1 Progression of M tuberculosis from Latency to Disease: In vitro and in vivo Tracking of Iron Content in Alveolar Macrophages Siddhartha Panda, Mukesh Sharma, Shantanu Bhattacharya, Ashok Kumar and Arnab Bhattacharya Indian Institute of Technology Kanpur, Kanpur, India Supported by S.K. Katiyar (formerly Principal and Head) and Shivesh Prakash Department of Tuberculosis and Respiratory Diseases, GSVM Medical College, Kanpur, India Section I. The Idea The basic idea of the proposed research is to understand the progression of M tuberculosis from latency to disease by tracking the in vivo iron content of the alveolar macrophages (AMs). Exposure to pollutants There are conclusive evidences that support the hypothesis that exposure to respirable pollutants from combustion of tobacco and biomass fuels increases the risk of both tuberculosis (TB) infection and TB disease [1]. Smoke also impairs the function of pulmonary AMs, which are not only the cellular target of M. tuberculosis infection but also constitute an important early defense mechanism against the bacteria. Iron content of AMs Investigators [2,3] noted that smoke-exposed AMs have a markedly elevated iron content. This iron overload impairs defense against intracellular microorganisms because of reduced production of both tumor necrosis factor-α and nitric oxide. The impairment of the iron-laden macrophages could be attributed to increased incidences of TB, with a progression from latency to disease. It is hypothesized that iron content and its temporal variations in AMs can provide leads to understand the TB latency and assist in a quick detection of state of the latency. Tracking iron content: technologies A novel method of in vivo tracking of the iron content in the AMs will be developed and utilized (see next section), which may provide insight on the host-bacillus interactions. Temporal data from a large population (see paragraph below) would be used to develop associative models between iron content and state of latency. As in vivo testing is inconvenient and not feasible on a long run, the in vivo data/models would be used to design more amenable and less expensive in vitro sensors. These in vitro sensors would be used for subsequent tracking of the state of latency. Study area The study area for this research is the city of Kanpur (longitude 88° 22′E and latitude 26° 26′N, population 4 million), India. Kanpur is an industrial city, having high fine particulate levels in air (seasonal average PM 2.5 levels ~ 100-400 µg/m 3 [4]). In addition to industrial and automobile pollution, there is a significant smoke exposure from domestic cooking using cheap fuels like wood, coal and biomass (as a large portion of the population is in the economically lower strata). Prevalent tobacco smoking further aggravates the ill effects of smoke exposures. The unusually large cases of TB infection (40%) [5] and high air pollution exposure in Kanpur makes it an appropriate study area. Uniqueness of this study • Human subjects for the study (as animal models are not representative) * • In vivo studies • Testing the hypothesis of association between iron content in AMs with latency • In vitro sensing to study state of latency (* all studies will be conducted under the ethics guidelines of the Indian Institute of Technology Kanpur and the Indian Council of Medical Research, India.)