change in one of these elements will result in the destruction of the filaria, at some stage of its development. In the vertebrate host, the intravascular stages will no longer be able to resist being carried passively towards the organs of destruction such as the lymph nodes or the lungs.
The study of human filariae is limited for obvious ethical reasons. The proportion of inoculated larvae that develop, their route of migration, pairing of the sexes, egg laying and migration of the microfilariae, to name only a few processes, remain unknown. However these filariae belong to a homogeneous group, the family Onchocercidae, from other members of which information can be extrapolated. Parasites of amphibians, reptiles, birds and non-human mammals are available for observation and further experimentation . The study of each species provides a fragment of information and these pieces, when assembled as in palaeontology, allow outlining the main features of the biology of filariae, which can be extended to the parasites of humans.
1 - The microfilaria: the morphological diversity of this stage reflects its different behavioural traits and niches accessible to the vectors
As a consequence of the slenderness of microfilariae, the female filaria may have considerable offspring, which is dependent on the vector for the completion of the larval development. Thus the tendency will be for the microfilariae to be borne earlier and earlier. This may explain some of the characters used empirically to distinguish human-dependent filarial strains: the lower number of nuclei in the microfilaria of Wuchereria bancrofti  indicates a more precocious arrest of cellular divisions; in Brugia malayi, the relatively high proportion of exsheathed microfilariae in blood films  indicates more rapid eclosion.
As we cannot directly observe the microfilariae in their natural environment, their behaviour is almost unknown. However, there are other ways of approaching this problem: analyses of the distribution of microfilariae in host skin snips, and of the ingestion by the vectors of different filarial species and of inert microspheres; and the study of the functional anatomy of microfilariae. This phase of the filarial life cycle appears to be astonishingly complex.
The lymphatic localization of the so-called dermal microfilariae is probably the primary condition. The filariae actually deposit their embryos in the connective tissue, drained by the initial lymphatic vessels  (Fig. 1I,1J). Lymph is a less aggressive medium than blood: no platelets, no complement system, incomplete coagulation system and no granulocytes; in addition, its flow is much less violent. These lymphatic microfilariae are not randomly distributed in the host, but are more often concentrated in precise regions, and this cannot be explained by the proximity of the female filariae [9–11]. The blood microfilariae also are not uniformly distributed and the patterns are characteristic of each species; this has been shown using a particularly favourable experimental model: a saimiri monkey naturally and concomitantly infected with four species of Mansonella; thus, the ingestion by the hematophagous vector of the different microfilarial species could be compared under identical conditions . It was found that each species is differently ingested and the observations suggest that, in the peripheral vessels accessible to the mouthparts of the vectors, each tends to have a particular niche, mainly defined by the vascular diameter.
Like all nematodes, the microfilariae detect their position owing to two amphids (Fig. 1B), receptors of physicochemical stimuli . Their powerful musculature and their internal osmotic pressure maintained by the excretory cell, allow them to stay in their niche against the lymph or blood flow. They are generally round in transverse section and, as can be seen in a drop of blood on a slide, they undulate laterally, like the free-living nematodes; but in the highly evolved worms with dorso-ventrally flattened microfilariae (Fig. 1G), they likely undulate like dolphins. Some microfilariae have developed means of maintaining the stability of their position in order to reduce to a minimum the expenditure of energy; in the large (350/10 μm) microfilaria of Mansonella (Tetrapetalonema) colombiensis of the saimiri, the body is barely mobile whereas the tail moves rapidly around its axis like a propeller; in a Cercopithifilaria species from a Japanese caprin, the cuticle has spiral ridges in the caudal region (Fig. 1H), which facilitate the flow of the surrounding fluid; even the whole body of some microfilarial species has acquired a spirally coiled shape, thus multiplying points of contact with the vessel walls. It is noticeable that this last morphological development appeared in widely disparate groups, a filaria of frogs and a species of Onchocerca (Fig. 1E,1F), which indicates that these features could be critical for the sustained maintenance of the transmissible developmental stages. Any alteration of that capacity has important consequences . In onchocerciasis, the pathogenesis seems to result from the accidental extravasion of the microfilariae into the peri-vascular connective tissue. Driving the microfilariae out of their niche seems to be a key factor of drug activity . DEC for example induces a simultaneous extravasion of lymphatic microfilariae, causing a multitude of inflammatory reactions in the subcutaneous and epidermal tissues that will eliminate the microfilariae but also have disastrous pathological consequences (Mazzotti reaction). Ivermectin, which is thought to act as an inhibitor of neuro-muscular transmission, very rapidly induces a release of Onchocerca volvulus microfilariae from their niche by centripetal migration. They are found firstly in the deepest layers of the subcutaneous tissue , and then in the draining lymph nodes, where they are destroyed . As a result of their passive intravascular migration to the regional lymph nodes, no new lesion is induced in the subcutaneous tissue with this drug .
