Schistosomiasis Treatment

Genomics Research on Schistosomiasis

Schistosomiasis Vaccine Development

P’ng Loke, Ph.D.

Chief, Type 2 Immunity Section

Major Areas of Research

  • Type 2 cytokine (IL-4 and IL-13) activated macrophages during helminth infections
  • Role of microbiota during helminth infections
  • Genetic and environmental contributions towards immune variation between individuals
  • Helminth infections, inflammatory bowel diseases, metabolic syndrome, atherosclerosis, chronic inflammation

Biography

Dr. P’ng Loke completed his Ph.D. research at the University of Edinburgh on IL-4 activated macrophages responding to Brugia malayi filarial parasites in 2001. He then did postdoctoral research on costimulatory molecules at University of California-Berkeley and studied macrophage responses to different parasites at University of California-San Francisco. In 2009, he joined New York University School of Medicine as an assistant professor and was a tenured associate professor before he joined the Laboratory of Parasitic Diseases as a senior investigator in 2020.

Program Description

Our research goal is to understand the heterogeneity of type-2 immune responses during helminth infections. Although we have co-evolved with helminths and most infections are asymptomatic, these parasites can cause pathology in some individuals that either mount a response that is too strong or too weak during infection. An appropriately regulated type-2 response is critical in maintaining the balance between expelling enough parasites and tolerating the remaining parasites without excessive collateral tissue damage, in order to maintain the fitness of the host.

Type-2 immunity induced by helminth infections may be therapeutically beneficial for improving symptoms of inflammatory bowel diseases and metabolic syndrome, but this may also benefit only specific subsets of individuals. The mechanisms underlying the heterogeneity of type-2 responses between individuals still remains poorly understood. We believe that characterizing these mechanisms will enable us to develop strategies to utilize helminth infections as treatment for specific inflammatory conditions (e.g., autoimmune diseases and metabolic conditions) for the right individuals, as well as designing better approaches toward limiting pathology that is caused by helminth infections.

Our basic immunological studies on macrophage biology and our translational research studies on the microbiota are converging toward the goal of understanding factors that regulate variation of type-2 immune responses in humans. Using a combination of mouse models, as well as field and clinical studies, our future plans are to test some of the concepts that we have developed on chromatin remodeling in macrophage responses to type-2 cytokines, as well as helminth-microbiota interactions, in mouse models, field studies and also human challenge infections.

Research Group

Jian-Da Lin, Ph.D., Staff Scientist

Selected Publications

Lee SC, Tang MS, Easton AV, Devlin JC, Chua LL, Cho I, Moy FM, Khang TF, Lim YAL, Loke P. Linking the effects of helminth infection, diet and the gut microbiota with human whole-blood signatures. PLoS Pathog. 2019 Dec 16;15(12):e1008066.

Gundra UM, Girgis NM, Gonzalez M, Ouimet M, Tang MS, Vozhilla N, Fisher EA, Moore KJ, Loke P. Vitamin A mediates conversion of monocyte-derived macrophages into tissue-resident macrophages during alternative activation. Nature Immunology. 2017 Jun;18(6):642-653.

Ramanan D*, Bowcutt R*, Lee SC, Tang MS, Honda K, Gause WC, Lim YAL, Loke P**, Cadwell K**. Helminth infection promotes colonization resistance via type 2 immunity. Science. 2016 Apr 29;352(6285):608-12. * Equally contributing first authors. ** Equally contributing senior authors.

Gundra UM, Girgis NM, Ruckerl D, Jenkins S, Ward LN, Kurtz ZD, Wiens KE, Tang MS, Basu-Roy U, Mansukhani A, Allen JE, Loke P. Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct. Blood. 2014 May 15;123(20):e110-22.

Broadhurst MJ, Leung JM, Kashyap V, McCune JM, Mahadevan U, McKerrow JH, Loke P. IL-22+ CD4+ T cells are associated with therapeutic trichuris trichiura infection in an ulcerative colitis patient. Sci Transl Med. 2010 Dec 1;2(60):60ra88.

