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Infection and Immunity, November 2009, p. 5025-5034, Vol. 77, No. 11
0019-9567/09/$08.00+0 doi:10.1128/IAI.00224-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Patients with Multidrug-Resistant Tuberculosis Display Impaired Th1 Responses and Enhanced Regulatory T-Cell Levels in Response to an Outbreak of Multidrug-Resistant Mycobacterium tuberculosis M and Ra Strains
Laura Geffner,1
Noemí Yokobori,1
Juan Basile,1
Pablo Schierloh,1
Luciana Balboa,1
María Mercedes Romero,1
Viviana Ritacco,2
Marisa Vescovo,3
Pablo González Montaner,3
Beatriz Lopez,2
Lucía Barrera,2
Mercedes Alemán,1
Eduardo Abatte,3
María C. Sasiain,1 and
Silvia de la Barrera1*
Instituto de Investigaciones Hematológicas Mariano R. Castex, Academia Nacional de Medicina,1 Instituto Nacional de Enfermedades Infecciosas, ANLIS Carlos G. Malbrán,2 Instituto de Tisioneumonología, Hospital Muñiz, Buenos Aires, Argentina3
Received 26 February 2009/ Returned for modification 14 May 2009/ Accepted 24 August 2009
In Argentina, multidrug-resistant tuberculosis (MDR-TB) outbreaks emerged among hospitalized patients with AIDS in the early 1990s and thereafter disseminated to the immunocompetent community. Epidemiological, bacteriological, and genotyping data allowed the identification of certain MDR Mycobacterium tuberculosis outbreak strains, such as the so-called strain M of the Haarlem lineage and strain Ra of the Latin America and Mediterranean lineage. In the current study, we evaluated the immune responses induced by strains M and Ra in peripheral blood mononuclear cells from patients with active MDR-TB or fully drug-susceptible tuberculosis (S-TB) and in purified protein derivative-positive healthy controls (group N). Our results demonstrated that strain M was a weaker gamma interferon (IFN-
) inducer than H37Rv for group N. Strain M induced the highest interleukin-4 expression in CD4+ and CD8+ T cells from MDR- and S-TB patients, along with the lowest cytotoxic T-lymphocyte (CTL) activity in patients and controls. Hence, impairment of CTL activity is a hallmark of strain M and could be an evasion mechanism employed by this strain to avoid the killing of macrophages by M-specific CTL effectors. In addition, MDR-TB patients had an increased proportion of circulating regulatory T cells (Treg cells), and these cells were further expanded upon in vitro M. tuberculosis stimulation. Experimental Treg cell depletion increased IFN- expression and CTL activity in TB patients, with M- and Ra-induced CTL responses remaining low in MDR-TB patients. Altogether, these results suggest that immunity to MDR strains might depend upon a balance between the individual host response and the ability of different M. tuberculosis genotypes to drive Th1 or Th2 profiles.
* Corresponding author. Mailing address: Instituto de Investigaciones Hematológicas, Immunology Department, Academia Nacional de Medicina, Pacheco de Melo 3081, 1425 Buenos Aires, Argentina. Phone: 5411-48055695. Fax: 5411-48039475. E-mail: sdelab{at}hematologia.anm.edu.ar
Published ahead of print on 31 August 2009.
Infection and Immunity, November 2009, p. 5025-5034, Vol. 77, No. 11
0019-9567/09/$08.00+0 doi:10.1128/IAI.00224-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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