Associate Professor of Internal Medicine and Adjunct Associate Professor of Microbiology and Immunology
MAIT cells, Cholera, Oral Vaccines, Diarrheal Diseases
Mucosal Associated Invariant T (MAIT) cells in Mucosal Infections
MAIT cells are recently identified innate-like lymphocytes. They are primarily found in mucosal tissues and represent up to 10% of circulating T cells in humans. They are restricted by MR1, the non-classical MHC class I related protein, and MAIT ligands belong to a class of transitory intermediates of the riboflavin synthesis pathway. MAITs are capable of releasing both pro- and anti- inflammatory cytokines in response to stimulation, and possess cytotoxic activity
We have recently reported that MAIT cells are activated in cholera and are associated with higher class-switched V. choleraepolysaccharide-specific antibody responses. In pilot studies, we have identified a subset of MAIT cells that express genes associated with B cell help. Additionally, in in vitro experiments, we show that MAIT cells can induce B cells to differentiate and produce antibodies. Thus, in collaboration with the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), we are examining the role that MAIT cells play in the adaptive response against V. cholerae infection and vaccination. We are characterizing the clonal expansions of MAIT cells during human V. cholerae infection and oral cholera vaccination. At the same time, we are examining the mechanisms through which MAIT cells affect B cell differentiation and antibody production. Through these studies, we hope to gain new information on the capacity of MAIT cells to impact polysaccharide-specific antibody responses, which are associated with protection against cholera. This information has the potential to critically inform the development of better vaccine strategies targeted at preventing cholera and other enteric infections in young children.
Recent studies have found that septic patients have an early decrease in circulating MAITs, associated with an increased risk of secondary infections. We have found that MAITs from septic patients are highly dysfunctional, and that animals deficient in MAITs have a much higher mortality from experimental sepsis. Our goal is to determine how MAIT cells contribute to protective host responses by regulating inflammatory mediators. We are using a number of immunologic, genomic, and epigenetic techniques to examine the role of MAIT cells in both human and experimental models of sepsis.
Estimating Cholera Burden with Cross-sectional Immunologic Data
Identifying key populations at high risk of cholera is essential to guide global efforts to fight cholera, including targeting use of the oral cholera vaccine. Current methods to estimate cholera burden are largely based on clinical reporting with infrequent microbiological confirmation. These methods are limited by the sporadic nature of outbreaks, poor surveillance infrastructure, and fundamental uncertainties in the number of asymptomatic or mildly symptomatic cases. Detection of immune responses in serum (serosurveillance) can provide a new avenue for rapid and accurate estimates of cholera exposure and risk. We currently do not understand what immunological and clinical parameters are most predictive of recent exposure, nor whether immune responses in areas with different levels of endemicity are similar. We are pioneering the use of longitudinal antibody response kinetics, paired with novel statistical and machine learning approaches, to provide generalizable tools to estimate the incidence of exposure to Vibrio cholerae from cross sectional serosurveys. In collaboration with scientists at the icddr,b in Bangladesh, GHESKIO in Haiti, Johns Hopkins, and University of Florida, we are developing models to estimate the time since exposure to Vibrio cholerae and exposure incidence from cross-sectional antibody profiles and demographic data from cohorts of patients in Bangladesh and Haiti. We are also working to optimize and validate field-adapted methods to measure cholera-specific antibodies, including the use of dried blood spotand lateral flow assays. Our goal is to develop new tools to measure susceptibility to cholera in a population. These tools will have the potential to transform cholera control efforts from the current reactive strategies to proactive ones, with the potential to contribute to disease elimination.
