T-Cell Responses and In Vivo Cytotoxicity in the Target Organ and the Regional Lymphoid Tissue During Airborne Infection with the Virulent Mycobacterium tuberculosis MT103 and its Lipid Mutant fadD26

Abstract

To ascertain the in vivo role of mycobacterial lipids phthiocerol dimycocerosates (PDIM) in experimental murine tuberculosis (Tb), airways infection was used to compare the parental virulent clinical isolate MT103 with its mutant fadD26, lacking PDIM. Lungs were assessed as the Tb‐target organ and mediastinal lymph nodes as the corresponding lymphoid tissue, in order to quantify: the major T‐cell subsets (CD4+/CD8+/γδ+) and their activation kinetics, bacillary burden, and in vivo cytotoxicity against inoculated target cells loaded with mycobacterial Ags. After 4 weeks, infection augmented total and activated CD4+ and CD8+ T cells in lungs and nodes mainly with MT103, while γδ+ T cells increased earlier in nodes. MT103 bacillary burden was bigger and appeared earlier than the mutant fadD26, especially in the lung than in mediastinal nodes. At day 14 of MT103 infection, there was no cytotoxicity in lungs and nodes; while with fadD26 there was some in the nodes. At day 21 of MT103 infection, important cytotoxicity was detected only in lungs; while with fadD26 both tissues showed important activity. Interestingly, unlike the infection with fadD26, cytotoxicity under MT103 fell considerably in the target organ (lung) from days 21 to 60, the advanced phase. Although upon airways infection both mycobacteria behaved similarly regarding T cell (CD4/CD8/γδ) stimulation kinetics; they differed in the magnitude of these responses, in the bacterial load within tissues, and to trigger in vivo cytotoxicity in lungs and regional lymph nodes. This highlights the relevance of certain mycobacterial lipids to modify crucial effector branches of immunity.

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

“…Infection with the highly virulent Mycobacterium tuberculosis Beijing (M. Beijing) causes a quick increase of cellular infiltrate with high numbers of colony forming units in the lungs (D. Aguilar et al, 2010;B. Marquina-Castillo et al, 2009).…”

“…Lipoarabinomanans and lipomanans are two of the major lipidic components that can reduce the activation and cytokine secretion of macrophages. Although limited evidence suggest that cell wall lipids are key in immune response subversion (L. Quintero-Macias et al, 2010;L. M. Rocha-Ramirez et al, 2008), strain-specific lipid characterization during infection represents a challenge yet to be fully engaged.…”

Novel GMO-Based Vaccines against Tuberculosis: State of the Art and Biosafety Considerations

“…The second deleted gene in MTBVAC is fadD26 whose gene product is required to synthesize phtiocerol dimycocerosates (PDIMs). PDIMs are unique components of the mycobacterial cell wall playing an important role as a permeability barrier and in pathogenicity of mycobacteria from the Mtb complex [ 88 , 89 ]. PDIMs have been shown to protect the intracellular pathogen from host defense and to be required for multiplication in mouse lungs [ 90 ].…”

Aerobiology and Inhalation Exposure to Biological Select Agents and Toxins

“…31 Pulmonary γδ T lymphocytes are important in immunity against M tuberculosis and respiratory syncytial virus. 12,56 γδ T lymphocytes have also been shown to be important in injury/repair responses of pulmonary epithelium and may play a role in suppressing or triggering airway hyperresponsiveness to allergens. 24,34 More work needs to be done to understand the role of γδ T lymphocytes in pulmonary immune responses and protection of the host against pathogens.…”