Overexposure to manganese (Mn) results in a parkinsonian disorder, manganism, which is clearly associated with basal ganglia lesions that include aberrations of neuroinflammatory nature and is best characterized in Mn miners. Besides Mn overexposure, Mn miners also have the highest prevalence of tuberculosis (TB), suggesting high likelihood of co-exposure to Mn and Mycobacterium tuberculosis (Mtb). However, the nature of the Mn-Mtb interaction within the context of Mn-induced neuropathology has not been studied until now. Our broader objectives are to study and decipher the mechanisms of Mn neurotoxicity within the context of exposure scenarios and co-morbidities, such as TB, that are of high human relevance. Hence, using complementary mouse models and in vitro approaches, combined with innovative and occupationally-relevant delivery method (intratracheal sprayer), and based on exciting preliminary data we will investigate the Mn-Mtb interaction from a Mn neuropathology perspective. We hypothesize that Mn and Mtb will interact both within the brain and in the periphery, such that combined Mn/Mtb exposure will lead to increased neuroinflammation, increased peripheral inflammation, and increased neuronal susceptibility to the effects of Mn. This hypothesis will be tested with the following two specific aims: (1) to determine the nature of the interaction between Mn and Mtb and to evaluate the neurotoxicity caused by co-administration of Mn and Mtb directly into the brain (globus pallidus) or by intratracheal Mn and Mtb exposure and (2) to determine whether direct Mtb infection of neurons modulates the neurotoxicity of Mn and whether such modulation is neuronal cell-type specific. Collectively, the work proposed in aims 1 and 2 will enable us to determine the role of TB comorbidity in the neuropathology associated with Mn overexposure. Such results will have transformative positive impact because they will be the first to report on a highly epidemiologically-relevant toxicant (Mn) and infectious agent (Mtb) interaction. The proposed studies will also have potential broader consequences to other conditions where bacterial infections in the face of metal excess (or deficiency) are of concern.
The research proposed in this application is significant because it is the next step in a continuum of research that underscores the importance of increasing our understanding of occupationally-relevant bacterial infection-neurotoxicant interaction. Findings from the proposed studies will have a direct impact on occupationally-exposed individuals, i.e., miners, and will aid in identifying other susceptible individuals that my be at a greater risk of developing neurological deficits from manganese overexposure. Data generated from the proposed research will also provide important new information on the interaction between manganese and Mycobacterium tuberculosis when it comes to neuronal susceptibility and to infection progression and colonization of the brain.
