Host directed therapy targeting M. tuberculosis infected macrophages
Date
2016
Authors
Lakey, Natalie, author
Basaraba, Randall, advisor
Podell, Brendan, committee member
Perera, Rushika, committee member
Chicco, Adam, committee member
Journal Title
Journal ISSN
Volume Title
Abstract
With the rise of drug resistant strains of Mycobacterium tuberculosis (Mtb) and lags in antimicrobial drug development, it is imperative to explore alternative methods of treatment through host-directed adjunct therapies. Hallmarks of Mtb infection are altered host cell glucose metabolism and non-diabetic hyperglycemia, which increase disease severity and bacterial burden. This can be targeted using a combination of metformin and 2-deoxyglucose (2DG) to lower systemic blood glucose and increase metabolic stress in infected macrophages to induce apoptotic cell death, enabling Mtb clearance and antigen presentation to activate cell-mediated immune responses. We hypothesized that bacterial survival is aided by glycolysis-dependent macrophages, which can be targeted using a combination of metformin and 2DG to strengthen host immune responses. Using an in vitro model of guinea pig bone marrow derived macrophages under normal and high glucose conditions, we determined that both basal respiration and glycolytic activity increased after infection. When singly treated, metformin inhibited basal respiration while increasing glycolysis while 2DG inhibited both processes. In combination metformin and 2DG treatment inhibited basal respiration more effectively than metformin treatment alone and inhibited glycolysis as effectively as 2DG by itself. Efficacy of metformin-2DG treatment is dependent on high cellular glycolytic activity, a characteristic of granulomatous cells. Metformin-2DG treatment decreased cell survival 48 hours post-treatment by increasing apoptotic cell death and decreased Mtb survival more effectively than metformin or 2DG alone. We conclude that apoptotic induction of macrophages by metformin-2DG treatment may be a viable adjunct treatment to antimicrobial drugs to reduce bacterial burden and increase an effective host adaptive immune response.