Neutrophil responses to Mycobacterium tuberculosis infection in genetically susceptible and resistant mice.

The role of neutrophils in tuberculosis (TB) resistance and pathology is poorly understood. Neutrophil reactions are meant to target the offending pathogen but may lead to destruction of the host lung tissue, making the defending cells an enemy. Here, we show that mice of the I/St strain which are genetically susceptible to TB show an unusually high and prolonged neutrophil accumulation in their lungs after intratracheal infection. Compared to neutrophils from more resistant A/Sn mice, I/St neutrophils display an increased mobility and tissue influx, prolonged lifespan, low expression of the CD95 (Fas) apoptotic receptor, relative resistance to apoptosis, and an increased phagocytic capacity for mycobacteria. Segregation genetic analysis in (I/St x A/Sn)F2 hybrids indicates that the alleles of I/St origin at the chromosome 3 and 17 quantitative trait loci which are involved in the control of TB severity also determine a high level of neutrophil influx. These features, along with the poor ability of neutrophils to restrict mycobacterial growth compared to that of lung macrophages, indicate that the prevalence of neutrophils in TB inflammation contributes to the development of pathology, rather than protection of the host, and that neutrophils may play the role of a "Trojan horse" for mycobacteria.

Mycobacterial dissemination and cellular responses after 1-lobe restricted tuberculosis infection of genetically susceptible and resistant mice.

BACKGROUND AND METHODS: To study mycobacterial dissemination and immune-cell trafficking in tuberculosis, we developed a mouse model in which we introduced 1 microL 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- gamma 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.