Бругия малаи: лимфалық филярия және энцефалопатия ауруы

Brugia malayi is a filarial (arthropod borne) nematode (roundworm), one of the three causative agents of lymphatic filariasis in humans. Lymphatic filariasis, also known as elephantiasis, is a condition characterized by swelling of the lower limbs. The two other filarial causes of lymphatic filariasis are Wuchereria bancrofti and Brugia timori, which both differ from B. malayi morphologically, symptomatically, and in geographical extent. B. malayi is transmitted by Mansonia mosquitoes and is restricted to South and Southeast Asia. It is one of the tropical diseases targeted for elimination by the year 2020 by the World Health Organization, which has spurred vaccine and drug development, as well as new methods of vector control.

B. malayi is one of the causative agents of lymphatic filariasis, a condition marked by infection and swelling of the lymphatic system. The disease is primarily caused by the presence of worms in the lymphatic vessels and the resulting inflammatory response of the host. Signs of infection are typically consistent with those seen in Bancroftian filariasis—fever, lymphadenitis, lymphangitis, lymphedema, and secondary bacterial infection—with a few exceptions.

Lymphadenitis, the swelling of the lymph nodes, is a commonly recognized symptom of many diseases. It is an early manifestation of filariasis, usually occurs in the inguinal area during B. malayi infection and can occur before the worms mature. Elephantiasis resulting from B. malayi infection typically affects the distal portions of the extremities. Unlike Bancroftian filariasis, B. malayi rarely affects genitalia and does not cause funiculitis, orchitis, epididymitis, hydrocele, or chyluria, conditions more often observed with Bancroftian infection. However, clinical manifestations of infection are variable and depend on several factors, including host immune system, infectious dose, and parasite strain differences. Most infections appear asymptomatic, yet vary from individual to individual. Individuals living in endemic areas with microfilaremia may never present with overt symptoms, whereas in other cases, only a few worms can exacerbate a severe inflammatory response.

Development and replication of B. malayi occurs in two discrete phases: in the mosquito vector and in the human. Both stages are essential to the life cycle of the parasite. Mosquito: The mosquito serves as a biological vector and intermediate host – it is required for the developmental cycle and transmission of B. malayi. 4. The mosquito takes a human blood meal and ingests microfilariae (worm like sheathed eggs) that circulate in the human blood stream. 5 7 In the mosquito, the microfilariae shed sheaths, penetrate the midgut, and migrate to the thoracic muscles were the microfilariae increase in size, molt, and develop into infective larvae (L1 and L3) over a span of 7–21 days. No multiplication or sexual reproduction of microfilariae occurs in the mosquito. 8 1 The infective larvae (L3) migrate to the salivary glands, enter the proboscis and escape onto human skin when the mosquito takes another blood meal. Human: B. malayi undergoes further development in the human as well as sexual reproduction and egg production. 1 2 The infective larvae (L3) actively penetrate the skin through the bite hole and develop into adults in the lymphatic system over a span of 6 months. Adult worms can survive in the lymphatic system for 5–15 years
3. The male and female adult worms mate and the females produce an average of 10,000 sheathed eggs (microfilaria) daily Adults are typically smaller than adult W. bancrofti, though few adults have been isolated. Female adult worms (50 mm) are larger than male worms (25 mm).

B. malayi microfilariae are 200–275  µm in length and have a round anterior end and a pointed posterior end. The microfilariae are sheathed, which stains heavily with Giemsa. The sheath is actually the egg shell, a thin layer that surrounds the egg shell as the microfilariae circulates in the bloodstream. The microfilariae retain the sheath until they are digested in the mosquito midgut.

B. malayi is transmitted by a mosquito vector. The principal mosquito vectors include Mansonia, Anopheles, and Aedes mosquitoes. Thus those at greatest risk for infection are individuals living in endemic areas—short term tourists are unlikely to develop lymphatic filariasis.

Tender or enlarged inguinal lymph nodes or swelling in the extremities can alert physicians or public health officials to infection. With appropriate laboratory equipment, microscopic examination of differential morphological features of microfilariae in stained blood films can aid diagnosis—in particular the examination of the tail portion, the presence of a sheath, and the size of the cephalic space. The ICT antigen card test is widely used in the diagnosis of W. bancrofti, but commercial antigens of B. malayi have not been widely available. However, new research developments have identified a recombinant antigen (BmR1) that is both specific and sensitive in the detection of IgG4 antibodies against B. malayi and B. timori in an enzyme linked immunosorbent assay and an immunochromatographic rapid dipstick (Brugia Rapid) test. However, it appears that immunoreactivity to this antigen is variable in individuals infected with other filarial nematodes. This research has led to the development of two new rapid immunochromatographic IgG4 cassette tests – WB rapid and PanLF rapid – which detect Bancroftian filariasis and all three species of lymphatic filariasis, respectively, with high sensitivity and selectivity.

Vector control has been effective in virtually eliminating lymphatic filariasis in some regions, but vector control combined with chemotherapy produces the best results. It is suggested that 11 to 12 years of effective vector control may eliminate lymphatic filariasis. Successful methods of B. malayi vector control include residual house spraying using DDT and insecticide treated bednets. Mansonia larvae attach their breathing tubes to underwater roots and plants in order to survive. While chemical larvicides have only provided partial control, plant removal could prevent vector development, but also potential adverse effects on the aquatic environment. Lymphatic filariasis vector control is neglected in comparison to the far more established efforts to control malaria and dengue vectors. Integrated vector control methods should be applied in areas where the same mosquito species is responsible for transmitting multiple pathogens.

