Brugia malayi

Taxobox
name = "Brugia malayi"


image_width = 240px
image_caption = "B. malayi", blood smear, Giemsa stain.
regnum = Animalia
phylum = Nematoda
classis = Secernentea
ordo = Spirurida
familia = Filariidae
genus = "Brugia"
species = "B. malayi"
binomial = "Brugia malayi"
binomial_authority = Brug 1927

"Brugia malayi" is a filarial roundworm which causes filariasis in humans.cite book | author = Cross JH | title = Filarial Nematodes. "In:" Baron's Medical Microbiology "(Baron S "et al", eds.)| edition = 4th ed. | publisher = Univ of Texas Medical Branch | year = 1996 | id = [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.section.4949 (via NCBI Bookshelf)] ISBN 0-9631172-1-1 ] Identified by Lichtenstein and named by Brug in 1927 as distinct from "Wuchereria bancrofti", they called it "Filaria malayi". In 1958 the separate genus "Brugia" was proposed by Buckley, and "Filaria malayi" became known as "Brugia malayi".

"B. malayi" is limited to tropical regions of Asia.

Life cycle

life cycle of "Brugia malayi".Infective larvae are transmitted by infected biting arthropods during a blood meal. The larvae migrate to the appropriate site of the host's body, where they develop into microfilariae-producing adults. The adults dwell in various human tissues where they can live for several years. The agents of lymphatic filariasis reside in lymphatic vessels and lymph nodes. "B. malayi" dwells particularly in the lymphatics, as with "Wuchereria bancrofti". The female worms produce microfilariae which circulate in the blood.

The microfilariae infect mosquitoes. Inside the mosquito, the microfilariae develop in 1 to 2 weeks into infective filariform (third-stage) larvae. During a subsequent blood meal by the insect, the larvae infect the vertebrate host. They migrate to the lymphatics, where they develop into adults, a slow process that can require up to 18 months.

Recently "B. malayi" was found to contain an endosymbiotic bacterium, "Wolbachia", in all life stages.cite journal | author=Taylor MJ | title=A new insight into the pathogenesis of filarial disease | journal=Curr Mol Med | year=2002 | pages=299–302 | volume=2 | issue=3 | pmid=12041732 | doi=10.2174/1566524024605662 ] The genome sequence of this bacterium was determined at New England Biolabs. Experimental results indicate that the "Wolbachia" can be killed by treatment of the human host with doxycycline. Nematodes cured of the Wolbachia are sterile and have increased morbidity.

Laboratory diagnosis

Identification of microfilariae by microscopic examination is the most practical diagnostic procedure.

Examination of blood samples will allow identification of microfilariae of Brugia malayi. It is important to time the blood collection with the known periodicity of the microfilariae. The blood sample can be a thick smear, stained with Giemsa or hematoxylin and eosin. For increased sensitivity, concentration techniques can be used. These include centrifugation of the blood sample lyzed in 2% formalin (Knott's technique), or filtration through a Nucleopore membrane.

Antigen detection using an immunoassay for circulating filarial antigens constitutes a useful diagnostic approach, because microfilaremia can be low and variable. Molecular diagnosis using polymerase chain reaction is also possible.

Identification of adult worms is possible from tissue samples collected during nodulectomies (onchocerciasis), or during subcutaneous biopsies or worm removal from the eye (loiasis).

Genome deciphered

On September 20, 2007, scientists sequenced the genome of "Brugia malayi". Identifying the genes of this organism might lead to development of new drugs and vaccines. [ [http://www.reuters.com/article/scienceNews/idUSN2042109920070920 Reuters, Genome deciphered for elephantiasis-causing worm] ] in the paper "Draft Genome for the Filarial Nematode Parasite Brugia Malayi" by Elodie Ghedin, et al Science 317, 1756 (2007); DOI:10.1126/science.1145406

To decipher the genome, “Whole Genome Shotgun Sequencing” was performed. The genome was found to be approximately 90-95 mega bases in size. The results of the sequencing was then compared to that of the C.elegans, along with its prototype C.briggsae. These other organisms were incorporated in the study and proved to be important for several reasons:
*comparing genomes using C.elegans was extremely beneficial in identifying similar linkages in genes.
**the researchers found a genomic conservation
**also found data that supported an absence of conservation at a more local gene level
***This demonstrated that rearrangements had occurred over time between the C.elegans and B.malayi and allowed researchers to identify genes or proteins that were more specific to B.malayi
***These unique genes were significant because they could have lead to the parasitism seen in B.malayi, and would therefore be seen as appropriate targets for future studies.
*gene linkages offer new insight into the evolutionary trend of parasitic genes that could possess clues to further explain their unique ability to successfully survive for many years in human hosts.

