* Professor of Global Health and Social Medicine * Department of Medicine * Harvard Medical School * Associate member – Broad Institute *

1. Host and bacterial determinants of tuberculosis phenotypes

We study host and bacterial factors associated with TB transmission, TB disease progression and treatment outcomes. Much of this work is done in the context of longitudinal cohort studies of TB patients and their household contacts that we have conducted in Lima, Peru in collaboration with the non-governmental organization, Socios en Salud. In an ongoing study, we are conducting a genome wide association study of

On the host side, some highlights of these studies have shown the following:

1. Vitamin A deficiency is a strong risk factor for TB disease progression.
2. Isoniazid preventive therapy is equally effective in preventing TB in children exposed to MDR compared to drug sensitive strains of TB.
3. Vitamin D deficiency has a modest impact on increasing the risk of TB progression.
4. Host genetic factors and native Peruvian ancestry are associated with the risk of TB progression.
5. A cluster of CD4⁺T_H17-like cells (labelled C12), defined by unbiased multimodal profiling of memory T cells, is significantly reduced in patients who have recovered from TB (progressors) compared to those who were infected but did not develop the disease.

References:

• Aibana O**, Franke MF, Huang CC, Galea JT, Calderon R, Zhang Z, Becerra MC, Smith ER, Ronnenberg AG, Contreras C, Yataco R, Lecca L, Murray MB. Impact of Vitamin A and Carotenoids on the Risk of Tuberculosis Progression.  Clin Infect Dis. 2017 Sep 15;65(6):900-909. https://pubmed.ncbi.nlm.nih.gov/28531276/
• Luo Y, Suliman S, Asgari S, Amariuta T, Calderon R, Lecca L, León SR, Jimenez J, Yataco R, Contreras C, Galea JT, Becerra M, Nejentsev S, Martínez-Bonet M, Nigrovic PA, Moody DB, Murray MB, Raychaudhuri S. Early progression to active tuberculosis is a highly heritable trait driven by 3q23 in Peruvians.  Nat Commun. 2019 Aug 21;10(1):3765. https://pubmed.ncbi.nlm.nih.gov/31434886/
• Aibana O, Huang CC, Aboud S, Arnedo-Pena A, Becerra MC, Bellido-Blasco JB, Bhosale R, Calderon R, Chiang S, Contreras C, Davaasambuu G, Fawzi WW, Franke MF, Galea JT, Garcia-Ferrer D, Gil-Fortuño M, Gomila-Sard B, Gupta A, Gupte N, Hussain R, Iborra-Millet J, Iqbal NT, Juan-Cerdán JV, Kinikar A, Lecca L, Mave V, Meseguer-Ferrer N, Montepiedra G, Mugusi FM, Owolabi OA, Parsonnet J, Roach-Poblete F, Romeu-García MA, Spector SA, Sudfeld CR, Tenforde MW, Togun TO, Yataco R, Zhang Z, Murray MB. Vitamin D status and risk of incident tuberculosis disease: A nested case-control study, systematic review, and individual-participant data meta-analysis. PLoS Med. 2019 Sep 11;16(9):e1002907. https://pubmed.ncbi.nlm.nih.gov/31509529/
• Huang CC, Becerra MC, Calderon R, Contreras C, Galea J, Grandjean L, Lecca L, Yataco R, Zhang Z, Murray M. Isoniazid Preventive Therapy in Contacts of Multidrug-resistant Tuberculosis. Am J Respir Crit Care Med. 2020 Jun 17.https://pubmed.ncbi.nlm.nih.gov/32551948/
• Chu AL, Lecca LW, Calderón RI, Contreras CC, Yataco RM, Zhang Z, Becerra MC, Murray MB, Huang CC. Smoking cessation in tuberculosis patients and the risk of tuberculosis infection in child household contacts. Clin Infect Dis. 2021 May 28:ciab504. doi: 10.1093/cid/ciab504. Epub ahead of print. PMID: 34049397. https://pubmed.ncbi.nlm.nih.gov/34049397/

