Harris & LaRocque Laboratory
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About the Lab
Vibrio cholerae is the cause of cholera, a severe, rapidly dehydrating diarrheal illness. Much of the world’s population lives in areas without safe drinking water and is vulnerable to cholera. Cholera is endemic in many areas where it disproportionately affects children, and also occurs in large epidemics, such as the devastating epidemic that has followed the introduction of cholera into Haiti in 2010. Our research is focused on host-pathogen interactions and the innate and adaptive immune response to Vibrio cholerae, cholera vaccines, and in the area of susceptibility to cholera. We are invested in highly collaborative studies with a number of collaborators in the U.S. and in Bangladesh and Haiti where cholera is endemic.
The Harris & LaRocque Laboratory is committed to training of investigators at all levels of experience, and to collaborations that enhance clinical and research capacity in areas where cholera and other enteric infections are endemic.
B cell Responses to Cholera and Enteric Infections
Antibodies secreted at the mucosal surface are thought to be the critical mediators of protection against cholera and other enteric pathogens. Current projects include ongoing studies of human B cell responses to Vibrio cholerae infection and cholera vaccination in Haiti and in Bangladesh. We have shown that infection induces long lasting memory B cell responses which are associated with protective immunity. Some of our current work is focused on the use of single cell methods to evaluate early B cell responses in patients and other work is focused on responses to oral cholera vaccines.
Susceptibility to Cholera and Enteric Infection
It is likely that a number of factors influence susceptibility to cholera and enteric infection. These include prior exposure, nutritional status, colonization with other microbes, and innate immune factors. We are interested in the intrinsic host and environmental factors in household contacts of patients with cholera that predict protection as well as genetic factors that influence susceptibility to cholera and other infections.
Pathogen Interactions with Innate Immune System
We are working on clinical and in vitro studies to understand the human innate immune response to Vibrio cholerae, and, in turn, how these host-responses impact the pathogen and other communal organisms in the small intestine.
Chin CS*, Sorenson J*, Harris JB*, Robins WP, Charles RC, Jean-Charles RR, Bullard J, Webster DR, Kasarskis A, Peluso P, Paxinos EE, Yamaichi Y, Calderwood SB, Mekalanos JJ, Schadt EE, Waldor MK. The origin of the Haitian cholera outbreak strain. N Engl J Med. 2011 Jan 6;364(1):33-42. Epub 2010 Dec 9. PMID: 21142692
Kuchta A, Rahman T, Sennott EL, Bhuyian TR, Uddin T, Rashu R, Chowdhurry F, Kahn AI, Arifuzzaman M, Weil AA, Podolsky A, LaRocque RC, Ryan ET, Calderwood SB, Qadri F, Harris JB. Vibrio cholerae O1 Infection Induces Pro-inflammatory CD4+ T Cell Responses in Blood and Intestinal Mucosa of Infected Humans. Clin Vaccine Immunol. 2011 Aug;18(8):1371-7. Epub 2011 Jun 22. PMID:21697339
Shin OS, Uddin T, Citorik R, Wang JP, Della Pelle P, Kradin RL, Bingle CD, Camilli A, Ryan ET, Calderwood SB, Finberg RW, Qadri FQ, LaRocque RC, Harris JB. LPLUNC1 Modulates Innate Immune Responses to Vibrio cholerae. J Infect Dis. 2011 Nov; 204(9):1349-57. Epub 2011 Sep 7. PMID:21900486
Weil AA, Ivers LC, Harris JB. Cholera: lessons from Haiti and beyond. Curr Infect Dis Rep. 2012 Feb;14(1):1-8. PMID: 2217993
Harris JB, LaRocque RC, Qadri F, Ryan ET, Calderwood SB. Cholera. The Lancet. 2012 Jun 30;379(9835):2466-76. PMID: 22748592
Patel SM, Rahman MA, Mohasin M, Riyadh MA, Leung DT, Alam MM, Chowdhury F, Khan AI, Weil AA, Aktar A, Nazim M, Larocque RC, Ryan ET, Calderwood SB, Qadri F, Harris JB. Memory B cell responses to Vibrio cholerae O1 lipopolysaccharide are associated with protection against infection in household contacts of cholera patients in Bangladesh. Clin Vaccine Immunol. 2012 Apr 18. [Epub ahead of print] PMID: 22518009
Karlsson EK, Harris JB, Tabrizi S, Rahman A, Shlyakhter I, Patterson N, O'Dushlaine C, Schaffner SF, Gupta S, Chowdhury F, Sheikh A, Shin OS, Ellis C, Becker CE, Stuart LM, Calderwood SB, Ryan ET, Qadri F, Sabeti PC, Larocque RC. Natural selection in a Bangladeshi population from the cholera-endemic Ganges river delta. Sci Transl Med. 2013 Jul 3;5(192):192ra86. doi: 10.1126/scitranslmed.3006338. PMID:23825302
