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WELCOME TO THE 2011 - Harvard Initiative for Global Health ...

WELCOME TO THE 2011 - Harvard Initiative for Global Health ...

transfer into irradiated

transfer into irradiated recipients, we find that CD8 + Rg T cell mediated protection requires IFN- �, but does not require perforin. This new Rg mouse model, the first expressing CD8 + T cells specific for an Mtb epitope, will be useful for defining the molecular basis of CD8 + T cell expansion during infection and the mechanism(s) underlying their protective capacity. Biography: Cláudio Nunes-Alves is a visiting PhD student in Sam Behar’s lab (BWH/HMS, Boston), co-supervised by Margarida Correia-Neves (ICVS, Braga, Portugal) and Christophe Benoist (HMS, Boston). He graduated in Biochemistry from Universidade do Porto (Portugal). During a short fellowship at the Bacterial Cell Surface and Pathogenesis Group at the ITQB (Lisbon, Portugal) he focused on the role of the bacterial cell wall on the host innate immune response, and became interested in the interaction between bacteria and the immune system. He then moved to ICVS (Braga, Portugal) where he started focusing on the immune response to mycobacterial infection. During these last years he has been focusing on different aspects of T cell biology at different stages of Mycobacterium tuberculosis (Mtb) infection such as MTb dissemination to the thymus and it’s influence on T cell differentiation; the kinetics of CD8 + T cell priming following infection; and the mechanisms behind CD8 + T cell protection during tuberculosis. 5) Evolution of drug-resistant tuberculosis: results of whole genome tests for natural selection Maha Farhat, MD 1 Jesse Shapiro, PhD 2 Razvan Sultana 3 , Megan Murray, MD ScD 4 1 Fellow Harvard Pulmonary and Critical Care Medicine. Massachusetts General Hospital. 2 Harvard Department of Organismic and Evolutionary Biology, Center for Communicable Disease Dynamics, and Broad Institute. 3 Boston University Bioinformatics and Computational Biology, Dana Farber Cancer Institute 4 Harvard School of Public Health, Division of Global Health and Equity Harvard Medical School Abstract: Background: Drug resistance occurs in the absence of a known causal mutation in 10-40% of clinically resistant Mycobacterium tuberculosis (MTb) strains. Theoretical work suggests that resistance is often accompanied by an initial loss of pathogenicity, which may be overcome by the acquisition of compensatory mutations. To date there has been no systematic genomewide search for novel genes causing or associated with resistance. Methods: Using a set of 123 whole genome sequences of resistant and sensitive MTb strains, we inferred mutations and genes under positive selection in resistant strains using three independent metrics: dN/dS, evolutionary convergence, and physical clustering of resistance-associated mutations in the genome. We validated each method by its sensitivity in detecting previously known drug resistance genes. Results: We successfully identified 11 of the known drug-resistant genes with convergence, which significantly outperformed the more commonly used dN/dS method. The clustering method performed comparably, with slightly lower sensitivity than convergence. Overall, we identified a high-confidence set of candidate genes associated with drug resistance. Among these candidate genes were rpoC, and genes associated with PDIM biosynthesis. Conclusion: Whole genome sequences can be used to identify candidate genes associated with drug resistance in tuberculosis. These genes may either be causally linked with resistance, or compensate for fitness losses associated with causal mutations. Biography: Maha Farhat,MD is a graduate of the American University of Beirut, and McGill Universities. She is currently a clinical and research fellow in Pulmonary and Critical Care at the Harvard affiliated hospitals. Her current research is under the mentorship of Dr. Megan Murray at the Harvard Medical School Department of Global Health and Social Medicine. She focuses 9

on using computational and evolutionary biology tools to understand drug resistance in TB through the study of its whole genome sequence. 6) Aggregate reports mask spatial clustering of drug-resistant tuberculosis Helen E. Jenkins 1,2* , Valeriu Plesca 3 , Anisoara Ciobanu 3 , Valeriu Crudu 4 , Irina Galusca 3 , Viorel Soltan 5 , Aliona Serbulenco 5 , Victoria Petrica 5 , Matteo Zignol 6 , Andrei Dadu 7 , Masoud Dara 7 , Ted Cohen 1,8 1 Brigham and Women’s Hospital, Boston, USA, 2 Harvard Medical School, Boston, USA, 3 National Centre of Health Management, Chisinau, Republic of Moldova, 4 Center for Health Policies and Studies, Chisinau, Republic of Moldova, 5 Ministry of Health, Chisinau, Republic of Moldova, 6 Stop TB Department, World Health Organization, Geneva, Switzerland, 7 World Health Organization, Regional Office for Europe, Copenhagen, Denmark, 8 Harvard School of Public Health, Boston, USA Abstract: Background: Multi-drug-resistant tuberculosis (MDR-TB) threatens tuberculosis (TB) control. The highest reported proportions of TB cases with MDR-TB are in countries of the former Soviet Union. Methods: We analyzed surveillance data on all TB cases notified between 2007 and 2010 from the Republic of Moldova, a small country where patients experience one of the highest risks of MDR-TB in the world. High drug susceptibility testing coverage (>95% of culture-positive TB cases) and availability of case location data allowed us to estimate local incidences of MDR-TB and identify sub-regional areas where cases were at relatively high risk of MDR-TB. We also investigated whether geographic concentration of cases with risk factors for MDR-TB could account for spatial variation in the risk of MDR-TB. Results: 3,447 MDR-TB cases were diagnosed; 24% of new and 62% of previously treated patients had MDR-TB. We estimated a nationwide MDR-TB incidence of 54 cases/100,000 persons/year and >1,000 cases/100,000 persons/year within penitentiaries. We found striking regional variation in the estimated incidence of MDR-TB (range: 18-102/100,000 persons/year); mapping of cases allowed us to identify local areas with increased MDR-TB risk. Locations where a relatively high proportion of cases had previously been in detention were more likely to be identified as MDR hotspots. Conclusions: Spatial analysis of drug-resistance surveillance data shows striking geographic heterogeneity of MDR-TB even within a small country and suggests possible local drivers of resistance. Identifying locations where cases are at increased risk of resistance suggests opportunities for prioritizing resources for control. This work was supported by Award Number U54GM088558 from the National Institute of General Medical Sciences. Biography: Helen Jenkins, Ph.D. is a Research Fellow in the Division of Global Health Equity at Brigham and Women's Hospital working with Ted Cohen on drug-resistant tuberculosis. She received her PhD from Imperial College, London where her work focused on the epidemiology and elimination of polio in Nigeria. Helen uses statistical methods to answer policy-relevant questions about infectious diseases. 10

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