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* Institute of Thoracic Diseases and Clementino Fraga Filho University Hospital of Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;
Division of International Medicine and Infectious Disease, Department of Medicine and
Division of Biostatistics and Epidemiology, Department of Public Health, Weill Medical College of Cornell University, New York, NY 10021;
Clinical Microbiology Service, New York-Presbyterian Hospital, Columbia University Medical Center, New York, NY 10032; and
¶ Laboratory of Molecular Biology Applied to Mycobacteria, Oswaldo Cruz Institute, Rio de Janeiro, Brazil
Immune mediators associated with human tuberculosis (TB) remain poorly defined. This study quantified levels of lung immune mediator gene expression at the time of diagnosis and during anti-TB treatment using cells obtained by induced sputum. Upon comparison to patients with other infectious lung diseases and volunteers, active pulmonary TB cases expressed significantly higher levels of mediators that counteract Th1-type and innate immunity. Despite the concomitant heightened levels of Th1-type mediators, immune activation may be rendered ineffectual by high levels of intracellular (SOCS and IRAK-M) and extracellular (IL-10 and TGF-βRII, IL-1Rn, and IDO) immune suppressive mediators. These modulators are a direct response to Mycobacterium tuberculosis as, by day 30 of anti-TB treatment, many suppressive factors declined to that of controls whereas most Th1-type and innate immune mediators rose above pretreatment levels. Challenge of human immune cells with M. tuberculosis in vitro up-regulated these immune modulators as well. The observed low levels of NO synthase-2 produced by alveolar macrophages at TB diagnosis, along with the heightened amounts of suppressive mediators, support the conclusion that M. tuberculosis actively promotes down-modulatory mediators to counteract Th1-type and innate immunity as an immunopathological strategy. Our data highlight the potential application of immune mediators as surrogate markers for TB diagnosis or treatment response.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Funding for this study was provided by National Institutes of Health (NIH) Grants R01 HL61960, R21 AI063147, and R21 AI063147 (to J.L.H.), NIH Fogarty International Center Training Grant (FICTG) D43 TW00018 under the AIDS International Training and Research Program (to Warren D. Johnson and J.L.H.), ICOHRTA AIDS/TB 5 U2R TW006883 (to J.R.L.e.S.), and grants from the Coordenação de Aperfeicoamento de Pessoal de Nivel Superior, Ministry of Education-Brazil, the Brazilian Research Council/Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Brazilian Research Council/World Bank Millennium Institute of Science, Programa de Apoio a Núcleos de Excelência (to J.R.L.e.S. and A.L.K.), and the Laura Cook Hull Trust Fund (LCHTF) (to W.D.J.). R.C.H., H.Z., and A.L.G. were supported by LCHTF as well as Grants R21 AI063147 and R21 AI063147, L.C.O.L. was supported by CNPq, and A.S.A. was a FICTG trainee. Completion of this study contributed to the Ph.D. requirements of A.S.A.
2 A.S.A. and P.M.L. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. John L. Ho, Division of International Medicine and Infectious Disease, Weill Medical College of Cornell University, 1300 York Avenue, Room A-421, New York, NY 10021. E-mail address: millennium.john{at}gmail.com or Dr. José Roberto Lapa e Silva, Laboratório Multidisplinar de Pesquisa, Universidade Federal do Rio de Janeiro, Avenida Prof. Rodolpho Paulo Rocco 255, 21941-590 Rio de Janeiro, Rio de Janeiro, Brazil. E-mail address: jrlapa.ntg{at}terra.com.br
4 Abbreviations used in this paper: TB, tuberculosis; BAL, bronchoalveolar lavage; GEE, generalized estimating equation; HCW, healthcare worker; IL-1Rn, IL-1R antagonist; IRAK-M, IL-receptor-associated kinase M: NEMO, NF-
B essential modulator IB kinase 
; NOS, NO synthase; OLD, other lung disease; SOCS, suppressor of cytokine signaling; TGF-βRI, TGF-β receptor type I; TGF-βRII, TGF-β receptor type II; IDO, indoleamine 2,3-dioxygenase.
5 The online version of this article contains supplemental material.
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