Enhanced mortality despite control of lung infection in mice aerogenically infected with a Mycobacterium tuberculosis mce1 operon mutant

Abstract

Mycobacterium tuberculosis causes a variety of host clinical outcomes. We previously showed that M. tuberculosis disrupted in an operon called mce1 proliferates unchecked in BALB/c mouse lungs. The observed outcome could be attributed either to the mutant bacterial burden or to the host immunopathologic response. To differentiate these possibilities, we studied the outcomes of infection in a mouse strain (C57BL/6) less susceptible to M. tuberculosis than BALB/c. We found that the mutant infection reached a plateau in the lungs at a rate similar to that of the wild type. All mice infected with the mutant, but only half of the groups of mice infected with the wild type or complemented strain, died by 40 weeks (p<0.05). At 12-21 weeks of infection, histological examination of the lungs of mice infected with the mutant showed a diffuse pattern of lymphocyte infiltration, while that of mice infected with the other strains exhibited a nodular cellular infiltration pattern. Surprisingly, the number of bacilli recovered from the lungs was similar in all three groups. These observations suggest that rather than the bacterial burden, products of the mce1 operon may directly or indirectly modulate the host immune response that is protective to both the tubercle bacilli and the host.

Bacterial immunostat: Mycobacterium tuberculosis lipids and their role in the host immune response

“…The mutant is unable to induce a strong T-helper 1 (Th1) type T cell immune response and organized granuloma formation in lungs 41 . Taken together, these observations suggest that the mce1 operon is involved in the remodeling of M. tuberculosis cell wall, dampening proinflammatory response in mouse that is associated with rapid progression to death 40,41 . The operon is not expressed in the wild type strain during the first 4-8 weeks of infection in mouse 42 , suggesting that the M. tuberculosis cell wall lipid profile can be altered according to the course and/or time of infection.…”

“…Both groups suggested that the operon might encode an importer system involved in recycling of MA. Also, disruption of the mce1operon renders the cells hypervirulent in mice 40,41 . The mutant is unable to induce a strong T-helper 1 (Th1) type T cell immune response and organized granuloma formation in lungs 41 .…”

Posttreatment Reactivation of Tuberculosis in Mice Caused byMycobacterium tuberculosisDisrupted inmce1R

“…Tissue samples for histopathologic studies were prepared as previously described [21, 22]. Briefly, left lung was fixed in 10% buffered formalin and sectioned.…”

Purification and structural characterization of Mce4A from Mycobacterium tuberculosis

“…mce4a gene of mce4 operon is the most studied gene which encodes mammalian cell entry protein (Mce4A). This protein is thought to be responsible for the survival of MTB during latent infection by either importing cholesterol or by utilizing it as source of carbon and energy [15][16][17]. Several studies show that the disruption or deletion of mce operon leads to either attenuation or hypervirulence for the host [15,16,18].…”