Accelerated immunopathological response of mice infected with Mycobacterium tuberculosis disrupted in the mce1 operon negative transcriptional regulator.
Mycobacterium tuberculosis causes a variety of clinical outcomes determined by host as well as bacterial factors. M. tuberculosis disrupted in the mce1 operon causes increased mortality in immunocompetent mice. This operon is negatively regulated by mce1R (Rv0165c). We studied the role of mce1R in infection outcome in mice. At 5 x 10(4) tail vein infectious dose, the median survival time (MST) of mice infected with the mce1R mutant M. tuberculosis H37Rv was 293 days, while mice infected with the wild-type H37Rv survived more than 350 days (P < 0.0001). At a higher dose (5 x 10(6)), the MST of mutant-infected mice was 32 days, compared with 127 days for wild type-infected mice (P < 0.0001). With either tail vein or aerosol infection, mutant-infected mice developed larger granulomatous lesions in their lungs than mice infected with the wild type. Mutant-infected mice were unable to control the bacterial burden in the first 4 weeks of infection, but even after achieving control later, these mice succumbed to granulomatous pneumonia. These observations suggest that the early deregulated expression of the mce1 operon products determines later granulomatous tissue response. mce1 operon may homeostatically regulate the cell wall architecture in vivo that elicits a steady-state granuloma tissue response permitting M. tuberculosis to establish a long-term infection.
Uchida
Yujiro
Y
Division of Infectious Diseases, School of Public Health, University of California, Berkeley, CA, USA.
Casali
Nicola
N
White
Amy
A
Morici
Lisa
L
Kendall
Lon V
LV
Riley
Lee W
LW
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006099:Granuloma / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D007150:Immunohistochemistry; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000254:growth & development / Q000276:immunology; D009876:Operon / Q000235:genetics*; D013623:Tail / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D013997:Time Factors; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D014680:Veins / Q000276:immunology / Q000382:microbiology / Q000473:pathology
D001426:Bacterial Proteins; D016207:Cytokines; C473802:mammalian cell entry protein Mce1A, Mycobacterium tuberculosis