Department of Medicine, Division of Pulmonary, Allergy and Clinical Care Medicine
Immunology and Infectious Disease | Microbiology | Nutritional and Metabolic Diseases
In this study, we developed a mouse model of type 2 diabetes mellitus (T2DM) using streptozotocin and nicotinamide and identified factors that increase susceptibility of T2DM mice to infection by Mycobacterium tuberculosis (Mtb). All Mtb-infected T2DM mice and 40% of uninfected T2DM mice died within 10 months, whereas all control mice survived. In Mtb-infected mice, T2DM increased the bacterial burden and pro- and anti-inflammatory cytokine and chemokine production in the lungs relative to those in uninfected T2DM mice and infected control mice. Levels of IL-6 also increased. Anti-IL-6 monoclonal antibody treatment of Mtb-infected acute- and chronic-T2DM mice increased survival (to 100%) and reduced pro- and anti-inflammatory cytokine expression. CD11c+ cells were the major source of IL-6 in Mtb-infected T2DM mice. Pulmonary natural killer (NK) cells in Mtb-infected T2DM mice further increased IL-6 production by autologous CD11c+ cells through their activating receptors. Anti-NK1.1 antibody treatment of Mtb-infected acute-T2DM mice increased survival and reduced pro- and anti-inflammatory cytokine expression. Furthermore, IL-6 increased inflammatory cytokine production by T lymphocytes in pulmonary tuberculosis patients with T2DM. Overall, the results suggest that NK-CD11c+ cell interactions increase IL-6 production, which in turn drives the pathological immune response and mortality associated with Mtb infection in diabetic mice.
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DOI of Published Version
PLoS Pathog. 2016 Oct 26;12(10):e1005972. doi: 10.1371/journal.ppat.1005972. eCollection 2016.. Link to article on publisher's site.
Cheekatla SS, Tripathi D, Venkatasubramanian S, Nathella PK, Paidipally P, Ishibashi M, Welch E, Tvinnereim AR, Ikebe M, Valluri VL, Babu S, Kornfeld H, Vankayalapati R. (2016). NK-CD11c+ Cell Crosstalk in Diabetes Enhances IL-6-Mediated Inflammation during Mycobacterium tuberculosis Infection. Open Access Publications by UMMS Authors. https://doi.org/10.1371/journal.ppat.1005972. Retrieved from https://escholarship.umassmed.edu/oapubs/2969
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