The Global Alliance to Eliminate Lymphatic Filariasis was launched by the World Health Organization in 2000 with two primary goals: 1) to interrupt transmission and 2) to alleviate the suffering of affected individuals. Mass drug treatment programs are the main strategy for interrupting parasite transmission, and morbidity management, focusing on hygiene, improves the quality of life of infected individuals.

A goal of community based efforts is to eliminate microfilariae from the blood of infected individuals in order to prevent transmission to the mosquito. This is primarily accomplished through the use of drugs. The treatment for B. malayi infection is the same as for Bancroftian filariasis. Diethylcarbamazine has been used in mass treatment programs as an effective microfilaricidal drug in several locations, including India. While diethylcarbamazine tends to cause adverse reactions like immediate fever and weakness, it is not known to cause any long term adverse drug effects. It has been shown to kill both adult worms and microfilariae. In Malaysia, diethylcarbamazine dosages (6 mg/kg weekly for 6 weeks; 6 mg/kg daily for 9 days) reduced microfilariae by 80% for 18–24 months after treatment in the absence of mosquito control. Since the discovery of the importance of Wolbachia bacteria in the life cycle of B. malayi and other nematodes, novel drug efforts have targeted the endobacterium. Tetracyclines, rifampicin, and chloramphenicol have been effective in vitro by interfering with larvae molting and microfilariae development. Tetracyclines have been shown to cause reproductive and embryogenesis abnormalities in the adult worms, resulting in worm sterility. Clinical trials have demonstrated the successful reduction of Wolbachia and microfilariae in onchocerciasis and W. bancrofti infected patients. These antibiotics, while acting through a slightly more indirect route, are promising antifilarial drugs.

Secondary bacterial infection is often observed with lymphatic filariasis. Rigorous hygiene practices, including washing with soap and water daily and disinfecting wounds can help heal infected surfaces, and slow and potentially reverse existing tissue damage. Promoting hygiene is essential for lymphatic filariasis patients given the compromised immune and damaged lymphatic systems and can help prevent suffering and disability. This involves mass drug administration (MDA), where entire at risk populations are treated annually with safe medicine combinations. The medicines used in MDA are primarily effective against the microfilariae, the immature larvae of the parasite, and have limited effects on the adult worms.

B. malayi infects 13 million people in south and southeast Asia and is responsible for nearly 10% of the world's total cases of lymphatic filariasis. Despite epidemiological studies identifying Filaria malayi in India, Sri Lanka, China, North Vietnam, and Malaysia in the 1930s, Lichtenstein and Brug's hypothesis was not accepted until the 1940s, when Rao and Mapelstone identified two adult worms in India. Based on the similarities with W. bancrofti, Rao and Mapelstone proposed to call the parasite Wuchereria malayi.

The relationship between the Wolbachia bacteria and B. malayi is not fully understood. Extrapolating from research done with Wuchereria bancrofti, another nematode that causes filariasis, Wolbachia may aid in embryogenesis of the worm, be responsible for potent inflammatory responses from macrophages and filarial disease, and be linked to the onset of lymphedema and blindness sometimes associated with B. malayi infections. In a study done by the University of Bonn in Ghana, doxycycline effectively depleted Wolbachia from W. bancrofti. It is likely that the mechanism of doxycycline is similar to that in other filarial species, i. e., a predominant blockade of embryogenesis, leading to a decline of microfilariae according to their half life. This could render doxycycline treatment an additional tool for the treatment of microfilaria associated diseases in Bancroftian filariasis, along with B. malayi fiariasis. The course of treatment with doxycycline could be much shorter as it would make the adult worm sterile in one shot rather than repeatedly have to target the replenished larvae that current treatments kill, and there would be fewer side effects for the infected individual.

Another hopeful use for the research is in the area of transplant research. Because the B. malayi genome is the first parasitic genome to have been sequenced, the implications on the mechanism of parasitism in humans are crucial to understand. According to Alan L. Scott, Ph. D., a collaborator at Johns Hopkins University, understanding how a particular parasite, such as B. malayi, can adapt to humans, may yield medical benefits far beyond treating elephantiasis. According to the author, "This worm can reside in the host for years and not necessarily cause disease, in fact the less disease the individual has, the more worms there are in circulation. Now that we know those genes don't exist in humans we can target them to control disease." Some of the predicted proteins for these new genes appear similar to known immuno modulator proteins, regulators of the immune system, suggesting that they are involved in deactivating the host's immune system to ensure the parasite remains undetected. Knowledge of these previously unknown immune suppressors could also be of use in organ transplants and to help treat autoimmune disease. According to the Filarial Genome Project being done by The Special Programme for Research and Training in Tropical Diseases, the Brugia malayi MIF gene is expressed in all life cycle stages of the parasite, and results suggest that B. malayi MIF may interact with the human immune system during the course of infection by altering the function of macrophages in the infected individual. Studies are currently testing the hypothesis that MIF may be involved in reducing the host's immune response to the microfilariae. Understanding how this particular parasite has adapted to humans may help organ transplant researchers by figuring out how to prevent the immune system from attacking the transplanted tissue.