Reduced in vivo Cytotoxicity and Increased Mycobacterial Burden Are Associated with VirulentMycobacterium tuberculosisStrains During Lung Infection

Abstract

Cytotoxic cellular responses are crucial for clearing intracellular pathogens and generating host resistance. Experimental pulmonary tuberculosis is associated with an early delay in T cell responses and with elevated lung bacterial burden during chronic infection. In this study we quantified the in vivo cytotoxicity and the mycobacterial burden from two pertinent tissues in groups of mice infected each with a mycobacterial strain of different virulence. None of the strains induced cytotoxic responses during early (day 14) infection. Interestingly, at 21 and 60 days post-infection, Mycobacterium canettii (lowest virulence) triggered the strongest in vivo cytotoxicity both in lungs and mediastinal lymph nodes. In contrast, Mycobacterium tuberculosis H37Rv (intermediate virulence) and Beijing strains (highest virulence) induced lower cytotoxic responses, and exhibited high bacterial growth, especially in lungs. These in vivo data suggest that virulence of Mycobacterium strains are somehow associated with subverting cytotoxic responses, thus contributing to early bacterial replication and subsequent persistence in the lungs.

Mycobacterium tuberculosis Multidrug Resistant Strain M Induces an Altered Activation of Cytotoxic CD8+ T Cells

“…However, studies focused on T cell mediated lysis of Mφ infected with different Mtb strains are scarce. It has been recently demonstrated that virulence of Mycobacterium strains are associated with subverting CTL responses, thus contributing to early bacterial replication and subsequent persistence in the lungs [22]. In this line, we have previously shown that strain M in vitro elicits a remarkably low CD8-dependent CTL activity in terms of ability to lyse M-pulsed Mφ and expression of the degranulation marker CD107 [11].…”

Mycobacterial Strains of Different Virulence Trigger Dissimilar Patterns of Immune System Activation In Vivo

“…Conversely, infection with smoothtype M. Canettii strains rarely cause TB in humans, and in the experimental mouse model, M. canettii strains show low cellular infiltrate with limited lung bacterial burden during chronic infection (M. Fabre et al, 2010). Importantly, among these three strains, virulence showed a direct correlation with inhibition of in vivo cytotoxicity (L. Quintero-Macias et al, 2011).…”

“…Armstrong & P. D. Hart, 1971) and cytotoxic CD8+ T cells (E. M. Weerdenburg et al, 2010). The analysis of these evasion mechanisms used by MTC strains, however, have barely been comparatively assessed (L. Quintero-Macias et al, 2011).…”

“…Conversely, smoothtype Mycobacterium tuberculosis Canettii (M. canettii) strains rarely cause TB in humans and in the experimental mouse model show low cellular infiltrate with limited chronic infection (M. Fabre et al, 2010). Interestingly, our previous results assessing the mechanisms causing the difference in virulence showed an inverse correlation between strain virulence and in vivo cytotoxic responses, as well as higher bacterial burden in the lungs of M. Beijing infected mice (L. Quintero-Macias et al, 2011).…”

ESAT-6 Targeting to DEC205+ Antigen Presenting Cells Induces Specific-T Cell Responses against ESAT-6 and Reduces Pulmonary Infection with Virulent Mycobacterium tuberculosis

“…DCs and AMs, both constituting the majority of lung antigen presenting cells (APC), defend against pulmonary infection by phagocytosing foreign particles and presenting these antigens to immune cells. Mtb specifically disrupts the function of lung APCs by causing the arrest of phagosome maturation [ 12 , 13 ], inhibition of phagosome-lysosome fusion [ 14 , 15 ], inhibition of cytotoxicity [ 16 , 17 ], and subversion of MHC-II intracellular trafficking[ 18 ]. Furthermore, Mtb delays the maturation and migration of lung dendritic cells [ 19 – 22 ].…”