Gnathostoma Spinigerum: Epidemiology and Potential Immunological Response

As travel and international commerce has increased so too has the reported cases of Gnathostoma spinigerum infections. As the prevalence of this parasite increases it may become an important organism in global health and economics. This paper is aimed at discussing the pathology and epidemiology of Gnathostoma. Points of focus are history, global distribution, lifecycle, and the occurrence of human infection including: diagnosis, treatment, and prevention. Moreover, this paper focuses on current research pertaining to Gnathostoma infection in humans and proposes additional research that may help in defining the differences between human and other mammalian nematode infections. Specifically it proposes research focusing on the immune response seen in humans and other animals with Gnathostoma spinigerum infections.

Literature Review

The parasite Gnathostoma spinigerum is a nematode that commonly infects cats, dogs, and other mammals, birds, crustaceans, frogs, and fish (Rojas-Molina et al., 1999). Gnathostoma spinigerum was first described by Owen in 1836 when it was isolated from the stomach of a lion at London zoo (Daengsvang, 1971). The first human infection of Gnathostoma occurred in Thailand in 1889 (Unknown, 2010). Recently, Gnathostoma infection by humans has been on the rise and new infections are being seen in places where Gnathostoma previously did not exist. These infections though only occasionally life threatening can be traumatic and painful for the infected individual.

According to Moore et al. (2003) Gnathostoma spinigerum is endemic in South East Asia, but the organism's prevalence has been on the rise in Mexico, Peru, and Ecuador. Several cases have also been reported in Botswana, Africa (Herman et al., 2009). Adult forms have also been found in the United States, though no human infections caused in the US have been reported (Unknown, 2010). The spreading of this organism is linked to an increase in trade and travel between Asian countries and the rest of the world.

The body of the adult Gnathostoma spinigerum is cylindrical with a swollen anterior known as the head bulb, which possesses eight rings of curved hooks (Swellengrebel and Sterman, 1961). The whole of the nematode is covered in cuticular spines which help in differentiating this organism from similar ones such as Gnathostoma hispidum (Tseng, 2003). Larval forms of this nematode greatly resemble the adult form though they are smaller (Belding, 1958). Additionally, the larval forms have only four rings of curved hooks (Unknown, 2010).

Gnathostoma spinigerum is sexually dimorphic; the body of the female has a flattened anterior end while the male has "bluntly rounded ends" both anteriorly and posteriorly (Tseng 2003). Females are larger than males and range in size from 25-54 mm while males can be between 11-25 mm (Faust, 1956). Moreover, male's posses four caudal and two sessile papillae as well as a spicule, while females posses a vulva and only two papillae (Tseng, 2003). The eggs of Gnathostoma are nonembryonated, oval in shape, transparent with a mucoid plug and pitted outer shell (Swellengrebel and Sterman, 1961)

Gnathostoma spinigerum is estimated to have as many as thirty-six naturally occurring secondary intermediate hosts alone, which make the parasite difficult to avoid or eradicate (Tseng, 2003). As described by Saksirisampant et al. (2002) the lifecycle of Gnathostoma spinigerum is as follows: the organism's eggs mature and hatch in water and a first stage larva emerges. The eggs take on average 20 days to mature before the larva emerges (Swellengrebel and Sterman, 1961). If the organism is ingested by a copepod it then becomes a second stage larva (L2). For the L2 to advance to a third stage larvae (L3), the copepod must be ingested by another intermediate host such as a bird, frog, or snake. This host must in turn be ingested by their definitive host (domestic and wild, canines and felines as well as several other mammals) in order for the L3 to mature into an adult parasite.

Inside of their definitive host, the parasite reaches the stomach or duodnem which it then bores out of and travels to the liver, connective tissue, or other muscles where it is able to mature (Swellengrebel and Sterman, 1961). Once Gnathostoma spinigerum has matured it returns to the gastric wall where it stimulates the surrounding tissue resulting in the formation of a small tumor which can contain several male and female worms. Females attract the male worms through use of pheromones (Unknown, 2010). Copulation and reproduction takes place in these tumors and 148-195 days after initial infection of the host, the eggs are released and excreted in the host animal's feces (Faust, 1956). The larvae and adult worms live off of nutrients derived from the host's body fluids which the nematode is able to digest thanks to its pharyngeal glands and intestinal epithelium which produce the necessary digestive enzymes (Tseng, 2003).

