Of the seven filarial parasites which commonly infect man (Table l) three are responsible for producing most of the significant pathology. Two of these, the subjects of the present discussion, are lymphatic dwelling parasites, Wuchereria bancrofti and Brugia malayi; and one is a subcutaneous dweller, Onchocerca voIvulus, which causes ocular pathology and blindness [-33]. These filarial parasites have several important features in common. First, they are all transmitted by biting arthropods (mosquitoes, flies, or midges) and all go through complex life cycles which include a slow maturation (often 3-12 months) from the infective larval stages carried by the insects to the adult worms (4-8 cm in length) which reside either associated with the lymph nodes of the lymphatic system or in the subcutaneous tissue. The offspring of these adults, the microfilariae, are 200-250 gm in length and either circulate in the blood (W. bancrofti and B. malayi) or migrate through the skin (0. volvulus) while waiting to be ingested by the insect vectors destined to propagate the parasite's life cycle. Second, patent infection is generally not established unless exposure to infective larvae is intense and prolonged. Third, though exposure to infection occurs throughout childhood in endemic regions, most of the pathology of these infections is found in the adult population.

Immunopathology of lymphatic filariasis in man

A 320-base-pair repeated sequence was observed when DNA samples from the filarial parasites Brugia malayi and Brugia pahangi were digested with the restriction endonuclease Hha I. A 640-base-pair dimer of the repeated sequence from B. malayi was inserted into the plasmid pBR322. When dot hybridization was used, the copy number of the repeat in B. malayi was found to be about 30,000. The 320-base-pair Hha I repeated sequences are arranged in direct tandem arrays and comprise about 12% of the genome. B. pahangi has a related repeated sequence that cross-hybridizes with the cloned B. malayi Hha I repeat. Dot hybridization with the cloned repeat shows that the sequence is present in B. malayi and in B. pahangi but not in four other species of filarial parasites. The cloned repeated DNA sequence is an extremely sensitive probe for detection of Brugia in blood samples. Hybridization with the cloned repeat permits the detection of DNA isolated from a single parasite in an aliquot of blood from animals infected with B. malayi. There are differences in the restriction sites present in the repeated sequences that can be used to differentiate between the two Brugia species. The B. malayi repeated DNA sequence is cleaved by Alu I and Rsa I but the B. pahangi sequence is not. A comparison of repeated sequences between the two species by DNA sequence analysis indicates that some regions of individual repeats are over 95% homologous, while other short regions are only 60-65% homologous. These differences in DNA sequence will allow the construction of species-specific hybridization probes.

https://scholarworks.smith.edu/cgi/viewcontent.cgi?article=1045&context=bio_facpubs

Cloning and comparison of repeated DNA sequences from the human filarial parasite Brugia malayi and the animal parasite Brugia pahangi

Loss of T lymphocyte proliferation and the emergence of a host response that is dominated by a Th2-type profile are well-established features of human filariasis. We have previously reported that adherent peritoneal exudate cells (PEC) from mice transplanted with adult Brugia malayi parasites suppress the proliferation of lymphocytes without blocking Ag-cytokine production in vitro. We now show that infection of mice with the infective larval (L3) stage of B. malayi generates a similar population of PEC. Suppressive cells are generated within 7 days of infection and mediate their effects through a nitric oxide-independent pathway. Both L3 and adult infection elicit high levels of host IL-4 whereas the microfilarial stage of the parasite induces IFN-gamma production and does not generate a similar form of suppression. Production of host IL-4 was necessary to allow the generation of suppressive PEC, given that IL-4-deficient mice implanted with adult parasites failed to induce proliferative block. However, IL-10-deficient mice implanted with adult parasites resulted in T cell suppression, indicating that IL-10 is not essential for the induction of hyporesponsiveness. Neither IL-4 nor IL-10 were directly responsible for ablating cellular proliferation in vitro, as the addition of neutralizing Ab to either cytokine did not reverse the proliferative block. Thus, IL-4 produced in vivo in response to filarial L3 and adult parasites is essential for the induction of proliferative suppression but is not itself the suppressive factor.

