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Tuberculosis Susceptibility of Diabetic Mice

¹ Department of Medicine, and ² Diabetes and Endocrinology Research Center, University of Massachusetts Medical School, Worcester, Massachusetts

Correspondence and requests for reprints should be addressed to Dr. Hardy Kornfeld, UMASS Medical School, LRB-303, 55 Lake Avenue North, Worcester, MA 01655. E-mail: hardy.kornfeld{at}umassmed.edu

Increased susceptibility to infections, including tuberculosis (TB), is a major cause of morbidity and mortality in patients with diabetes. Despite the clinical importance of this problem, little is known about how diabetes impairs protective immunity. We modeled this phenomenon by infecting acute ( 1 mo) or chronic ( 3 mo) diabetic mice with a low aerosol dose of Mycobacterium tuberculosis (Mtb) Erdman. Diabetes was induced by streptozotocin (STZ) treatment of C57BL/6 mice, while another mouse strain and diabetes model were used to confirm key observations. Lungs from acute diabetic and euglycemic mice had similar bacterial burdens, cytokine expression profiles, and histopathology. In contrast, chronic diabetic mice had > 1 log higher bacterial burden and more inflammation in the lung compared with euglycemic mice. The expression of adaptive immunity was delayed in chronic diabetic mice, shown by reduced early production of IFN- in the lung and by the presence of fewer Mtb antigen (ESAT-6)–responsive T cells compared with euglycemic mice within the first month of infection. However, after 2 months of TB disease proinflammatory cytokines levels were higher in chronic diabetic than euglycemic mice. Here we show that Mtb infection of STZ-treated mice provides a useful model to study the effects of hyperglycemia on immunity. Our data indicate that the initiation of adaptive immunity is impaired by chronic hyperglycemia, resulting in a higher steady-state burden of Mtb in the lung.

Key Words: diabetes mellitus • host defense • mouse • Mycobacterium tuberculosis

CLINICAL RELEVANCE Diabetes increases susceptibility to infections, including tuberculosis (TB). We present a model of TB in diabetic mice to investigate the mechanisms underlying this complication of diabetes and to inform the rational development of therapies to overcome it.