Humans become infected by Gnathostoma when they consume undercooked poultry or fish infected with the L3, or when water that is contaminated with copepods that contain the L2 are ingested (Rojas-Molina et al., 1999). Recently, researchers have found a strong link between a popular Mexican dish known as ceviche and the occurrence of gnathostomiasis (Unknown, 2010).

Humans are paratenic hosts of Gnathostoma, and the larvae cannot mature outside of their definitive host (Saksirisampant et al., 2002). Interestingly, according to Daengsvang (1971) a similar scenario occurs in other primates. Therefore, the larvae migrate aimlessly through the body of the infected individual seeking a place to mature into adult worms (Moore et al., 2003). The cutaneous form of this disease occurs when the larvae are near the surface of the body. Migration in this part of the body causes occasional swelling of the skin and subcutaneous tissue; sometimes resulting in a mark known as a cutaneous larva migrans where the path of the larva can be seen (Moore et al, 2003). In some forms of cutaneous gnathostomiasis the larva have been known to spontaneously exit the body by boring through the skin (Tseng, 2003)

Another form of gnathostomiasis is the visceral form (Moore et al., 2003). In this form of gnathostomiasis the larva migrate to varying subcutaneous parts of the body including the GI tract, the brain, the pulmonary regions, ears, nose, throat and even the eyes of the victim (Unknown, 2010). In cases where the larva has migrated to the eye, symptoms ranging from iritis and uveitis, to hemorrhage and orbital cellulitis have been reported (Belding, 1958). Rarely, a larva migrates to the brain or spinal cord, resulting in damage to the central nervous system (Moore et al, 2003). In this scenario the individuals sometimes experience an acute meningitic illness resulting in paraplegia and radiculopathy (Moore et al., 2003). Other general symptoms of gnathostomiasis in humans include eosinophilia, hematuria, abscesses, angioneurotic edema, edema of the pharynx, and dyspnea; all of which are helpful with diagnosis (Belding, 1958).

Apart from the basic symptoms and blood tests to detect high eosinophil levels, doctors should ask infected individuals about prior travel to countries where Gnathostoma is endemic, thus an accurate patient history is helpful for diagnosis (Unknown, 2010). Immunoblots have also become a useful diagnostic tool particularly in cases that may not have clear cut symptoms. Immunoblots of those infected by Gnathostoma spinigerum show a prevalent band at 24kDa which is a L3 specific antigen (Anantaphruti et al., 2005). Other detection methods for Gnathostoma spinigerum include the use of ELISA which detects immunoglobulin G subclasses (Anantaphruti et al., 2005). Like many other parasites however, the only definitive way to know if someone is infected with Gnathostoma spinigerum is to isolate the larva. Despite diagnostic advances this parasitic disease is often under diagnosed due to the lack of knowledge about its symptoms and risk factors, leaving many individuals without treatment.

Without treatment, human victims who exhibit neurological symptoms have a 8-25 percent mortality rate (Tseng, 2003) Treatment of human gnathostomiasis is currently a twenty-one day course of 400 mg albendazole twice a day, coupled with 0.2 mg/kg ivermectin immediately or for two consecutive days (Herman et al., 2009). Surgical excision of Gnathostoma spinigerum formerly the only treatment method is also a possibility if medication is not available or effective (Moore et al., 2003). Often use of the previously mentioned drugs simply cause outward migration of the parasite allowing for the larvae to be picked out with a needle from the surface of the skin (Unknown, 2010) Recent findings in hepatitis C patients also indicate additional ways of combating this parasite through use of IFN alpha (Sangchan et al., 2006). INF alpha promotes the migration of Gnathostoma to the outside of the body. According to Sangchan et al. (2006) this spontaneous migration may be due to the suppression of interleukin-5 which is known to suppress migration of other parasites.

Prevention of gnathostomiasis infection involves thorough cooking of all fish in areas known to harbor Gnathostoma spinigerum (Belding, 1958). Many infected individuals are those who reside in third world countries, therefore prevention of this emerging parasitic problem is education about Gnathostoma symptoms and the benefits of cooking fish (Unknown, 2010).

