We are studying the basis for increased tuberculosis (TB) susceptibility in diabetes mellitus (DM). The global population-attributable TB risk conferred by DM equals that of HIV/AIDS. Immune deficiency in DM is less severe than AIDS, but DM is more prevalent and is increasing sharply in India and China, which already have high rates of TB. In the first 3+ years of this project we discovered that mice with chronic hyperglycemia are more susceptible to TB than controls with higher bacillary burden and worse lung pathology. Diabetic mice with TB mount an exuberant Th1 biased cell mediated immune response with no evident gaps in leukocyte recruitment or expression of cytokines critical for TB defense. A key discovery was that the adaptive immune response to Mycobacterium tuberculosis (Mtb) is delayed in diabetic mice during the period of logarithmic bacillary replication. Diabetic mice are slow to develop aggregates of myeloid cells around Mtb-infected alveolar macrophages (AMF) and slow to deliver bacilli to the thoracic lymph nodes (TLN) where immunity is primed. Our data suggest the hypothesis that DM impairs a critical early step in TB defense where dendritic cells (DC) are recruited to foci of infected AMF to acquire bacilli and bring them to the TLN to initiate the adaptive response. We plan to test that hypothesis and to investigate its immunological and biochemical basis. Pilot data indicate that chemokines which signal DC recruitment are expressed in lower levels in diabetic than control mice early in TB. We will study DC trafficking in vivo and test the sentinel function of AMF in vivo and in vitro, as well as the impact of DM on AMF activation and cell death. Most human diabetics with TB have type 2 diabetes (T2D), whereas we have so far modeled insulin-deficient type 1 diabetes (T1D). We will therefore test TB susceptibility in mouse models of T2D. Most diabetic complications are mediated by chronic hyperglycemia and are shared by T1D and T2D, so we anticipate finding more similarities than differences in these models. Some diabetic complications are exacerbated by dyslipidemia. We discovered that hypercholesterolemia independently impairs TB defense. We now plan testing whether combined high glucose and high cholesterol or triglyceride synergistically weaken TB defense. Or studies so far used naove diabetic mice but humans may acquire latent TB infection before developing DM, which then raises the risk of developing active TB disease. Latency is not readily modeled in mice, but relevant data can be derived from proposed studies testing the impact of DM on the secondary response to Mtb in clinically relevant models of BCG vaccination and antimicrobial therapy. Finally, we will investigate the biochemical basis of diabetic TB susceptibility by testing effect of insulin or experimental DM complication therapies to restore TB defense. Diabetes is the most significant acquired risk factor for TB outside of Africa. Despite its significance this subject has received little attention from basic scientists. We are addressing a major gap in knowledge about a topic of growing public health importance and at the same time using our models to investigate fundamental issues in TB defense.

Public Health Relevance

Tuberculosis kills two million people every year and one third of the world's population is infected with the germ that causes this disease. Diabetes increases the risk that people carrying the tuberculosis germ will develop tuberculosis disease and people with diabetes are more likely to have severe disease and a worse response to treatment. The goal of this project is to find the reason increased tuberculosis susceptibility in diabetes so that better methods to prevent or treat this complication can be designed.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL081149-06
Application #
8104819
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Peavy, Hannah H
Project Start
2005-07-01
Project End
2015-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
6
Fiscal Year
2011
Total Cost
$411,250
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Critchley, Julia A; Restrepo, Blanca I; Ronacher, Katharina et al. (2017) Defining a Research Agenda to Address the Converging Epidemics of Tuberculosis and Diabetes: Part 1: Epidemiology and Clinical Management. Chest 152:165-173
Cheng, Catherine Y; Gutierrez, Nuria M; Marzuki, Mardiana B et al. (2017) Host sirtuin 1 regulates mycobacterial immunopathogenesis and represents a therapeutic target against tuberculosis. Sci Immunol 2:
Ní Cheallaigh, Clíona; Sheedy, Frederick J; Harris, James et al. (2016) A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling. Immunity 44:368-79
Martinez, Nuria; Ketheesan, Natkunam; West, Kim et al. (2016) Impaired Recognition of Mycobacterium tuberculosis by Alveolar Macrophages From Diabetic Mice. J Infect Dis 214:1629-1637
Smith, Clare M; Proulx, Megan K; Olive, Andrew J et al. (2016) Tuberculosis Susceptibility and Vaccine Protection Are Independently Controlled by Host Genotype. MBio 7:
Cheekatla, Satyanarayana Swamy; Tripathi, Deepak; Venkatasubramanian, Sambasivan et al. (2016) NK-CD11c+ Cell Crosstalk in Diabetes Enhances IL-6-Mediated Inflammation during Mycobacterium tuberculosis Infection. PLoS Pathog 12:e1005972
Repasy, Teresa; Martinez, Nuria; Lee, Jinhee et al. (2015) Bacillary replication and macrophage necrosis are determinants of neutrophil recruitment in tuberculosis. Microbes Infect 17:564-74
Moraco, Andrew H; Kornfeld, Hardy (2014) Cell death and autophagy in tuberculosis. Semin Immunol 26:497-511
Martinez, Nuria; Vallerskog, Therese; West, Kim et al. (2014) Chromatin decondensation and T cell hyperresponsiveness in diabetes-associated hyperglycemia. J Immunol 193:4457-68
Martinez, Nuria; Kornfeld, Hardy (2014) Diabetes and immunity to tuberculosis. Eur J Immunol 44:617-26

Showing the most recent 10 out of 20 publications