Abstract
A better understanding of the kinetics of accumulated immune cells that are involved in pathophysiology during Mycobacterium tuberculosis (Mtb) infection may help to facilitate the development of vaccines and immunological interventions. However, the kinetics of innate and adaptive cells that are associated with pathogenesis during Mtb infection and their relationship to Mtb virulence are not clearly understood. In this study, we used a mouse model to compare the bacterial burden, inflammation and kinetics of immune cells during aerogenic infection in the lung between laboratory-adapted strains (Mtb H37Rv and H37Ra) and Mtb K strain, a hyper-virulent W-Beijing lineage strain. The Mtb K strain multiplied more than 10- and 3.54-fold more rapidly than H37Ra and H37Rv, respectively, during the early stage of infection (at 28 days post-infection) and resulted in exacerbated lung pathology at 56 to 112 days post-infection. Similar numbers of innate immune cells had infiltrated, regardless of the strain, by 14 days post-infection. High, time-dependent frequencies of F4/80-CD11c+CD11b-Siglec-H+PDCA-1+ plasmacytoid DCs and CD11c-CD11b+Gr-1int cells were observed in the lungs of mice that were infected with the Mtb K strain. Regarding adaptive immunity, Th1 and Th17 T cells that express T-bet and RORγt, respectively, significantly increased in the lungs that were infected with the laboratory-adapted strains, and the population of CD4+CD25+Foxp3+ regulatory T cells was remarkably increased at 112 days post-infection in the lungs of mice that were infected with the K strain. Collectively, our findings indicate that the highly virulent Mtb K strain may trigger the accumulation of pDCs and Gr1intCD11b+ cells with the concomitant down-regulation of the Th1 response and the maintenance of an up-regulated Th2 response without inducing a Th17 response during chronic infection. These results will help to determine which immune system components must be considered for the development of tuberculosis (TB) vaccines and immunological interventions.
Highlights
Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB) and leads to the most infectious bacteria-related mortalities in the world [1]
RORγt-expressing CD4+ T cells, which are thought to be Th17-type T cells, were only present in the lungs of mice infected with the reference strains, Mtb H37Ra and H37Rv, at 28, 56 and 112 days post-infection; this type of T cell was not induced in mice infected with Mtb K (Fig 4E, lower-left panel)
We established an aerosol infection model in mice with different strains of virulent Mtb to investigate their differential pathogenesis in terms of bacterial growth and lung pathology
Summary
Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB) and leads to the most infectious bacteria-related mortalities in the world [1]. Current TB pathogenesis paradigms are changing with respect to pathogen diversity because more virulence has been identified in Mtb clinical isolates than was previously anticipated [3]. The paradigm has shifted to focus on understanding the immunology of and granuloma formation in primary and post-primary TB [4]. Virulent Mtb releases large amounts of trehalose-6,6’-dimycolate (TDM; known as cord factor) during growth [4]. Cord factor could influence granuloma development after the adaptive transfer of CD4+ T cells from TDM-immunized mice, which could provide a better understanding of TB pathogenesis in terms of cellular immunity [4, 5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
