Major Areas of Research
- Treatment of neurocysticercosis
- Natural history, disease association, morbidity, prevention, and treatment of perilesional edema episodes associated with calcific cysticercosis
- Development of model cestodes infection to determine best treatments for neurocysticercosis
- Immune response associated with treatment and measures to ameliorate acute inflammatory responses
- Antigenic variation in Giardia, cellular biology, and differences among Giardia groups/isolates
The research goals of this program are to develop better treatments for neurocysticercosis through testing of treatments in vitro and in model systems in vivo, in human clinical trials, and by understanding the basis of the inflammatory immune response to theTaenia solium parasite. Research studies related to Giardia lamblia, a protozoan gastrointestinal-dwelling parasite that is the most common parasitic infection in the United States and worldwide is limited to collaborative activities. Clinical research studies of neurocysticercosis both at the National Institutes of Health (NIH) and in Lima, Peru, related to cysticercosis predominate. There are two laboratory components: a focused laboratory at NIH headed by Dr. Siddhartha Mahanty and another in Lima, Peru, headed by Drs. Nash, Mahanty, and Garcia, our major collaborator in Peru.
Neurocysticercosis is a brain infection of the larval stage of the tapeworm parasite T. solium. People who harbor the intestinal-dwelling tapeworm excrete large numbers of infectious ova in parasite segments called proglottids or as free eggs in the feces. Ova, when ingested by free-roaming pigs or accidently by humans, hatch, enter the intestinal wall, and are carried by the bloodstream to the host’s tissues, where they develop into viable cysts. These are found primarily in the brain, muscle, and subcutaneous tissues. Humans acquire tapeworms following ingestion of undercooked or raw pork.
Neurocysticercosis occurs after humans inadvertently ingest ova released by tapeworm carriers through person-to-person spread or by ingestion of fecally contaminated food or water. Close personal contacts and tapeworm carriers are most at risk. Almost all the important clinical manifestations are due to infection of the brain. Although the clinical manifestations and signs are particularly varied, the most common symptom is seizures. Neurocysticercosis is the most common cause of adult-acquired epilepsy and seizures worldwide and therefore is a major preventable and treatable illness.
Normally, viable cysts are clinically silent and invoke little discernable inflammatory response. However, when cysts die or are exposed to anthelmintic drugs, an intense immune response occurs, which results in seizures and/or mass effects. It is the control of inflammation that prevents brain injury, seizures, or mass effects. Degenerating cysts tend to calcify, and, because calcified cysts accumulate in the tissues and brain, they are found in a significant minority (10 to 20 percent) of endemic populations; it is frequently the only abnormality seen in patients who have seizures. Although previously thought to be inert, some calcified lesions are foci of seizure activity and are associated with the periodic occurrence of perilesional edema around calcified lesions. Our reports both at NIH and in Peru early on emphasized the real and potential clinical importance of this phenomenon.
Controlling the inflammatory response due to degenerating cysts is a major therapeutic dilemma. Although corticosteroids are commonly employed, their use has not been systemically studied. A trial investigating higher dosing and prolonged administration compared to conventional lower dosing of a shorter duration in the treatment of parenchymal disease is ongoing in Lima in collaboration with Dr. Garcia. We are in the forefront to characterize the importance, frequency, morbidity, pathophysiology, and treatment of perilesional edema at NIH and our study site in Lima.
Perilesional edema is associated with seizures and occurs in about 50 percent of those with calcifications and a history of seizures. Other studies at NIH include PET scanning of these patients using a newly developed peripheral benzodiazepine receptor ligand (Drs. Innis and Fujita), which is a marker of microglial activation and inflammation. Treatment trials and the incidence of perilesional edema in endemic populations are in the planning stages. In other studies we reported and continue to expand the use of methotrexate and other immunomodulatory agents as corticosteroid-sparing agents in the treatment of subarachnoid neurocysticercosis and other inflammatory conditions associated with the disease.
Dr. Mahanty has developed an animal model for cysticercosis due to T. solium brain infection by injecting small cysts of T. crassiceps, a related Taenia, into rat brains. As measured by MRI and direct microscopic observations, cysts grow and respond to anthelmintics treatment. This is the most appropriate brain model of neurocysticercosis, and it is being used to develop correlates of successful treatment and to evaluate regimens that control brain injury. We have developed a cestode parasite antigen assay in cerebrospinal fluid (CSF) and serum, as published by others, with modifications to determine its usefulness in assessment of treatment end points.