Potential for New Drugs to Treat B. Malayi

Sequence comparisons between the two genomes allow us to map C. elegans orthologs to B. malayi genes. Using these orthology mappings (between C. elegans and B.malayi) and by incorporating the extensive genomic and functional genomic data, including genome-wide RNAi screens, that already exist for C. elegans, we identify potentially essential genes in B. malayi. Scientists are hoping to be able to use these genes as potential new drug targets for new drug treatments. The longevity of this parasite complicates treatment because existing drugs target the larvae and, thus, do not completely kill the worms. The drugs often must be taken periodically for years, and the worm can cause a massive immune reaction when it dies and releases foreign molecules in the body. Drug treatments for filariasis have not changed significantly in over 20 years, and with the risk of resistance rising, there is an urgent need for the development of new anti-filarial drug therapies. From the genome sequence, Dr. Ghedin and her co-investigators identified several metabolic pathways containing dozens of gene products that they believe are likely to be helpful for the discovery of more targeted and effective drug therapies.
*Possible new drug targets include:
**molting
**nuclear receptors
**collagens and collagen processing
**neuronal signaling
**the B.Malayi kinome
**reliance on host (B.malayi) and endosymbiont (Wolbachia) metabolism.

These potential new targets for drugs or vaccines should provide new opportunities for understanding, treating and preventing elephantiasis.

Endosymbiotic Relationship of Brugia Malayi with Wolbachia

The relationship between the bacteria wolbachi and B. malayi is not fully understood. Some theories based on research done with W. bancrofti, another worm that causes filariasis, believe that Wolbachi may: aids in embryogenesis for the worm, be responsible for potent inflammatory responses from macrophages and filarial disease, and may be linked to the onset of lyphodema and blindness sometimes associated with B. malayi infections. According to a study done by University of Bonn in Ghana, doxycycline was effective in depleting 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 doxycycline course of treatment would be much shorter as it would be able to target the adult worm rather than the larvae current treatments kill, and there would be fewer side effects for the infected individual.

Genome use in Transplant Research

Another hopeful use for the research is in the area of transplant research. Due to the fact that 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 John Hopkins University, it is this understanding of how a particular parasite, such as B.malayi, which can adapt to humans, that 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 to be 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.

A specific gene of interest is the Brugia malayi MIF (macrophage migration inhibition factor) gene. 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, and studies are currently testing the hypothesis that MIF may be involved in reducing the host’s immune response to the filarial parasite.

According to the Filarial Genome Project being done by The Special Programme for Research and Training in Tropical Diseases (TDR), 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. TDR also states that studies are currently testing the hypothesis that MIF may be involved in reducing the host’s immune response to the filarial parasite. 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.

Overall hope for the use of the Genome Sequencing

The genomic information gives us a better understanding of what genes are important for different processes in the parasite’s life cycle. So, it will now be possible to target these genes more specifically and interrupt its life cycle. And, understanding how this particular parasite has adapted to humans may yield medical benefits far beyond treating elephantiasis, says collaborator Alan L. Scott, Ph.D., of the Bloomberg School of Public Health at Johns Hopkins University. “Parasitic worms are a lot like foreign tissue that has been transplanted into the human body. But unlike baboon hearts or pig kidneys, which the immune system quickly recognizes as foreign and rejects, worms can survive for years in the body. Discovering how they do so may someday benefit transplant surgery,” explained Dr. Scott.

References

*The article is based on the public domain (U.S. Government website) source [http://www.dpd.cdc.gov/dpdx/HTML/Filariasis.htm US Dept. of Health and Human Services / Center for Disease Control: Filariasis]
* [http://www.filariasiscenter.org/news/dance.html "Brugia malayi" worm dance video by R. Rao. Ph.D]
* [http://animaldiversity.ummz.umich.edu/site/accounts/information/Brugia_malayi.html "Brugia malayi" at UMich]

*The Special Programme for Research and Training in Tropical Diseases (TDR). “Functional analysis of Brugia malayi genes”. 2004. http://www.who.int/tdr/research/progress/fil_str/function.htm

*University of Pittsburgh. “Researchers reveal genetic secrets of devastating human parasite”. 20 September 2007. http://www.physorg.com/news109517312.html

*Hoerauf, Achim. “Targeting wolbachia, doxycycline reduces pathology of lymphatic filariasis”. 18, September 2006. http://www.eurekalert.org/pub_releases/2006-09/plos-twd091806.php