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BCG vaccination reduces the mortality of Mycobacterium tuberculosis–infected type 2 diabetes mellitus mice
Rajesh Kumar Radhakrishnan, … , Buka Samten, Ramakrishna Vankayalapati
Rajesh Kumar Radhakrishnan, … , Buka Samten, Ramakrishna Vankayalapati
Published March 12, 2020
Citation Information: JCI Insight. 2020;5(5):e133788. https://doi.org/10.1172/jci.insight.133788.
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Research Article Immunology Infectious disease

BCG vaccination reduces the mortality of Mycobacterium tuberculosis–infected type 2 diabetes mellitus mice

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Abstract

Diabetes is a significant risk factor for the development of active tuberculosis. In this study, we used a mouse model of type 2 diabetes mellitus (T2DM) to determine the effect of prior Bacillus Calmette-Guérin (BCG) vaccination on immune responses to Mycobacterium tuberculosis (Mtb) infection. We found that, at 6–7 months after Mtb infection, 90% of the Mtb-infected T2DM mice died, whereas only 50% of BCG-vaccinated T2DM-Mtb–infected mice died. Moreover, 40% of the PBS-treated uninfected T2DM mice and 30% of the uninfected BCG-vaccinated T2DM mice died, whereas all uninfected and infected nondiabetic mice survived. BCG vaccination was less effective in reducing the lung bacterial burden of Mtb-infected T2DM mice compared with Mtb-infected nondiabetic mice. BCG vaccination significantly reduced lung inflammation in Mtb-infected T2DM mice compared with that of unvaccinated T2DM mice infected with Mtb. Furthermore, reduced mortality of BCG-vaccinated Mtb-infected T2DM mice is associated with expansion of IL-13–producing CXCR3+ Tregs in the lungs of Mtb-infected T2DM mice. Recombinant IL-13 and Tregs from BCG-vaccinated Mtb-infected T2DM mice converted proinflammatory M1 macrophages to antiinflammatory M2 macrophages. Our findings suggest a potentially novel role for BCG in preventing excess inflammation and mortality in T2DM mice infected with Mtb.

Authors

Rajesh Kumar Radhakrishnan, Ramya Sivangala Thandi, Deepak Tripathi, Padmaja Paidipally, Madeline Kay McAllister, Sachin Mulik, Buka Samten, Ramakrishna Vankayalapati

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Figure 1

BCG vaccination enhances the survival of Mtb-infected T2DM mice.

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BCG vaccination enhances the survival of Mtb-infected T2DM mice.
(A) A s...
(A) A schematic representation of BCG vaccination, T2DM induction, and Mtb H37Rv infection is shown. Six- to 8-week-old C57BL/6 mice (15 mice per group) were given 100 μL of phosphate-buffered saline (PBS; unvaccinated) or vaccinated s.c. with 1 × 106 CFU of BCG in 100 μL of PBS. Three months after vaccination, T2DM was induced in some of the mice by the i.p. injection of streptozotocin (180 mg/kg body weight) and nicotinamide (60 mg/kg body weight), as described in Methods. PBS control, BCG-vaccinated, T2DM, or BCG-vaccinated T2DM mice were infected with ~100 CFU of aerosolized Mtb. (B) The P value for percent survival was calculated using the log rank test. The Kaplan–Meier survival curves of mice are shown. Data were pooled from 2 independent experiments (n = 10 mice in 1 experiment; n = 5 mice in another experiment). (C) Mouse body weight changes were determined every 15 days. (D) Random blood glucose levels were determined at monthly intervals for up to 10 months. (E–H) One, 4, and 6 months after Mtb infection, the serum insulin (E), triglyceride (F), free fatty acid (G), and cholesterol (H) levels were estimated. Experiments were performed 2 times, and each time, 2–3 mice per group were used (C–H). The data are shown as mean ± SDs of n = 5 mice per group. The statistical analysis was performed by 1-way ANOVA, followed by Tukey’s multiple comparisons test. *P < 0.05, **P < 0.01, and ***P < 0.001.
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