AUTHOR=Lozano-Ordaz Vasti , Rodriguez-Miguez Yadira , Ortiz-Cabrera Angel E. , Hernandez-Bazan Sujhey , Mata-Espinosa Dulce , Barrios-Payan Jorge , Saavedra Rafael , Hernandez-Pando Rogelio 

TITLE=Beneficial or detrimental activity of regulatory T cells, indoleamine 2,3-dioxygenase, and heme oxygenase-1 in the lungs is influenced by the level of virulence of Mycobacterium tuberculosis strain infection

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=Volume 13 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2023.1105872

DOI=10.3389/fcimb.2023.1105872

ISSN=2235-2988

ABSTRACT=Tuberculosis (TB) caused by the complex Mycobacterium tuberculosis (Mtb) is the main cause of death by a single bacterial agent. Many biological and immunological aspects of TB are not completely elucidated, such as the complex process of immunoregulation (Treg, IDO and HO-1). In this study, the contribution of these immunoregulatory factors was compared in mice infected with Mtb strains with different levels of virulence. By intratracheal route, Balb/c mice were infected with a high dose of mild virulence reference strain H37Rv or with a highly virulent clinical isolate (strain 5186). In the first part of this study in the lungs were determined the kinetics of Treg cells during the infection. Mice infected with the mild virulent strain showed a progressive increment of Treg cells, showing this highest number at the beginning of the late phase of the infection (28 days), the same trend was observed in the expression of both enzymes. In the second part of the study, the contribution of immune-regulation was determined by treating infected animals with specific cytotoxic monoclonal antibodies for Treg cells depletion (PC61 clone) or by blocking IDO and HO-1 activity using specific inhibitors. In comparison with non-treated animals, mice infected with strain H37Rv with depletion of Treg cells or treated with the enzymes blockers during late infection showed a significant decrease of bacilli loads, higher expression of IFN-g and lower IL-4 but with a similar extension of inflammatory lung consolidation determined by automated morphometry. In contrast, the depletion of Treg cells in infected mice with the highly virulent strain 5186 produced diffuse alveolar damage that was similar to severe acute viral pneumonia, lesser survival and increase of bacillary loads, while blocking of both IDO and HO-1 produced high bacillary loads and extensive pneumonia with necrosis. Thus, it seems that Treg cells, IDO and HO-1 activities are detrimental during late pulmonary TB induced by mild virulence Mtb. In contrast, Treg cells, IDO and HO-1 are beneficial when the infection is produced by a highly virulent strain, by regulation of excessive inflammation that produced alveolar damage, pulmonary necrosis, acute respiratory insufficiency, and rapid death.