Research Proposal

In humans and other primates the nematode parasite, Gnathostoma spinigerum is unable to mature resulting in aimless migration throughout the visceral and cutaneous regions of the hosts body. Likewise, in its definitive hosts, which include mammals such as dogs, cats, tigers, and pigs, the organism is able to travel from the gastric regions, mature, and then return to the gastric wall area for reproduction. What makes humans and some other primates different from the mammals that act as definitive hosts for this organism? I hypothesize that Gnathostoma infection in primates triggers a slightly different level of immune response that is not seen in the definitive hosts, resulting in the creation of a hostile environment that is not conducive to maturation.

Previous studies have proposed that interleukin- 5 suppresses the migration of some parasites including Gnathostoma spinigerum (Sangchan et al., 2006). This same study reports that use of interferon alpha promotes spontaneous outward migration of Gnathostoma through the skin. Interferon's are proteins that the immune system produces in response to parasites, viruses, and other foreign antigens. In humans eosinophilia is associated with infection of this tropical disease as is increased levels of IgG. Therefore this research study will look specifically at the levels of IgG, interferon's, interleukin-5, and the occurrence of eosinophilia in naturally infected humans (if available) and artificially infected primates, and cats.

The artificially infected organisms will be infected at the same time with L3 larvae that have been isolated from infected eels. Blood samples will be taken on a weekly basis for two months. Interferon prevalence will be measured through the use of a western blot, which will be examined for significant differences. Eosinophil levels can be measured and compared through a simple blood test. While, detection of IL-5 can be measured through use of ELIZA; IgG comparisons can also be made through the use of the ELIZA method. In human test subjects who have confirmed cases these tests will only be conducted based on one set of samples enabling the individual to commence treatment.

Once two months have elapsed the larvae are then excised from their host organism and examined for morphological changes that indicate maturation. Once the the samples have been processed and the previous tests completed a comparison can be made between the three organisms selected, and a conclusion can be made. If my hypothesis is correct then human/primate hosts and definitive hosts of Gnathostoma spinigerum have a slightly different immune response to this parasite.

Literature Cited

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Faust, E.C. (1956). Animal agents and vectors of human disease. Philadelphia, PA: Lea and Febiger.

Herman, J.S. , Wall, E.C. , Tulleken, C.V. , Godfrey-Faussett, P., & Bailey, R.L. . (2009). Gnathostomiasis acquired by British tourists in Botswana. Emerging Infectious Diseases, 15(4), Retrieved from www.cdc.gov/eid

Moore, D.A.J., McCroddan, J., Dekumyoy, P., & Chiodini, P.L. (2003). Gnathostomiasis: an emerging imported disease. Emerging Infectious Diseases, 9(6),

Rojas-Molina, N., Pedraza-Sanchez, S., Torres-Bibiano, B., Meza-Martinez, H., & Escobar-Gutierrez, A. (1999). Gnathostomosis, an emerging fooborne zoonotic disease in Acapulco, Mexico. Emerging Infectious Diseases, 5(2), 0-1.

Saksirisampant, W., Kulkaew, K. , Nuchproayoon, S. , Yentakham, S. , & Wiwanitkit, V. (2002). A Survey of the infective larvae of Gnathostoma spinigerum in swamp eels bought in a local market in Bangkok, Thailand. Annals of Tropical Medicine and Parasitology, 96(2), 191-195.

Sangchan, A., Sawanyawisuth, K., Intapan, P.M. , & Mahakkanukrauh, A. . (2006). Outward migration of gnathostoma spinigerum in interferon alpha treated hepatitis c patient. Parasitology International, 55, 31-32.

Swellengrebel, N.H., & Sterman, M.M. . (1961). Animal parasites in man. Princeton, NJ: D. Van Nostrand Company, Inc.

Tseng, J. 2003. "Gnathostoma spinigerum" (On-line), Animal Diversity Web. Accessed April 29, 2010 at http://animaldiversity.ummz.umich.edu/site/accounts/information/Gnathostoma_spinigerum.html.

Unknown Author. (2010). Online parasitological center for gnathostomiasis. Retrieved from http://www.stanford.edu/class/humbio103/ParaSites2001/gnathostomiasis/PAGES/index.htm