Additional File 1: Mesenteric blood vessels of a Meriones unguiculatus with 1300 Litomosoides sigmodontis microfilariae / 1 blood μl. Each microfilaria is visualised in the blood stream by a pale, sometimes squirming patch amongst the red blood cells (a live L. sigmodontis microfilaria is 80–100 μm long and 4 μm wide). (MOV 9 MB)
The behaviours and shapes being linked, microfilariae are a relevant source of taxonomic features. However, as expected, convergences are frequent, so it is generally impossible to identify the genus on the basis of the microfilarial morphology alone when studying new material. The cephalic hook of the microfilaria seems to have generic value (Fig. 1A,1D), but its very minute size does not facilitate the use of this character.
2 - The larval stages in the vector: the movements of the ingested microfilariae induce important regulatory processes of translocation through the vector's stomach wall
The life cycle in the vector (Fig. 2) follows a constant pattern: migration of microfilariae through the digestive cells (Fig. 2A), and through the basal lamina, which may offer particular resistance (hematophagous Diptera); arrival in the hemocoel, penetration into a cell, and migration into several contiguous cells of the same tissue: these cells are immediately differentiated into a syncytium (unless the tissular structure is already syncytial, like a muscle). The cephalic hook of the microfilaria, situated on the left side and resting in one of two amphidial pockets  (Fig. 1B), plays an important role during this phase. Observation of a microfilaria of Acanthocheilonema viteae, which had just entered a muscle fibre of an argasid tick, showed that the hook caught and stretched the cytoplasmic membrane (which, interestingly, was not ruptured thereafter) while the very motile microfilaria coiled up in the peripheral undifferentiated sarcoplasma (Fig. 2B). During their development in the syncytium, the larvae are often arched, with the ventral face towards the exterior, and the anus and future rectal plug buried in the cytoplasm; the syncytial nuclei are grouped close to the dorsal face (Fig. 2D). Stage 1, from the microfilaria to the first moult, is unmotile, relatively long-lasting and corresponds to the end of organogenesis: connection of the diverse digestive primordia and multiplication of the mesenchymal R1 cell (Fig. 1C). Growth occurs mainly during stage 2. After the second moult, the larva is transformed in a motile resistant form (cytoplasmic reduction), the infective larva, which is freed into the hemocel and will escape from the vector by rupture of the latter's mouthparts.
The vector's reactivity is initiated principally at the onset of the filaria cycle, in the mesenteron [20–22]. When the parasite load is too high, the stomach wall can be largely abraded by the numerous microfilariae migrating from a digestive cell to another; however the vector is prevented from haemorrhage by the basal lamina, which remains intact; the vector ultimately dies because it can no longer digest its blood meal. Penetration through the stomach wall may also be regulated, reducing drastically the proportion of microfilariae that escape into the hemocoel [limitation phenomenon, ]. The stomach wall of hematophagous arthropods reacts to the physical stimuli caused by the microfilariae moving on the clot surface with remarkably diverse mechanisms, due to the zoological diversity of the vectors. For example, in some Simulium species from savannah, limitation is linked to more rapid and more extensive secretion of the peritrophic matrix: in non or low infected flies the peritrophic membrane is very thin, whereas it thickens immediately after feeding on heavily infected carriers. The percentage of ingested microfilariae that reach the hemocel can decline from 33 % to 0. 4 % . In Aedes aegypti, limitation is due to a kind of "acquired" reactivity of the digestive epithelium: whereas the first microfilariae cross the stomach wall freely, later each digestive cell attacked by a microfilaria dies; the microfilaria is prevented from migrating further, probably due to the destruction of the cell's internal structures .
The adaptations of the parasite to the vector assessed by an improved success of transmission are rarely visible, but two examples can be cited. A filaria of a Malaysian rodent, which develops in the adipose tissue of a mosquito, has acquired a remarkable high degree of independence of the vector's trophic habits: contrary to what happened in another filaria-mosquito pair, the infected syncytium is no longer stimulated by a blood meal, which normally induces the synthesis of provitellogen . A. viteae shows another adaptation: the infective larvae occupy empty spaces throughout the whole body, but half a minute after the tick has attached itself to the skin of its rodent host, they migrate to the mouthparts (Fig. 2E), thus facilitating their transmission .