On the bacterial side, we have accrued at large archive of well-characterized MTB strains, both drug resistant and sensitive, many of which have quantitative drug resistance profiles (Mean inhibitory concentrations). WE have used these resources to:

1. Identify and characterize novel resistance mutations
2. Show that multi-drug resistant strains of TB are equally likely to be transmitted and cause disease as drug sensitive strains.
3. Compare the transmissibility of different lineages of Mtb.
4. Compare BCG efficacy against different lineages
5. Conduct genomic epidemiologic studies to track infection transmission routes
6. Study differentially detectable strains of Mtb and the role of carbon sources in growth and drug resistance phenotypes of Mtb.

References:

• Farhat MR, Freschi L, Calderon R, Ioerger T, Snyder M, Meehan CJ, de Jong B, Rigouts L, Sloutsky A, Kaur D, Sunyaev S, van Soolingen D, Shendure J, Sacchettini J, Murray M. GWAS for quantitative resistance phenotypes in Mycobacterium tuberculosis reveals resistance genes and regulatory regions. Nat Commun.  2019 May 13;10(1):2128. https://pubmed.ncbi.nlm.nih.gov/31086182/
• Becerra MC, Huang CC, Lecca L, Bayona J, Contreras C, Calderon R, Yataco R, Galea J, Zhang Z, Atwood S, Cohen T, Mitnick CD, Farmer P, Murray M. Transmissibility and potential for disease progression of drug resistant Mycobacterium tuberculosis: prospective cohort study.  BMJ. 2019 Oct 24;367:l5894. https://pubmed.ncbi.nlm.nih.gov/31649017/
• Huang CC, Chu AL, Becerra MC, Galea JT, Calderon R, Contreras C, Yataco R, Zhang Z, Lecca L, Murray MB. Mycobacterium tuberculosis Beijing lineage and the risk of tuberculosis in child household contacts.  Emerg Infect Dis.  2020 Mar;26(3):568-578. https://pubmed.ncbi.nlm.nih.gov/32091363/

2. Tuberculosis diagnostic tools

We work with a range of partners to identify ways to improve the diagnosis of drug resistant and pediatric TB. This work includes assessment of nucleic acid based and other biomarker-based tools to differentiate TB disease from latent TB.

References:

• CRyPTIC Consortium and the 100,000 Genomes Project, Allix-Béguec C, Arandjelovic I, Bi L, Beckert P, Bonnet M, Bradley P, Cabibbe AM, Cancino-Muñoz I, Caulfield MJ, Chaiprasert A, Cirillo DM, Clifton DA, Comas I, Crook DW, De Filippo MR, de Neeling H, Diel R, Drobniewski FA, Faksri K, Farhat MR, Fleming J, Fowler P, Fowler TA, Gao Q, Gardy J, Gascoyne-Binzi D, Gibertoni-Cruz AL, Gil-Brusola A, Golubchik T, Gonzalo X, Grandjean L, He G, Guthrie JL, Hoosdally S, Hunt M, Iqbal Z, Ismail N, Johnston J, Khanzada FM, Khor CC, Kohl TA, Kong C, Lipworth S, Liu Q, Maphalala G, Martinez E, Mathys V, Merker M, Miotto P, Mistry N, Moore DAJ, Murray M, Niemann S, Omar SV, Ong RT, Peto TEA, Posey JE, Prammananan T, Pym A, Rodrigues C, Rodrigues M, Rodwell T, Rossolini GM, Sánchez Padilla E, Schito M, Shen X, Shendure J, Sintchenko V, Sloutsky A, Smith EG, Snyder M, Soetaert K, Starks AM, Supply P, Suriyapol P, Tahseen S, Tang P, Teo YY, Thuong TNT, Thwaites G, Tortoli E, van Soolingen D, Walker AS, Walker TM, Wilcox M, Wilson DJ, Wyllie D, Yang Y, Zhang H, Zhao Y, Zhu B. Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing.  N Engl J Med. 2018 Oct 11;379(15):1403-1415. https://pubmed.ncbi.nlm.nih.gov/30280646/
• Mesman AW**, Soto M, Coit J, Calderon R, Aliaga J, Pollock NR, Mendoza M, Mestanza FM, Mendoza CJ, Murray MB, Lecca L, Holmberg R, Franke MF. Detection of Mycobacterium tuberculosis in pediatric stool samples using TruTip technology. BMC Infect Dis. 2019 Jun 27;19(1):563. https://pubmed.ncbi.nlm.nih.gov/31248383/