Rahman A, Rashu R, Bhuiyan TR, Chowdhury F, Khan AI, Islam K, LaRocque RC, Ryan ET, Wrammert J, Calderwood SB, Qadri F, Harris JB. Antibody-secreting cell responses after Vibrio cholerae O1 infection and oral cholera vaccination in adults in Bangladesh. Clin Vaccine Immunol. 2013 Oct; 20(10):1592-8. PMID:23945156
Charles RC, Hilaire IJ, Mayo-Smith LM, Teng JE, Jerome JG, Franke MF, Saha A, Yu Y, Ková? P, Calderwood SB, Ryan ET, LaRocque RC, Almazor CP, Qadri F, Ivers LC, Harris JB. Immunogenicity of a Killed Bivalent (O1 and O139) Whole Cell Oral Cholera Vaccine, Shanchol, in Haiti. PLoS Negl Trop Dis. 2014 May 1;8(5):e2828. doi: 10.1371/journal.pntd.0002828. eCollection 2014 May.PMID: 2478664
Seed KD, Yen M, Shapiro BJ, Hilaire IJ, Charles RC, Teng JE, Ivers LC, Boncy J, Harris JB, Camilli A. Evolutionary consequences of intra-patient phage predation on microbial populations. Elife. 2014 Aug 26;3:e03497. doi: 10.7554/eLife.03497. PMID: 25161196
Dr. Harris is an Associate Professor of Pediatrics at Harvard Medical School and a Pediatric Infectious Disease Attending at Massachusetts General Hospital and MassGeneral Hospital for Children in Boston, Massachusetts. Dr. Harris received his MD from Duke University and MPH from the Harvard School of Public Health. He completed his residency training at the Massachusetts General Hospital and a fellowship in pediatric infectious disease at Boston Children's Hospital. Dr. Harris is a Fellow of the American Academy of Pediatrics and a Fellow of the Infectious Diseases Society of America, and certified by the American Board of Pediatrics in general pediatrics and pediatric infectious diseases.
Dr. Harris is a physician-investigator with a National Institutes of Health-funded research program in the areas of host-pathogen interactions in Vibrio cholerae infection and cholera vaccines. Dr. Harris has published over 75 peer reviewed journal articles and chapters. His group has been working in collaboration with investigators at the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh (since 2003) and in collaboration with investigators at Partners In Health / Zanmi Lasante in Haiti (since 2010). Currently work in the Harris Laboratory is focused on:
- Identification and characterization of memory B cell responses to enteric bacterial infections
- Identification of proximate markers of protective immunity to enteric infection
- Host and environmental factors that modulate susceptibility to diarrheal illness
- Pathogen interactions with novel components of the innate immune system that influence the development of protective immunity
In addition to his research, Dr. Harris maintains an active clinical practice, with clinical interests in bacterial infections, enteric infections, and vaccines.
Along with other colleagues in the Infectious Diseases Division, Dr. LaRocque collaborates with the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh (ICDDR,B) on a large field study of Vibrio cholerae infection in an endemic setting. Her particular interest is the identification of human genetic factors that relate to the risk of cholera in the Bangladeshi population. The group has published a number of studies in support of this work. Among family members of cholera patients enrolled in the field study, the group observed that individuals who were first-degree relatives of an index case had significantly higher odds of being infected with V. cholerae than less closely related individuals in the same household. The group also performed a candidate gene association study of five genes in 76 pedigrees from the study population in Bangladesh. They found that a variant in the promoter region of LPLUNC1 was significantly associated with cholera. LPLUNC1 is a member of a family of evolutionarily conserved innate immunity proteins that is a member of the bactericidal/permeability-increasing protein and LPS-binding protein superfamily. In follow-up studies, the group demonstrated that LPLUNC1 is expressed in Paneth cells of cholera patients and that it modulates innate immune responses to V. cholerae LPS. Most recently, the group identified novel associations between cholera and a group of innate immunity genes that show evidence of natural selection in the Bangladeshi population.
Dan Bourque, MD
Brie Falkard, PhD
Ana Weil, MD
Leslie Mayo-Smith, BS