Impact of Diabetes and Hyperlipidemia on Host Defense

It is well recognized that people with diabetes are at increased risk for infections, including TB. Surprisingly little is known about mechanisms whereby diabetes impairs protective immunity. To fill that knowledge gap we have combined mouse models of metabolic disorders and infection, probing the influence of diabetes and hyperlipidemia on host defense in TB. We found that mice with chronic hyperglycemia have increased TB susceptibility that is not seen in the first 4 weeks after diabetes onset (Martens et al. Am. J. Respir. Cell Mol. Biol. 37:518). This suggests that impaired host defense may result from cumulative damage of hyperglycemia as occurs with other diabetic complications. We discovered a major immunological mechanism of TB susceptibility in mice with chronic diabetes, namely a delay in priming adaptive immunity following aerosol Mtb challenge due to late recruitment of dendritic cells to collect antigen from infected alveolar macrophages (Vallerskog et al. J. Immunol. 184:6275). We are now focusing on defining the biochemical mechanism responsible for this effect and searching for other adverse impacts of diabetes on TB defense. We are also initiating clinical research projects on TB and diabetes in parallel with our basic research.

In related stuides we found that very high levels of serum cholesterol profoundly reduce TB defense in ApoE null mice, with susceptibility comparable to interferon-gamma deficient animals (Martens et al. Infect. Immun. 76:3464). This result suggests that elevated serum cholesterol could synergize with diabetes to impair host defense, similar ot the effects of elevated cholesterol to accelerate other diabetic complications. In more recent studies we found that LDL receptor null mice infected with M. tuberculosis shared the ApoE neutrophilic inflammation phenotype but controlled bacterial replication like wildtype controls (Martens et al. J. Leuk. Biol. Epub ahead of print). These two mouse strains had similar elevation of total serum cholesterol but are known to have different patterns of LDL vs. VLDL cholesterol that may partially account for their differential TB susceptibility. The underlying mechanisms and the potential for intercations between elevated serum cholesterol and glucose in the aerosol TB model are being studied.