3. Operational research on improving TB care

We collaborate with teams in India and Indonesia on projects designed to identify obstacles to optimal detection and treatment of drug sensitive and resistant TB. These efforts involve optimizing TB reporting and treatment by private providers, assessing spatially targeted active case finding and assessing the causes of TB treatment default.

References:

• McAllister S, Wiem Lestari B, Sullivan T, Fortuna Hadisoemarto P, Afifah N, Arosdiani Apip R, Murray M, Hill P, Alisjahbana B. Out-of-pocket costs for patients diagnosed with tuberculosis in different health care settings in Bandung, Indonesia.  Am J Trop Med Hyg.  2020 Sep;103(3):1057-1064. https://pubmed.ncbi.nlm.nih.gov/32618253/
• Bony Wiem Lestari, McAllister S, Hadisoemarto PF, Afifah F, Jani ID, Murray M, van Crevel R, Hill PC, Alisjahbana B, Patient pathways and delays to diagnosis and treatment of tuberculosis in an urban setting in Indonesia, The Lancet Regional Health – Western Pacific,5,2020, 100059,https://doi.org/10.1016/j.lanwpc.2020.100059. https://pubmed.ncbi.nlm.nih.gov/34327397/

4. Other emerging/re-emerging infectious diseases

Our team also studies the prevalence and consequences of Covid-19, especially in low and middle income countries and we collaborate with a consortium of researchers in countries in which the non-governmental organization, Partners in Health, works. We have also worked with field based partners on a range of infectious diseases including Ebola, HIV, and Yaws.

References:

• Broadhurst MJ, Kelly JD, Miller A, Semper A, Bailey D, Groppelli E, Simpson A, Brooks T, Hula S, Nyoni W, Sankoh AB, Kanu S, Jalloh A, Ton Q, Sarchet N, George P, Perkins MD, Wonderly B, Murray M, Pollock NR. ReEBOV Antigen Rapid Test kit for point-of-care and laboratory-based testing for Ebola virus disease: a field validation study. Lancet. 2015 Aug 29;386(9996):867-74. https://pubmed.ncbi.nlm.nih.gov/26119838/
• Mooring EQ**, Mitjà O, Murray MB. Spatial-temporal clustering analysis of yaws on Lihir Island, Papua New Guinea to enhance planning and implementation of eradication programs.  PLoS Negl Trop Dis.  2018 Oct 29;12(10):e0006840. https://pubmed.ncbi.nlm.nih.gov/30372426/
• Li R**, Rivers C, Tan Q, Murray MB, Toner E, Lipsitch M. Estimated Demand for US Hospital Inpatient and Intensive Care Unit Beds for Patients With COVID-19 Based on Comparisons with Wuhan and Guangzhou, China.  JAMA Netw Open. 2020 May 6;3(5):e208297. https://pubmed.ncbi.nlm.nih.gov/32374400/
• Musanabaganwa C, Cubaka V, Mpabuka E, Semakula M, Nahayo E, Hedt-Gauthier BL, Ng KCS, Murray MB, Kateera F, Mutesa L, Nsanzimana S. One hundred thirty-three observed COVID-19 deaths in 10 months: unpacking lower than predicted mortality in Rwanda. BMJ Glob Health. 2021 Feb;6(2):e004547. PMID: 33627363; PMCID: PMC7907833. https://pubmed.ncbi.nlm.nih.gov/33627363/
• Mesman AW, Baek SH, Huang CC, Kim YM, Cho SN, Ioerger TR, Barreda NN, Calderon R, Sassetti CM, Murray MB. Characterization of Drug-Resistant Lipid-Dependent Differentially Detectable Mycobacterium tuberculosis. J Clin Med. 2021 Jul 23;10(15):3249. PMID: 34362035; PMCID: PMC8348819. https://pubmed.ncbi.nlm.nih.gov/34362035/
• Fulcher IR, Boley EJ, Gopaluni A, Varney PF, Barnhart DA, Kulikowski N, Mugunga JC, Murray M, Law MR, Hedt-Gauthier B; Cross-site COVID-19 Syndromic Surveillance Working Group. Syndromic surveillance using monthly aggregate health systems information data: methods with application to COVID-19 in Liberia. Int J Epidemiol. 2021 May 31:dyab094. doi: 10.1093/ije/dyab094. Epub ahead of print. PMID: 34058004; PMCID: PMC8195038. https://pubmed.ncbi.nlm.nih.gov/34058004/

