Mycobacterial Dissemination and Cellular Responses after 1‐Lobe Restricted Tuberculosis Infection of Genetically Susceptible and Resistant Mice
1Laboratory for Immunogenetics, Central Institute for Tuberculosis, Moscow, Russia; 2Department of Infectious Diseases & Microbiology, Imperial College, London, United Kingdom
Background and methods.
To study mycobacterial dissemination and immune‐cell trafficking in tuberculosis, we developed a mouse model in which we introduced 1 μL of Mycobacterium tuberculosis directly into the middle lobe of the right lung. We investigated the kinetics of both mycobacterial spread to different anatomical sites and recruitment of phagocytes and activated lymphocytes.
Results.Mycobacterial dissemination was independent of susceptibility to infection and was identical in H‐2–congenic mouse strains with high and low resistance to tuberculosis. In resistant mice, recruitment of phagocytic cells to the uninfected lung occurred before the appearance of mycobacteria and decreased shortly thereafter. In susceptible mice, this recruitment was delayed in both lungs but increased during a 10‐week period. Recruitment of CD4+ and CD8+ lymphocytes to the contralateral lung was observed before mycobacterial dissemination in both strains, so mycobacterial seeding of secondary tissues occurred in the presence of immune lymphocytes. In resistant mice, more T cells expressed the CD44hi CD62lo activation phenotype, and higher levels of interferon‐γ were produced.
Conclusions.Mycobacterial spread to lymphoid organs preceded spread to the initially uninfected contralateral lung. Genetic differences in susceptibility to tuberculosis are associated with differences in dynamics of the immune response, rather than differences in mycobacterial trafficking.
Received 4 May 2004; accepted 24 June 2004; electronically published 15 November 2004.
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Online publication date: 1-Nov-2008.
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Financial support: Wellcome Trust (Cooperative Research Initiative Grant to D.B.Y. and A.S.A.); Howard Hughes Medical Institute (grant 75301564101 to A.S.A. as a Howard Hughes International Research Scholar); US National Institutes of Health (R01 grant HL 68532‐02).