Requirement for In Vivo Production of IL-4, But Not IL-10, in the Induction of Proliferative Suppression by Filarial Parasites

Metazoan parasites are the most complex of human pathogens and of these the nematodes are a most ubiquitous yet diverse phylum. These roundworm parasites constitute an enormous medical and veterinary burden in many parts of the world, and as a public health problem are most severe in tropical countries. The numbers of individuals infected with nematodes such as hookworm, Ascaris or those causing filariasis run into hundreds of millions (Muller 1975), and yet our understanding of how these parasites successfully invade the host is still at an early stage. Nematodes evoke a full spectrum of immunological responses {Mitchell 1979, Ogilvie 1979) yet in many infections immunity is insufficient, or even misdirected to an extent which permits parasite establishment and long persistence. Indeed, the host's immune response may by quite inappropriate, and the pathogenic consequences of over-vigorous responsiveness are illustrated by elephantiasis in filarial infections. It is clear, however, that in many instances of successful parasite rejection by the host there is an excess capacity to eliminate, with an overlap of mechanisms which ensures immunity (Wakelin 1978, Haque et al. 1980, Miller 1980). The persistent parasite must therefore circumvent a number of barriers and doubtless has evolved the ability to use a series of evasive or diversive manoeuvres during its development. Over the course of a nematode infection immunity can act at many different stages. There is often a rapid response to the invading larvae, particularly if reinfection is occurring {Ogilvie & Jones 1971, Love & Ogilvie 1975,Chiacumpa

Molecules on the surface of parasitic nematodes as probes of the immune response in infection.

There is little information about naturally occurring protective immunity in individuals living in areas endemic for lymphatic filariasis, though an immunologically hyperresponsive, uninfected group of "endemic normal" individuals that may be immune has been previously recognized. To analyze the nature of the hyperresponsiveness and its potential relation to a state of protective immunity in such individuals, strict clinical, parasitological, and serological criteria were applied to select seven "infection-free" endemic normal individuals (ENs) from a population of 459 persons resident in an area heavily endemic for bancroftian filariasis. Immunoblot analysis was used to compare the qualitative antigen recognition patterns of these endemic normal individuals to those of a group of 12 clearly infected microfilaremic individuals (MFs) from the same endemic area. Though immunoblot analysis using microfilarial and adult stage filarial antigens revealed no distinct differences in antigen recognition patterns between the two groups, when responses to infective larval stage antigens were assessed, 7/7 (100%) of the ENs were found to recognize a 43-kD antigen that was recognized by only 1/12 (8%) of the MFs. These findings are consistent with the concept that recognition of unique larval antigens may induce protective immunity to human filarial parasites and they identify a candidate immunogen for further functional assessment.

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Selective Recognition of a 43-kD Larval Stage Antigen by Infection-free Individuals in an Endemic Area

Publisher Summary Filarial nematodes are arthropod-borne parasites, which sometimes cause serious disease in man and animals. The most important filarial worms of man are Onchocerca volvulus, the cause of river-blindness and severe skin disease, and Wuchereria bancrofti, the cause of tropical elephantiasis and hydrocoel. Another serious pathogen of man is Brugia malayi (B. malayi), and its distribution is limited to Asia. There are two well-defined strains of B. malayi, which differ in their microfilarial periodicity patterns. The nocturnally subperiodic strain is found in the dense swamp forest where its mosquito vectors prefer to feed at night but also bite during the day. The nocturnally periodic strain of B. malayi is found in the open plains where the vectors feed only at night. The correlation between peak peripheral microfilaraemia and peak biting time suggests that filarial nematodes have adapted their periodicity patterns to vector periodicity patterns for facilitating their transmission by mosquitoes. Nocturnally subperiodic B. malayi is common in wild monkeys, and this led to the assumption that it is zoonotic. Mansonia mosquitoes, the vectors of subperiodic B. malayi, feed on a variety of animal hosts, including man. The chapter presents the vector-parasite and definitive host–parasite relationships.

D.A. Denham

Papers

Brugian filariasis: epidemiological and experimental studies.