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

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

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housekeeping function of macrophages, our work indicates that now it should also be viewed as an antimicrobial effector mechanism. Work was supported by R01 AI 084161 22) A novel antimicrobial from uncultured bacteria with specific activity against Mycobacterium tuberculosis Ekaterina Gavrish 1 , Anthony Bissell 1 , Aaron Peoples 2 , Amy Spoering 2 , William Millett 2 , Losee Ling 2 , Dallas Hughes 2 , and Kim Lewis 1 1 Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA; 2 NovoBiotic Pharmaceuticals, LLC, Cambridge, MA There is an urgent need for novel antimicrobials to combat drug-resistant pathogens, as the slow pace of antibiotic discovery is being outpaced by rapid acquisition of resistance. The need is especially acute in the case of Mycobacterium tuberculosis (Mtb), where strains of extensively resistant Mtb are spreading rapidly. Most antibiotics are derived from microorganisms. However, the vast majority of microbial species do not grow under laboratory conditions, limiting the biodiversity available for the discovery of new drugs. We have developed methods to grow uncultured organisms using in situ cultivation, which provides an untapped source of new antibiotics. In the course of screening natural products for antibacterial agents, a novel narrowspectrum antibiotic, Novo23, was discovered from two rare actinomycete strains. Extracts from 1760 strains of previously uncultured microorganisms were screened in whole-cell assays for antimycobacterial-specific compounds. We identified a novel peptide, Novo23, derived from extracts of two phylogenetically distant actinomycetes. The peptide shows strong activity against drug-resistant Mycobacterium tuberculosis strains, while possessing no activity against other bacteria. Studies with mammalian cell lines showed no cytotoxicity. To identify the target of Novo23, the genomes of spontaneous resistant mutants of M. tuberculosis were sequenced. Analysis of SNPs revealed ClpC1, an essential ATPase subunit of ClpP1P2 protease, as the putative target. A fluorescent protein-degradation assay in M. smegmatis suggests that Novo23 activates proteolytic activity. A new antibiotic target and potent killing activity make Novo23 a prime candidate for antitubercular drug development. This work was supported by NIH- 1R01AI085005-01A1. 23) T cell responses in elderly nursing home residents with latent TB infection, Boston Sergey Rekhtman, Sina Helbig, C. Robert Horsburgh, Gabriel Brandeis, Lisa Ganley-Leal, Natasha S Hochberg Boston University School of Public Health, Boston, MA; Infectious Diseases Section, Department of Medicine, Boston University School of Medicine, Boston, MA; Geriatrics Section, Department of Medicine, Boston University School of Medicine, Boston, MA Introduction: In the United States, the rates of TB disease are highest in the elderly. Tuberculin skin testing (TST) sensitivity declines with increasing age potentially due to cleared infection or immunosenescence. We sought to determine whether TST responsiveness in the elderly reflects latent TB infection (LTBI) as characterized by T-spot.TB, T central memory (TCM) and T effector memory cell (TEM) responses. Methods: We evaluated TST, T-spot.TB and immune responses in cases (persons with prior TST-positivity) and controls (no prior TST-positivity) from 3 Boston area nursing homes at baseline, 1 and 2-3 weeks. We stimulated cells with TB whole cell lysate (WCL) for three days 27

and performed flow cytometry to quantify T cell activation (CD69+), TCM cells (CD62L+, CD45RO+), and TEM cells (CD62L-, CD45RO+). Results: 28 subjects (15 cases, 13 controls) were enrolled. The median age was 77 years (range 65-84) and 23 (82%) were men. Among cases, 14/15 (93%) were TST-positive including 12/14 (86%) who were T-spot.TB-positive; 1 case had a negative TST and negative T-spot.TB. Initial analyses found that at baseline, cases had increased activated CD69+ T cells than controls (22.2% v. 6.6%). T cell responses to WCL were also higher in cases as evidenced by an increase in TEM differentiation (8.4% v. 3.1%). Conclusion: Preliminary findings suggest that diagnosing LTBI in the elderly is complicated by TST-T-spot.TB discordance. Elderly persons with LTBI have a greater proportion of experimentally differentiated TEM cells than controls suggesting the potential for persistent antigenic stimulation or sustained memory in the elderly. This work was supported by the National Institutes of Health and the Office of Women’s Health (NIH-K12-057-809-2673-6). 24) COX-2 in infection with Mycobacterium tuberculosis Matthew G. Booty, Cláudio Nunes-Alves, and Samuel M. Behar Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School Eicosanoids are a family of signaling molecules derived from arachidonic acid (AA). Among their many functions, these lipid mediators play vital roles in regulating both innate and adaptive immune responses. During infection with Mycobacterium tuberculosis (Mtb), eicosanoids impact bacterial virulence through several mechanisms. One eicosanoid, prostaglandin E2 (PGE2), protects Mtb-infected macrophages against necrosis in vitro, and in vivo, promotes crosspriming and the expedited development of protective T cell immunity. Surprisingly, mice lacking the enzyme necessary to produce PGE2 (PTGES -/- ) are not dramatically more susceptible to infection with Mtb. PTGES -/- mice have a greater bacterial burden than WT mice. However, this early difference is transient, and the mice show a decrease in survival only late during infection. Given the complexity of eicosanoid biosynthetic pathways, we hypothesize that other prostanoids play a role in protective immunity against tuberculosis. To address this question, we infected mice that are deficient in cyclooxygenase 1 or 2 (COX-1 -/- or COX-2 -/- ), the upstream enzymes required for all prostanoid production. Our preliminary findings indicate that only COX- 2 -/- mice are more susceptible to aerosol infection with Mtb (100 CFU). At lower infectious doses (10 CFU), COX-2 -/- mice survive but have dramatically reduced numbers of CD8 + T cells specific for the immunodominant antigen TB10.4. This defect in the adaptive immune response is accompanied by an increase in bacterial burden in the lungs and spleens of COX-2 -/- mice. We are now conducting experiments to precisely define the mechanisms of enhanced susceptibility in COX-2 -/- mice. This work was supported by the National Institute of Allergy and Infectious Disease (NIH-AI AI 072143 and NIH-AI 098637). 25) Increased risk of deaths in TB-hepatitis C virus co-infected patients in Karachi, Pakistan U Khan 1,2 , AJ Codlin 1 , A Nadeem 3 , Asra Parekh 3 , A Bhurgri 3 , N Salahuddin 4 , S Keshavjee 2 , AJ Khan 1 1 Interactive Research and Development (IRD); Karachi, Pakistan; 2 Program in Infectious Disease and Social Change, Department of Global Health and Social Change, Harvard Medical School; Boston, MA, USA; 3 Indus Hospital Research Center; Karachi, Pakistan; 4 Division of Infectious Diseases, Indus Hospital; Karachi, Pakistan 28

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