Development of Clinical Decision Tools for Management of Diarrhea of Children in High and Low Resource Settings
Diarrheal diseases are the among the leading cause of death in children worldwide, most of which occur in low-income countries. In high-income countries, pediatric diarrhea remains a major utilization of healthcare resources. Treatment of diarrhea is mostly empiric, with antibiotic use mostly based on clinical suspicion for bacterial causes. However, the majority of cases of diarrhea do not benefit from antibiotic use, and inappropriate use leads to toxicity and resistance. Furthermore, despite the increasing availability of rapid molecular testing, there is little data to base a decision of whom or when to test. Our goal is to develop and validate clinical decision tools for management of diarrheal illnesses in children of both high and low resource settings. In collaboration with investigators at Intermountain Healthcare and the University of Maryland, we are using machine learning and natural language processing methods to derive and validate such prediction tools. For a US-based prediction rule, we are using data from IMPACT, a study of 1200 children from 5 US Emergency Departments. For a prediction rule targeted at children in lower and middle-income country settings, we are using data from GEMS, a study of over 9400 children across 7 countries in sub-Saharan Africa and south Asia. Ultimately, we hope to make available of a number of clinical tools that healthcare workers worldwide can use for evidence-based care of children with diarrhea.
Respiratory Immune Dysregulation Following Intestinal Infection
The human intestinal and respiratory tracts share a common mucosal immune system. Infections of the intestine and respiratory tracts are the two most common infections occurring in children in low-resource settings. Very little is known of how an intestinal infection may affect the immunity and health of the respiratory tract. We are examining how lung immune responses changes during an intestinal infection, and if susceptibility to pneumonia challenge is affected. Our goal is to determine whether (and how) intestinal infections affect the lung, and whether intervening on intestinal infections could help prevent respiratory health problems.
Our Research is Funded by the Following:
NIH/NIAID (R01AI130378, R01AI135114, R01AI135115)
Bill & Melinda Gates Foundation (OPP1198876)
References (Selected Publications)
- Bhuiyan TR, Rahman MA, Trivedi S, Afroz T, Al Banna H, Hoq MR, Pop I, Jensen O, Rashu R, Uddin MI, Hossain M, Khan AI, Chowdhury F, Harris JB, Calderwood SB, Ryan ET, Qadri F, Leung DT. Mucosal-Associated Invariant T (MAIT) cells are highly activated in duodenal tissue of humans with Vibrio cholerae O1 infection: A preliminary report. PLoS Negl Trop Dis. 2022 May 12;16(5):e0010411. doi: 10.1371/journal.pntd.0010411.
- Garbern SC, Nelson EJ, Nasrin S, Keita AM, Brintz BJ, Gainey M, Badji H, Nasrin D, Howard J, Taniuchi M, Platts-Mills JA, Kotloff KL, Haque R, Levine AC, Sow SO, Alam NH, Leung DT. External validation of a mobile clinical decision support system for diarrhea etiology prediction in children: a multicenter study in Bangladesh and Mali. Elife. 2022 Feb 9;11:e72294. doi: 10.7554/eLife.72294.
- Pender MA, Smith T, Brintz BJ, Pandey P, Shrestha SK, Anuras S, Demons S, Sornsakrin S, Bodhidatta L, Platts-Mills JA, Leung DT. Weather variables as important clinical predictors of bacterial diarrhea among international travelers. J Travel Med. 2022 Feb 3:taac012. doi: 10.1093/jtm/taac012.
- Jensen O, Trivedi S, Meier JD, Fairfax KC, Hale JS, Leung DT. A subset of follicular helper-like MAIT cells can provide B cell help and support antibody production in the mucosa. Sci Immunol . 2022 Jan 14;7(67):eabe8931. doi: 10.1126/sciimmunol.abe8931.
- Bhuiyan MD, Brintz B, Whitcombe AL, Markmann AJ, Bartelt LA, Moreland MJ, Azman AS, Leung DT. Combining antibody markers for serosurveillance of SARS-CoV-2 to estimate seroprevalence and time-since-infection. Epidemiology & Infection, 150, E20. doi:10.1017/S0950268821002764.
- Wahlig TA, Brintz BJ, Prettyman M, Azman AS, Leung DT. A Novel Luminescence-Based Serum Bactericidal Assay for Vibrio cholerae Reduces Assay Variation, Is Time- and Cost-Effective, and Directly Measures Continuous Titer Values. Am J Trop Med Hyg. 2021 Jul 8;105(3):622-626.
- Trivedi S, Grossmann AH, Jensen O, Cody MJ, Wahlig TA, Hayakawa Serpa P, Langelier C, Warren KJ, Yost CC, Leung DT. Intestinal Infection Is Associated With Impaired Lung Innate Immunity to Secondary Respiratory Infection. Open Forum Infect Dis. 2021 May 7;8(6):ofab237.
