Reduced thyroxine production in young household contacts of tuberculosis patients increases active tuberculosis disease risk
Kamakshi Prudhula Devalraju, Deepak Tripathi, Venkata Sanjeev Kumar Neela, Padmaja Paidipally, Rajesh Kumar Radhakrishnan, Karan P. Singh, Mohammad Soheb Ansari, Martin Jaeger, Romana T. Netea-Maier, Mihai G. Netea, Sunmi Park, Sheue-yann Cheng, Vijaya Lakshmi Valluri, Ramakrishna Vankayalapati
Kamakshi Prudhula Devalraju, Deepak Tripathi, Venkata Sanjeev Kumar Neela, Padmaja Paidipally, Rajesh Kumar Radhakrishnan, Karan P. Singh, Mohammad Soheb Ansari, Martin Jaeger, Romana T. Netea-Maier, Mihai G. Netea, Sunmi Park, Sheue-yann Cheng, Vijaya Lakshmi Valluri, Ramakrishna Vankayalapati
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Research Article Immunology Pulmonology

Reduced thyroxine production in young household contacts of tuberculosis patients increases active tuberculosis disease risk

Abstract

In the current study, we followed 839 household contacts (HHCs) of tuberculosis (TB) patients for 2 years and identified the factors that enhanced the development of TB. Fourteen of the 17 HHCs who progressed to TB were in the 15- to 30-year-old age group. At baseline (the “0“ time point, when all the individuals were healthy), the concentration of the thyroid hormone thyroxine (T4) was lower, and there were increased numbers of Tregs in PBMCs of TB progressors. At baseline, PBMCs from TB progressors stimulated with early secretory antigenic target 6 (ESAT-6) and 10 kDa culture filtrate antigen (CFP-10) produced less IL-1α. Thyroid hormones inhibited Mycobacterium tuberculosis (Mtb) growth in macrophages in an IL-1α–dependent manner. Mtb-infected Thra1PV/+ (mutant thyroid hormone receptor) mice had increased mortality and reduced IL-1α production. Our findings suggest that young HHCs who exhibit decreased production of thyroid hormones are at high risk of developing active TB disease.

Authors

Kamakshi Prudhula Devalraju, Deepak Tripathi, Venkata Sanjeev Kumar Neela, Padmaja Paidipally, Rajesh Kumar Radhakrishnan, Karan P. Singh, Mohammad Soheb Ansari, Martin Jaeger, Romana T. Netea-Maier, Mihai G. Netea, Sunmi Park, Sheue-yann Cheng, Vijaya Lakshmi Valluri, Ramakrishna Vankayalapati

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Figure 6

Thyroid hormones induce IL-1α production by Mtb-infected monocytes/monocyte-derived macrophages.

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Thyroid hormones induce IL-1α production by Mtb-infected monocytes/monoc...
Freshly isolated monocytes/monocyte-derived macrophages (MDMs) from 18- to 30-year-old donors (n = 5) were infected with H37Rv at an MOI of 2.5, as described in Methods. Some of the infected MDMs were cultured in the presence of T3 (15 nmol/L) or T4 (150 nmol/L) for 5 days. (A) The supernatants were aspirated, and cytokine and chemokine production were measured by multiplex ELISA. P values were derived using 1-way ANOVA with Tukey’s multiple-comparison test. The mean values, SD, and P values are shown. (B) The Mtb-infected MDMs in the presence or absence of T4 (150 nmol/L) were examined for TR-α1/β1 expression and IL-1α production by confocal microscopy. The images were taken at 63× magnification with oil immersion. Scale bar: 20 μm. (C) The respective immunofluorescence intensities are shown (n = 5). P values were derived using 1-way ANOVA with Tukey’s multiple-comparison test. Mean values, P values, and SD are shown. (D) Freshly prepared MDMs from 18- to 30-year-old donors (n = 6) were infected with H37Rv at an MOI of 2.5, as described in Methods. The infected MDMs were cultured in the presence of T4 (150 nmol/L), and the anti–IL-1α (10 μg/mL) antibody was added to some wells. The supernatant was aspirated; MDMs were lysed and plated on 7H10 agar. The number of colonies was counted after 3 weeks. The mean ± SD and P values are shown. The P values were determined using 1-way ANOVA with Tukey’s multiple-comparison test. (E) The MDMs (n = 5) were infected with H37Rv and cultured in the presence or absence of recombinant IL-1α (10 ng/mL); the number of bacterial colonies was determined. The P values were derived using an unpaired, 2-tailed, independent t test. Mean values and SD are shown.