Published ahead of print on June 21, 2007, doi:10.1165/rcmb.2006-0478OC Am. J. Respir. Cell Mol. Biol., Volume 37, Number 5, November 2007, 518-524 A more recent version of this article appeared on November 1, 2007
Submitted on December 29, 2006 Tuberculosis Susceptibility of Diabetic MiceGregory W Martens1,1 Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA * To whom correspondence should be addressed. E-mail: hardy.kornfeld{at}umassmed.edu.
Increased susceptibility to infections, including tuberculosis (TB), is a major cause of morbidity and mortality in diabetic patients. Despite the clinical importance of this problem little is known about how diabetes impairs protective immunity. We modeled this phenomenon by infecting acute (
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1 month) or chronic (
3 months) 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 to euglycemic mice. The expression of adaptive immunity was delayed in chronic diabetic mice, evidenced by reduced early production of interferon (IFN)-
in the lung and by the presence of fewer Mtb antigen (ESAT-6) responsive T cells compared to euglycemic mice within the first month of infection. However, after 2 months of TB disease pro-inflammatory 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 affects 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.