- Trivedi S, Afroz T, Bennett MS, Angell K, Barros F, Nell RA, Ying J, Spivak AM, Leung DT. Diverse Mucosal-Associated Invariant TCR Usage in HIV Infection. Immunohorizons. 2021 May 27;5(5):360-369.
- Chen X, Chen Z, Azman AS, Deng X, Sun R, Zhao Z, Zheng N, Chen X, Lu W, Zhuang T, Yang J, Viboud C, Ajelli M, Leung DT*, Yu H*. Serological evidence of human infection with SARS-CoV-2: a systematic review and meta-analysis. Lancet Glob Health. 2021 Mar 8:S2214-109X(21)00026-7.
- Reimer JR, Ahmed SM, Brintz B, Shah RU, Keegan LT, Ferrari MJ*, Leung DT*. Using a clinical prediction rule to prioritize diagnostic testing leads to reduced transmission and hospital burden: A modeling example of early SARS-CoV-2. Clin Infect Dis. 2021 Feb 23:ciab177.
- Ahmed SM, Shah RU, Fernandez V, Grineski S, Brintz B, Samore MH, Ferrari MJ, Leung DT*, Keegan LT*. Robust Testing in Outpatient Settings to Explore COVID-19 Epidemiology: Disparities in Race/Ethnicity and Age, Salt Lake County, Utah, 2020. Public Health Rep. 2021 Feb 4:33354920988612. *co-senior authors
- Brintz BJ, Haaland B, Howard J, Chao DL, Proctor JL, Khan AI, Ahmed SM, Keegan LT, Greene T, Keita AM, Kotloff KL, Platts-Mills JA, Nelson EJ, Levine AC, Pavia AT, Leung DT. A modular approach to integrating multiple data sources into real-time clinical prediction for pediatric diarrhea. Elife. 2021 Feb 2;10:e63009.
- Trivedi S, Labuz D, Anderson CP, Araujo CV, Blair A, Middleton EA, Jensen O, Tran A, Mulvey MA, Campbell RA, Hale JS, Rondina MT*, Leung DT*. Mucosal-associated invariant T (MAIT) cells mediate protective host responses in sepsis. Elife. 2020 Nov 9;9:e55615.
- Brintz BJ, Howard JI, Haaland B, Platts-Mills JA, Greene T, Levine AC, Nelson EJ, Pavia AT, Kotloff KL, Leung DT. Clinical predictors for etiology of acute diarrhea in children in resource-limited settings. PLoS Negl Trop Dis. 2020 Oct 9;14(10):e0008677.
- Diep TT, Jensen O, Van Thuong N, Nhi NTN, Thu NNA, Quang VN, Hieu TC, Thang HA, Thuy ND, Thang HV, Tuyen HT, Ngan LD, Ha NTT, Dung TD, Anderson CP, Azman AS, Leung DT. Sero-evaluation of Immune Responses to Vibrio cholerae in a Postelimination Setting. Open Forum Infect Dis. 2020 Apr 21;7(5):ofaa136.
- Bryant JE, Azman AS, Ferrari MJ, Arnold BF, Boni MF, Boum Y, Hayford K, Luquero FJ, Mina MJ, Rodriguez-Barraquer I, Wu JT, Wade D, Vernet G, Leung DT. Serology for SARS-CoV-2: Apprehensions, opportunities, and the path forward. Sci Immunol. 2020 May 19;5(47):eabc6347.
- Langelier C, Graves M, Kalantar K, Caldera S, Durrant R, Fisher M, Backman R, Tanner W, DeRisi JL, Leung DT. Microbiome and Antimicrobial Resistance Gene Dynamics in International Travelers. Emerg Infect Dis. 2019 Jul;25(7):1380-1383.
- Azman AS, Lessler J, Luquero FJ, Bhuiyan TR, Khan AI, Chowdhury F, Kabir A, Gurwith M, Weil AA, Harris JB, Calderwood SB, Ryan ET, Qadri F, Leung DT. Estimating cholera incidence with cross-sectional serology. Sci Transl Med. 2019 Feb 20;11(480).