Although physiological functions – such as enzyme secretion – are lost by the filariae, species of a given genus, and sometimes the same species, may be transmitted by vectors as different as ceratopogonids and simuliids (Onchocerca species for example), alike a spirurid which can develop in orthopters as well as in coleopters. The vector, interesting and important as it may be [25, 26], does not seem to have a significant evolutionary impact.
There is, however, one exception, the genus Cercopithifilaria, the whole evolution of which seems to have been determined by its vectors. Its distribution is worldwide and its host range is "incoherent" [27, 28]: cercopithecids, bovids and cervids, several groups of rodents, carnivora, and marsupials. The vectors are rhipicephalid ticks; their lifespan is long, their capacity for travelling great, and their trophic cycles necessitate several different hosts. All these features probably favoured captures, i.e. the passage of a parasite from one host group to another, zoologically distant, one .
As a result of their intracellular habitat in the vector, the morphology of filariae is homogeneous during the larval development. The infective stages, specialized for penetrating the skin of the host, are all thin with a large glandular part of oesophagus and, in general, an attenuated head (Fig. 2F). However they have some morphological traits with phyletic value, such as the caudal extremity (Fig. 2G), and they are identifiable at the generic level .
3 - The final larval stages and adults in the vertebrate host: once they have escaped from the immune effectors at point of entry, they must resist liquid fluxes.
The details of many fewer life cycles are known in the vertebrate host than in the vector: 18 compared to a hundred . These species belong mainly to the Onchocercinae and Dirofilariinae: their hosts are mammals or, rarely, birds or reptiles. The laboratory filarial models using cats  and, especially, rodents [33–39] are those that have provided most data. Comparative analyses have revealed a fundamental uniformity, which remains generally unrecognized. Thus it is justified to extrapolate these experimental results to the human parasites.
The lymphatic system offers shelter to the larvae at periods when their developmental stages are the most vulnerable. It allows them to escape different molecules, leukocytes, present and/or recruitable in the skin. It then provides easy routes of migration within the connective tissues, which rapidly react as assessed by leukocyte infiltrates. The inflammatory process follows the migration of the larvae (Fig. 3D) but the lymphatic wall generally prevents the penetration of granulocytes into the vessel lumen; even if thrombosis occurs, the larva can continue to migrate to its next sites. A lymphatic phase is thus not an exclusive property of the so-called lymphatic filariae; Wenk  revealed it with L. sigmodontis and, previously, Menon et al.  had done so with a lizard filaria. This behaviour seems to be a common trait during the first phase of the life of filariae in the vertebrate host [43, 44]. From this perspective, it becomes possible to interpret certain biological enigmas. (i) The nodule of O. volvulus may originate from a lymphatic vessel, in which a thrombosis developed as a result of a dysregulated inflammatory process, within which the filaria secondarily adapted in order to survive. (ii) The cardio-vascular localization of Dirofilaria immitis and its migrations: the filariae initially remain in the connective and aponeurotic tissues, alike D. repens; they are then found in the abdominal cavity for a long period ; finally, they arrive in the heart when they are as long as 6 cm. These successive localizations are identical to those of a filaria of the genus Monanema that, as its natural host is a small rodent, provides a model easier to study  (Fig. 3E). This model has shown that the filarial worms recovered at necropsy from the peritoneal cavity in fact inhabit the lymphatics. The lymphatic system is connected anatomically to the cardio-pulmonary circulation, so that the lymph, collected by the thoracic duct, mingles with the blood just before reaching the heart, carrying with it, for example, developing D. immitis worms. It is no longer necessary to envisage a dangerous and improbable perforation of the myocardium by the larvae, or a migration via the blood. In addition, micrographs published by Kume and Itagaki  show that D. immitis larvae in the vena cava are not in its lumen but in the wall, and are surrounded by a structure that suggests a lymphatic vessel. Lymphatic vessels have a remarkable capacity for dilatation, because of the interlocked structure of their cells, and they can contain large worms (38). The speciality of D. immitis is that it has adapted to living in blood. (iii) The filarial pulmonary nodules: the migrating larvae or the adult filariae must actively resist the centripetal lymphatic flow in order to move forward or even to stay in one place. Those of M. martini normally migrate against the lymph stream from the abdominal lymph nodes to the lymphatic vessels of the mesentery and then to those of the large intestine; once there, they resist expulsion by means of contractions of their body (which are adapted to the peristaltic movements of the host-organ, features which can account for the mild lesions with this filarial species). Similarly, an adult female of B. malayi, inside a very dilated lymphatic vessel of which the transparent wall had been hardened by fibrosis (this is a signature of the inflammatory process), was observed to undulate constantly in a plane parallel to the flow. Likewise W. bancrofti was found dancing in a lymphatic vessel  thereby maintaining its position. However either by chance or, more especially, following drug delivery as seen with M. martini, weakened worms may be carried along passively with the lymph and thus reach, via the right heart, the pulmonary arteries (Fig. 3E) where they are destroyed. This would explain the presence of nodules of W. bancrofti and B. malayi in the lungs of humans .