Visit PubMed for a complete publication list.

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Type 2 Immunity Section
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P’ng
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Loke
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Program Description

Our research goal is to understand the heterogeneity of type-2 immune responses during helminth infections. Although we have co-evolved with helminths and most infections are asymptomatic, these parasites can cause pathology in some individuals that either mount a response that is too strong or too weak during infection. An appropriately regulated type-2 response is critical in maintaining the balance between expelling enough parasites and tolerating the remaining parasites without excessive collateral tissue damage, in order to maintain the fitness of the host.

Type-2 immunity induced by helminth infections may be therapeutically beneficial for improving symptoms of inflammatory bowel diseases and metabolic syndrome, but this may also benefit only specific subsets of individuals. The mechanisms underlying the heterogeneity of type-2 responses between individuals still remains poorly understood. We believe that characterizing these mechanisms will enable us to develop strategies to utilize helminth infections as treatment for specific inflammatory conditions (e.g., autoimmune diseases and metabolic conditions) for the right individuals, as well as designing better approaches toward limiting pathology that is caused by helminth infections.

Our basic immunological studies on macrophage biology and our translational research studies on the microbiota are converging toward the goal of understanding factors that regulate variation of type-2 immune responses in humans. Using a combination of mouse models, as well as field and clinical studies, our future plans are to test some of the concepts that we have developed on chromatin remodeling in macrophage responses to type-2 cytokines, as well as helminth-microbiota interactions, in mouse models, field studies and also human challenge infections.

Selected Publications

Devlin JC, Axelrad J, Hine AM, Chang S, Sarkar S, Lin JD, Ruggles KV, Hudesman D, Cadwell K, Loke P. Single-Cell Transcriptional Survey of Ileal-Anal Pouch Immune Cells From Ulcerative Colitis Patients. Gastroenterology. 2021 Apr;160(5):1679-1693.

Gause WC, Rothlin C, Loke P. Heterogeneity in the initiation, development and function of type 2 immunity. Nat Rev Immunol. 2020 Oct;20(10):603-614.  

Lin JD, Devlin JC, Yeung F, McCauley C, Leung JM, Chen YH, Cronkite A, Hansen C, Drake-Dunn C, Ruggles KV, Cadwell K, Graham AL, Loke P. Rewilding Nod2 and Atg16l1 Mutant Mice Uncovers Genetic and Environmental Contributions to Microbial Responses and Immune Cell Composition. Cell Host Microbe. 2020 May 13;27(5):830-840.e4.

Lee SC, Tang MS, Easton AV, Devlin JC, Chua LL, Cho I, Moy FM, Khang TF, Lim YAL, Loke P. Linking the effects of helminth infection, diet and the gut microbiota with human whole-blood signatures. PLoS Pathog. 2019 Dec 16;15(12):e1008066.

Gundra UM, Girgis NM, Gonzalez MA, San Tang M, Van Der Zande HJP, Lin JD, Ouimet M, Ma LJ, Poles J, Vozhilla N, Fisher EA, Moore KJ, Loke P. Vitamin A mediates conversion of monocyte-derived macrophages into tissue-resident macrophages during alternative activation. Nat Immunol. 2017 Jun;18(6):642-653.

Ramanan D, Bowcutt R, Lee SC, Tang MS, Kurtz ZD, Ding Y, Honda K, Gause WC, Blaser MJ, Bonneau RA, Lim YA, Loke P, Cadwell K. Helminth infection promotes colonization resistance via type 2 immunity. Science. 2016 Apr 29;352(6285):608-12.

Visit PubMed for a complete publication list.

Additional Information

Training Program

NIH-Penn Immunology Graduate Partnership Program
https://www.med.upenn.edu/nih-igg-partnership/

Major Areas of Research
  • Type 2 cytokine (IL-4 and IL-13) activated macrophages during helminth infections
  • Role of microbiota during helminth infections
  • Genetic and environmental contributions towards immune variation between individuals
  • Helminth infections, inflammatory bowel diseases, metabolic syndrome, atherosclerosis, chronic inflammation
Research Group Page

Bioinformatics Resource Centers (BRCs) for Infectious Diseases

The NIAID-funded Bioinformatics Resource Centers provide data-driven, production-level, sustainable computational platforms to enable sharing and access to data, portable computational tools, and standards that support interoperability for the infectious diseases research community.

