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

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

This work was supported

This work was supported by the AERAS Global TB Vaccine Foundation, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD 5T32HD055148-04), the Harvard Global Health Institute, the Annenberg Foundation and the Pott’s Memorial Foundation. 15) Antimicrobial effector functions of iNKT cells activated by Mycobacterium tuberculosis-infected macrophages Alissa C. Rothchild 1, 2 and Samuel M. Behar 2 . 1 Division of Medical Sciences, Graduate Program in Immunology, Harvard University; 2 Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA. Invariant natural killer T (iNKT) cells recognize and rapidly respond to lipids presented by CD1d. Our lab previously showed that transfer of iNKT cells reduces the bacterial burden in the lungs of Mtb infected mice. Clinical studies have found that active TB disease is highly associated with decreased peripheral iNKT cells compared to latent cases or healthy controls. Using an in vitro infection model, we found that iNKT cells inhibit intracellular Mtb replication by their interaction with infected macrophages. We have identified the molecular signals that activate iNKT cells when cultured with Mtb-infected macrophages and determined how iNKT cells control Mtb infection in vitro. iNKT cell activation, as measured by upregulation of CD69 and CD25 surface expression and production of IFN�, is primarily driven by production of IL-12 and IL-18 by Mtb-infected macrophages. In contrast, the ability of iNKT cells to control intracellular bacterial replication is predominantly CD1d-dependent. Our studies demonstrate that upregulation of activation markers by iNKT cells does not always correlate with effector functions. We have found that activated iNKT cells can control bacterial replication independent of IFN�, as demonstrated by co-cultures using an IFN� -/- iNKT cell line and IFN�R -/- macrophages. iNKT cell-mediated control is independent of cytolytic pathways and involves a soluble factor. We found that iNKT cells produce GM-CSF following co-culture with Mtb-infected macrophages. Treatment of infected macrophages with recombinant GM-CSF reduces Mtb growth in vitro. We are now investigating how GM-CSF leads to bacterial control in this system and what role GM- CSF plays in vivo during infection. This work was supported by National Institutes of Health grants R01 HL80312 and HL080330 to SMB. 16) Genetic regulation of the methylmalonyl pathway by the cAMP-associated transcription factor, Cmr Gwendowlyn S. Knapp 1 , Eric A. Smith 1 and Kathleen A. McDonough 1,2 1 Wadsworth Center New York State Department of Health 120 New Scotland Ave. Albany, NY 12208; 2 Department of Biomedical Sciences, SUNY Albany Albany, NY 12203 Mycobacterium tuberculosis (Mtb) in the host catabolizes fatty acids and lipids for energygenerating compounds. Regulation of the metabolic and energy generating pathways is key to adapting to changing host environments during infection. To avoid accumulation of propionyl- CoA, a toxic by-product of odd-chain fatty acid oxidation, must be metabolized through either the methylcitrate cycle (MC) or the methylmalonyl pathway (MM). The MC provides growth intermediates by oxidizing propionyl-CoA to pyruvate and succinate. The methylmalonyl pathway is an essential pathway in Mtb and the product, methylmalonyl-CoA, is the building 23

lock for branched-chained fatty acid and lipid biosynthesis. The genetic regulation of the genes of these two pathways is not understood. Changes in expression levels of accA3, mutAB and prpDC, genes encoding for enzyme components of the MM or MC pathways, were identified in an RNA expression microarray comparing Mtb �cmr to wild-type. Cmr’s ability to bind to each of these promoter regions was tested by electrophoretic mobility shift assays. A shift occurred with accA3 and mutAB, components of the methylmalonyl pathway, suggesting direct regulation of the MM pathway by Cmr. Gene reporter fusions to the upstream regions of accA3, mutAB and prpDC showed Cmr dependent regulation. Further, this regulation was affected by oxygen and CO2 levels and by exogenously added dibutyryl-cAMP. Additionally, promoter fusion truncations identified a larger promoter region of prpDC than originally expected, as well as an alternative translational start site for prpD. Combined, these data demonstrate Cmr as a modulator of the MM and MC pathway usage. This work was funded by NIH F32GM095038 to G.S.K. and R21AI092078-01 to K.A.M. 17) Bacteria isolation for point-of-care diagnosis of pulmonary tuberculosis using microfluidic technology Anh Hoang 1 , Joseph Martel 1 , Nil Gural 1 , Marta Fernández-Suárez 1,2 , Mehmet Toner 1 , and Sarah Fortune 2 . 1 Center for Engineering in Medicine Massachusetts General Hospital, Boston, Massachusetts; 2 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts Current methods for microbiologic diagnostic testing of bacteria require sputum handling and culturing of bacteria. Due to its complex nature, sputum handling requires multiple, manual sample processing steps while culture is time intensive and requires special facilities. To address the need of a robust and automated sputum processing and bacteria purification platform as well as its integration with a detection system, we have developed a microfluidic device that is simple and inexpensive. It is ideally suited for isolating and concentrating small numbers of bacteria in sputum, without the need for culture, and is suitable for coupling with a detection platform. For this study, the fluid dynamic phenomenon known as inertial focusing was utilized to isolate and concentrate spiked bacteria (Streptococcus Pneumonia, Staphylococcus Aureus, Escherichia coli, and Mycobacterium Tuberculosis) from liquefied sputum samples. The microfluidic device was fabricated using standard microfabrication techniques, cast in polydimethylsiloxane (PDMS), and then bonded to a glass microscope slide. A syringe pump was used to push the bacteria-containing liquefied sputum samples through the microfluidic channels on the device. Particles (i.e. cells and bacteria) within the solutions were forced or ‘focused’ to different positions in the microchannel depending on their shape and size, flow rate and microchannel design. The purified bacteria sample obtained from the microfluidic device can then be fed into a detection platform for diagnostic purposes. This system will drastically reduce the time needed for diagnosis and requires only the push of a button and simple solution mixing for collection of the concentrated bacteria sample. 18) Elucidation of the biosynthesis and transport of Mycobacterium tuberculosis outer membrane lipids Megan A. Himmler, B. Gopal Reddy, Dane Buenten, Peter J. Tonge, Jessica C. Seeliger 24

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