5. Health system strengthening

We work to evaluate projects designed to improve health systems in LMICs including in Rwanda and Madagascar. For this work, we focus on developing observational methods to assess complex district level interventions.

References:

• Miller AC, Ramananjato RH, Garchitorena A, Rabeza VR, Gikic D, Cripps A, Cordier L, Rahaniraka Razanadrakato HT, Randriamanambintsoa M, Hall L, Murray M, Safara Razanavololo F, Rich ML, Bonds MH. Baseline population health conditions ahead of a health system strengthening program in rural Madagascar.  Glob Health Action. 2017;10(1):1329961. https://pubmed.ncbi.nlm.nih.gov/28621206/
• Garchitorena A, Miller AC, Cordier L, Rabeza VR, Randriamanambintsoa M, Razanadrakato HR, Hall L, Haruna J, Randrianambinina A, Thomson DR, Atwood S, Murray MB, Ratsirarson J, Ouenzar MA, Bonds MH. Early changes in intervention coverage and mortality rates following the implementation of an integrated health system intervention in Madagascar: a cohort study. BMJ Glob Health. 2018 Jun 4;3(3):e000762. https://pubmed.ncbi.nlm.nih.gov/29915670/
• Ezran C, Bonds MH, Miller AC, Cordier LF, Haruna J, Mwanawabenea D, Randriamanambintsoa M, Razanadrakato HR, Ouenzar MA, Razafinjato BR, Murray M, Garchitorena A. Assessing trends in the content of maternal and child care following a health system strengthening initiative in rural Madagascar: a longitudinal cohort study.  PLoS Med. 2019 Aug 20;16(8):e1002869. https://pubmed.ncbi.nlm.nih.gov/31430286/
• Garchitorena A, Miller AC, Cordier LF, Randriamanambintsoa M, Razanadrakato HR, Randriamihaja M, Razafinjato B, Finnegan KE, Haruna J, Rakotonirina L, Rakotozafy G, Raharimamonjy L, Atwood S, Murray MB, Rich M, Loyd T, Solofomalala GD, Bonds MH. District-level health system strengthening for universal health coverage: evidence from a longitudinal cohort study in rural Madagascar, 2014-2018. BMJ Glob Health. 2020 Dec;5(12):e003647. doi: 10.1136/bmjgh-2020-003647. PMID: 33272943; PMCID: PMC7716667. https://pubmed.ncbi.nlm.nih.gov/33272943/

6. Research Equity

References:

• Hedt-Gauthier B, Airhihenbuwa CO, Bawah AA, Burke KS, Cherian T, Connelly MT, Hibberd PL, Ivers LC, Jerome JG, Kateera F, Manabe YC, Maru D, Murray M, Shankar AH, Shuchman M, Volmink J. Academic promotion policies and equity in global health collaborations.  Lancet. 2018 Nov 3;392(10158):1607-1609. https://doi.org/10.1016/S0140-6736(18)32345-6

MD, 1990, Harvard Medical School
MPH, 1996, Harvard School of Public Health
DPH, 2001, Harvard School of Public Health