Systems Biology Consortium Resources

The Systems Biology Consortium for Infectious Diseases is a community of systems biologists who integrate experimental biology, computational tools and modeling across temporal and spatial scales to improve our understanding of infectious diseases. Through collaborative efforts, scientists test and validate hypotheses that drive innovation and discovery. The Consortium seeks to develop strategies that predict and alleviate disease severity and ultimately provide solutions to the world's most important health challenges.

Therapeutic Development Services

The Therapeutic Development Services program offers a collection of preclinical services to support the development of products intended for use in the cure, mitigation, diagnosis, or treatment of disease caused by a pathogen or certain toxins.

This is one of several programs provided by NIAID's Division of Microbiology and Infectious Diseases to support infectious disease product developers.

Tropical Medicine Research Centers (TMRCs)

Background

Neglected tropical diseases (NTDs) are a major global health problem affecting nearly 1.6 billion people, most of whom live in low- and middle-income countries. NTDs are caused by a wide range of organisms and can be transmitted by a variety of vectors and intermediate hosts (mosquitoes, sand flies, black flies, tsetse flies, triatomine insects, and snails) as well as by contaminated water, food, and soil. Since available medical or public health measures are currently inadequate to control most NTDs, research is urgently needed to identify and evaluate new tools and interventions. Efforts are also needed to strengthen local research capacity and infrastructure in endemic areas.

NIAID established the Tropical Medicine Research Centers (TMRC) program in 1991 to fund NTD research centers in disease-endemic countries. The centers are designed to conduct research on the cause, diagnosis, prevention, and treatment of NTDs, and to build in-country research capacity. The program has increased capacity of local TMRC awardees to support independent research activities, conduct future clinical trials, and implement new treatment, prevention, and vector control strategies.

The TMRC program has been renewed several times since 1991, most recently in 2022. At present the TMRC program includes seven centers with field sites in nine countries: Brazil, Ethiopia, India, Kenya, Peru, the Philippines, Sudan, Uganda, and Vietnam. In addition to the seven centers, a Coordinating Center was awarded in 2022 to facilitate collaboration and data sharing across the Program. 

For more information about the TMRC network, please visit https://tmrc-network.org.

Main Areas of Focus

  • To conduct research on NTDs such as schistosomiasis, hookworm infection, ascariasis, leishmaniasis, Chagas disease, lymphatic filariasis, foodborne trematodiases, leishmaniasis, and neurocysticercosis.
  • To support clinical and field site development.
  • To build capacity and enable TMRCs to conduct future clinical trials, implement new treatment and prevention strategies, and develop novel vector control strategies.

Locations

There are seven TMRCs worldwide, including two in Africa, two in South America, and three in Asia, that conduct clinical studies, implement new treatment and prevention strategies, and develop novel vector control strategies.

Sites and primary investigators 

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Vaccine and Treatment Evaluation Units (VTEUs) Services

The Vaccine and Treatment Evaluation Units (VTEUs), supported by the Division of Microbiology and Infectious Diseases (DMID) since the 1960s, provide a ready resource for the conduct of clinical trials to evaluate promising vaccines, treatments, and diagnostics for infectious diseases. The sites are part of DMID's Infectious Diseases Clinical Research Consortium (IDCRC).

Centers for Research on Structural Biology of Infectious Diseases (CRSTAL-ID)—Resources

The Centers for Research on Structural Biology of Infectious Diseases (CRSTAL-ID) provide the research community with: 3-D protein structures and protein-ligand complexes; Sequence-verified clones and peptides; Services that deliver requested 3-D structure determination; and Molecular screening of proteins in complex with inhibitors, cofactors and substrate analogs