- Iyer AS, Azman AS, Bouhenia M, Deng LO, Anderson CP, Graves M, Kováč P, Xu P, Ryan ET, Harris JB, Sack DA, Luquero FJ, Leung DT. Dried Blood Spots for Measuring Vibrio cholerae-specific Immune Responses. PLoS Negl Trop Dis. 2018 Jan 29;12(1):e0006196.
- Leung DT, LaRocque RC, Ryan ET. Travel Medicine. Ann Intern Med. 2018 Jan 2;168(1):ITC1-ITC16.
- Bliss J, Bouhenia M, Hale P, Couturier BA, Iyer AS, Rumunu J, Martin S, Wamala JF, Abubakar A, Sack DA, Luquero FJ, Couturier MR, Azman AS, Leung DT. High Prevalence of Shigella or Enteroinvasive Escherichia coli Carriage among Residents of an Internally Displaced Persons Camp in South Sudan. Am J Trop Med Hyg. 2018 Feb;98(2):595-597.
- Bennett MS, Trivedi S, Iyer AS, Hale JS, Leung DT (2017). Human mucosal-associated invariant T (MAIT) cells possess capacity for B-cell help. J Leukoc Biol.
- Andrews JR, Leung DT, Ahmed S, Malek MA, Ahmed D, Begum Y, Qadri F, Ahmed T, Faruque ASG, Nelson EJ (2017). Determinants of life-threatening diarrheal disease at hospital presentation: evidence from 22 years of admissions in Bangladesh. PLoS Negl Trop Diseases 11(4): e0005512.
- Gruninger RJ, Johnson RA, Das SK, Nelson EJ, Spivak ES, Contreras JR, Faruque AS, Leung DT (2017). Socioeconomic Determinants of Ciprofloxacin-resistant Shigella Infections in Bangladeshi Children. Pathog Immun.
- Michal Stevens A, Esposito DH, Stoney RJ, Hamer DH, Flores-Figueroa J, Bottieau E, Connor BA, Gkrania-Klotsas E, Goorhuis A, Hynes NA, Libman M, Lopez-Velez R, McCarthy AE, von Sonnenburg F, Schwartz E, van Genderen PJ, Scott Benson L, Leung DT (2017). Clostridium difficile infection in returning travellers.LID – 10.1093/jtm/taw099 [doi]. J Travel Med, 24(3).
- Uddin MI, Islam S, Nishat NS, Hossain M, Rafique TA, Rashu R, Hoq MR, Zhang Y, Saha A, Harris JB, Calderwood SB, Bhuiyan TR, Ryan ET, Leung DT, Qadri F (2016). Biomarkers of Environmental Enteropathy are Positively Associated with Immune Responses to an Oral Cholera Vaccine in Bangladeshi Children. PLoS Negl Trop Dis, 10(11), e0005039.
- Tsuha S, Taniguchi T, Shiiki S, Narita M, Leung DT (2016). Clinical characteristics of laboratory-confirmed leptospirosis in Okinawa, Japan, 1974-2015: high incidence of Jarisch-Herxheimer reaction. Trans R son Trop Med Hyg, 110(9), 558-565.
- Iyer, AS, Bouhenia M, Rumunu J, Abubakar A, Gruninger RJ, Pita J, Lino RL, Deng LL, Wamala JF, Ryan ET, Martin S, Legros D, Lessler J, Sack DA, Luquero FJ, Leung DT, Azman AS (2016). Immune Responses to an Oral Cholera Vaccine in Internally Displaced Persons in South Sudan. Sci Rep, 6, 35742.
- Bennett MS, Round JL, Leung DT (2015). Innate-like lymphocytes in intestinal infections. Curr Opin Infect Dis. (5):457-63.
- Leung DT, Bhuiyan TR, Nishat NS, Hoq MR, Aktar A, Rahman MA, Uddin T, Khan AI, Chowdhury F, Charles RC, Harris JB, Calderwood SB, Qadri F, Ryan ET (2014). Circulating Mucosal Associated Invariant T cells are Activated in Vibrio cholerae O1 Infection and Associated with Lipopolysaccharide Antibody Responses. PLoS Negl Trop Dis. 8(8):e3076.