Tuberculosis (TB) has attracted attention as a leading global public problem resulting in the commitment of substantial resources to research and control activities. Although significant scientific advances have ensued, key translational tools are lacking. Chief among these are biomarkers to assist in developing new approaches and modalities for the prevention and management of TB. Their development has been retarded, in part, is because of limited understanding of the host-bacterial relationship. The current proposal broadens the focus of the U.S.-Brazil collaboration to address more fundamental issues concerning host susceptibility to Mycobacterium tuberculosis (Mtb) infection, the immunodynamics of recent TB infection, and bacterial factors that may play a role in treatment relapse. The high impact translational goal of this program, then, is to discover biomarkers of clinical importance to the prevention and treatment of TB.
The Specific Aims are 1 .To determine the immunologic basis for resistance and susceptibility to Mtb infection and the correlate biomarkers. The results may provide new concepts as well as biomarkers relevant to the development of novel treatments, TB vaccines and adjuvants that target innate immunity. 2. to elucidate the immunodynamics of evolving Mtb infection and to discover measurable biomarkers in clinical samples that could accurately identify recent Mtb infection and/or active Mtb replication, thereby identifying persons at high risk of TB. 3. to determine whether Mtb isolates associated with relapse 1) have sub clinical resistance below or around clinical breakpoints for the antibiotic, 2) are more tolerant of antibiotics as measured by BACTEC assays or 3) display a "loss-of-synergy" phenotype. Further, to determine whether genetic mechanisms associated with these phenotypes include 1) embB mutations, 2) pump mutations such as iniA 3) and to discover other as yet unknown mechanisms. These studies will characterize phenotypic and genotypic biomarkers of Mtb that are associated with treatment failure. TB patients infected with such isolates may require alternative approaches to treatment.
TB is a major global public health concern. The available approaches to prevention and control of TB have failed. This research will provide biomarkers that will be essential to develop improved tools and approaches to control TB.
|Jones-López, Edward C; Kim, Soyeon; Fregona, Geisa et al. (2014) Importance of cough and M. tuberculosis strain type as risks for increased transmission within households. PLoS One 9:e100984|
|Ribeiro-Rodrigues, Rodrigo; Kim, Soyeon; Coelho da Silva, Flávia Dias et al. (2014) Discordance of tuberculin skin test and interferon gamma release assay in recently exposed household contacts of pulmonary TB cases in Brazil. PLoS One 9:e96564|
|Colangeli, Roberto; Arcus, Vic L; Cursons, Ray T et al. (2014) Whole genome sequencing of Mycobacterium tuberculosis reveals slow growth and low mutation rates during latent infections in humans. PLoS One 9:e91024|
|Salgame, Padmini; Yap, George S; Gause, William C (2013) Effect of helminth-induced immunity on infections with microbial pathogens. Nat Immunol 14:1118-26|
|Safi, Hassan; Lingaraju, Subramanya; Amin, Anita et al. (2013) Evolution of high-level ethambutol-resistant tuberculosis through interacting mutations in decaprenylphosphoryl-*-D-arabinose biosynthetic and utilization pathway genes. Nat Genet 45:1190-7|
|Rafi, Wasiulla; Ribeiro-Rodrigues, Rodrigo; Ellner, Jerrold J et al. (2012) 'Coinfection-helminthes and tuberculosis'. Curr Opin HIV AIDS 7:239-44|
|Salgame, Padmini (2011) MMPs in tuberculosis: granuloma creators and tissue destroyers. J Clin Invest 121:1686-8|
|Yuan, Zhe; Ledesma, Kimberly R; Singh, Renu et al. (2010) Quantitative assessment of combination antimicrobial therapy against multidrug-resistant bacteria in a murine pneumonia model. J Infect Dis 201:889-97|
|Motiwala, Alifiya S; Dai, Yang; Jones-López, Edward C et al. (2010) Mutations in extensively drug-resistant Mycobacterium tuberculosis that do not code for known drug-resistance mechanisms. J Infect Dis 201:881-8|
|Chakravorty, Soumitesh; Aladegbami, Bola; Motiwala, Alifiya S et al. (2008) Rifampin resistance, Beijing-W clade-single nucleotide polymorphism cluster group 2 phylogeny, and the Rv2629 191-C allele in Mycobacterium tuberculosis strains. J Clin Microbiol 46:2555-60|