On its arrival in the host, the larva immediately begins its development: the head loses its attenuated shape and chemical changes occur at the surface of the cuticle . The third larval stage hardly grows and seems to have little trophic requirement, so that this stage may develop in vitro apparently without its duration being modified either in this artificial environment or in a surrogate host. Two moulting strategies have been demonstrated . Moult no. 3 occurs generally between 7 and 10 days post inoculation, as it does in Wuchereria, Brugia, Acanthocheilonema, Litomosoides, Monanema and Molinema among the Onchocercinae, and Loa loa in the Dirofilariinae. In contrast, in Onchocerca and in Dirofilaria, respectively typical genera of these two subfamilies, the third moult occurs much earlier, 2–3 days p.i. [51, 45, 52]. This biological character, as well as molecular markers of both these filariae  and their endosymbiontic bacteria Wolbachia , suggest a close relationship between Dirofilaria and Onchocerca and on the contrary places Loa closer to the other Onchocercinae. The morphology of the infective stages also fits better with these new hypotheses.
The mechanisms involved in egg laying are largely unknown; they have to satisfy two constraints: the need to meet a vector and the need not to exacerbate the host immune response. In L. sigmodontis, it has been possible to observe microfilariae expelled in small groups of 5–6, previously accumulated in the vagina. But the morphological diversity of the vagina suggests the existence of different modes of egg laying to achieve these ends. The vagina may be fairly curved, with a simple shape (Onchocerca for example) or it may present a succession of chambers and sphincters of great complexity (Fig. 4A), to which the spicules of the male have to adapt .
At the beginning of the patent phase of infection, the microfilarial density is inversely correlated with the number of adult filariae , because the size and fertility of female worms are reduced as the parasite load increases [ongoing work]. Later, the quantitative relationships become extremely complex because they are dependent to a large extent on the immune response acquired during infection. This response has been proved to be able to reduce the survival of microfilariae in several experimental infections, and even to totally eliminate microfilaraemia although uterine microfilariae are still abundant in the female worms [59–61]. The adaptations to ensure completion of the life cycle may vary. In L. sigmodontis, the microfilarial densities are exceptionally high, reaching 1500 per μl of blood (about 0.06% of the bodyweight of the rodent); the vector, the macronyssid mite Ornithonyssus bacoti, ingests only a small amount of blood due to its small size and, in addition, 80% of the microfilariae arrive dead in the digestive caeca because they are torn by the mite's pharyngeal teeth . In another example, a filaria parasitic in birds, the adult worms die after one season of egg laying and the maintenance of the species is ensured by the microfilariae which are transmitted to the nestlings by the mallophagean vector .
The above observations indicate the importance of physical factors in the relations between the filariae and their two successive hosts, haematophagous arthropods and terrestrial vertebrates. Like any other nematode, the filaria is active thanks to its locomotor system, muscles and 'endoskeleton', the high osmotic pressure maintained by the excretory cell. Any drug that affects this system should be very efficient.
The filaria uses this locomotor system either to change its location, due to the necessity of mating for example or, more fundamentally, to avoid moving. It is obvious that parasites inhabiting the digestive tract must resist expulsion by actively maintaining themselves in one place. Because of this constraint, they have developed various mechanisms, with different origins, to achieve this single end. These mechanisms include the suckers of cestodes and trematodes, the longitudinal crests of the trichostrongylids that are coiled around the intestinal villi, and the cuticular cephalic flanges that ensure the anchoring of some spirurids. A number of this last group have also chosen to invade the host's tissues.
Filariae adopted a similar method to that of their spirurid ancestors. The resulting protection is still not perfect because the circulation of fluids can drive them to organs in which they will be destroyed, such as the lungs and liver. To resist this they have been forced to develop their own, more subtle, methods of active mechanical resistance.
We thank Profs J. Dufaux and G. Guiffant (Laboratoire de Biorhéologie et d'Hydrodynamique Physico-chimique, Université Paris VII) and Mr F. Roturier (Galerie de l'Evolution, Muséum National d'Histoire Naturelle, Régie Audiovisuel) for their help in preparing the film sequences of blood microfilariae. Many thanks to Dr J. Baker who patiently corrected the English version and to Dr G. Milon for her constructive comments. A great part of our observations were made thanks to WHO and EU contracts (currently VARBO number ICA 4CT 1999 10002).
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