A laboratory in Peru headed by Drs. Mahanty, Nash, and Garcia employs the infected pig model and T. solium cysts to evaluate efficacy of drugs in vitro and in vivo to determine the immune response to T. solium in natural infection and after treatment. Responses to humans before and after treatment are also being studied in collaboration with Drs. Mahanty, Garcia, and Gilman. More recently we produced new monoclonal antibodies to T. solium and are employing these reagents to develop antigen assays that inform about the clinical state of patients.
Giardia infecting humans are caused by two unique types. The representative Group 1 and closely related Group 2 (Assemblage A) organism type Giardia, the WB isolate, has been sequenced, and a Group 3 or Assemblage B organism, isolate GS, has been partially sequenced and reported. Assemblage B, specifically the GS isolate, is biologically and genetically unique. Our studies, which are much more extensive than those published to date, expand on the differences between these groups and should definitively distinguish them as different species. Analysis of the variant-specific proteins WB reveals a variety of types and different possible controlling mechanisms. More recently in collaboration with Dr. Michael Grigg of the LPD, a more extensive genomic comparison confirmed our earliest grouping and showed significant exchange.
Drs. Nash and Mahanty head a group of physician/scientists to further studies on clinical neurocysticercosis. The group is in the process of collecting data retrospectively on previously treated patients and developing a multi-centered collaborative prospective study.
Dr. Nash received his M.D. from the University of Miami in 1968 and completed his internship and residency at Duke University. In 1970, he was appointed a fellow in the NIAID Laboratory of Clinical Investigation and, in 1973, became a staff fellow in the Laboratory of Parasitic Diseases (LPD). After an infectious disease fellowship at the Beth Israel-Children’s Hospital in Boston and a fellowship in biological chemistry at Harvard University, he returned to LPD as a senior scientist in 1976. He is currently a principal investigator in the Clinical Parasitology Section.
- American Society of Tropical Medicine and Hygiene
- American Society for Microbiology
- American Association for the Advancement of Science
- Infectious Diseases Society of America
- Alpha Omega Alpha
Nash TE, Garcia HH. Diagnosis and treatment of neurocysticercosis. Nat Rev Neurol. 2011 Sep 13;7(10):584-94.
Ooi WW, Wijemanne S, Thomas CB, Quezado M, Brown CR, Nash TE. A calcified Taenia solium granuloma associated with recurrent perilesional edema causing refractory seizures: histopathological features. Am J Trop Med Hyg. 2011 Sep;85(3):460-3.
Nash TE, Mahanty S, Garcia HH; Cysticercosis Group in Peru. Corticosteroid use in neurocysticercosis. Expert Rev Neurother. 2011 Aug;11(8);1175-83.
Ramanathan R, Talaat KR, Fedorko DP, Mahanty S, Nash TE. A species-specific approach to the use of non-antimony treatments for cutaneous leishmaniasis. Am J Top Med Hyg. 2011 Jan;84(1):109-17.
Nash TE, Pretell EJ, Lescano AG, Bustos JA, Gilman RH, Gonzalez AE, Garcia HH; Cysticercosis Working Group in Peru.Perilesional brain oedema and seizure activity in patients with calcified neurocysticercosis: a prospective cohort and nested case-control study. Lancet Neurol. 2008 Dec;7(12):1099-105.
Touz MC, Rópolo AS, Rivero MR, Vranych CV, Conrad JT, Svard SG, Nash TE. Arginine deiminase has multiple regulatory roles in the biology of Giardia lamblia. J Cell Sci. 2008 Sep 1;121(Pt 17):2930-8.
- Hector H. Garcia, M.D., Ph.D., Department of Microbiology, Universidad Peruana Cayetano Heredia, Lima, Peru
- Siddhartha Mahanty, M.D., NIAID
- Armando E. Gonzalez, D.V.M., Ph.D., Department of Public Health, School of Veterinary Medicine, Universidad Nacional Mayor de San Marcos, Lima, Peru
- Andres G. Lescano, Ph.D.
- Robert H. Gilman, M.D., D.T.M.H., Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
- Rod Adam, M.D., University of Arizona College of Medicine
- Steve Porcella, Ph.D., NIAID