Altered cellular infiltration and cytokine levels during early Mycobacterium tuberculosis sigC mutant infection are associated with late-stage disease attenuation and milder immunopathology in mice.
BACKGROUND
Mouse virulence assessments of certain Mycobacterium tuberculosis mutants have revealed an immunopathology defect in which high tissue CFU counts are observed but the tissue pathology and lethality are reduced. M. tuberculosis mutants which grow and persist in the mouse lungs, but have attenuated disease progression, have the immunopathology (imp) phenotype. The antigenic properties of these strains may alter the progression of disease due to a reduction in host immune cell recruitment to the lungs resulting in disease attenuation and prolonged host survival.


RESULTS
In this study we focused on the mouse immune response to one such mutant; the M. tuberculosis Delta sigC mutant. Aerosol infection of DBA/2 and SCID mice with the M. tuberculosis Delta sigC mutant, complemented mutant and wild type strain showed proliferation of mutant bacilli in mouse lungs, but with decreased inflammation and mortality in DBA/2 mice. SCID mice shared the same phenotype as the DBA/2 mice in response to the Delta sigC mutant, however, they succumbed to the infection faster. Bronchoalveolar lavage (BAL) fluid analysis revealed elevated numbers of infiltrating neutrophils in the lungs of mice infected with wild type and complemented Delta sigC mutant strains but not in mice infected with the Delta sigC mutant. In addition, DBA/2 mice infected with the Delta sigC mutant had reduced levels of TNF-alpha, IL-1beta, IL-6 and IFN-gamma in the lungs. Similarly, there was a reduction in proinflammatory cytokines in the lungs of SCID mice. In contrast to the mouse model, the Delta sigC mutant had reduced initial growth in guinea pig lungs. A possible mechanism of attenuation in the Delta sigC mutant may be a reduction in neutrophilic-influx in the alveolar spaces of the lungs, and decreased proinflammatory cytokine secretion. In contrast to mouse data, the M. tuberculosis Delta sigC mutant proliferates slowly in guinea pig lungs, a setting characterized by caseating necrosis.


CONCLUSIONS
Our observations suggest that the immunopathology phenotype is associated with the inability to trigger a strong early immune response, resulting in disease attenuation. While macrophages and T cells have been shown to be important in containing M. tuberculosis disease our study has shown that neutrophils may also play an important role in the containment of this organism.
Abdul-Majid
Khairul-Bariah
KB
Center for Tuberculosis Research, Division of Infectious Diseases, Department of Medicine, Johns Hopkins University, Baltimore, MD 21231-1001, USA. kmajid@aeras.org
Ly
Lan H
LH
Converse
Paul J
PJ
Geiman
Deborah E
DE
McMurray
David N
DN
Bishai
William R
WR
D000818:Animals; D021461:Animals, Outbred Strains; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D016867:Immunocompromised Host; D007167:Immunotherapy; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D016513:Mice, SCID; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000254:growth & development / Q000276:immunology*; D020556:Neutrophil Infiltration; D012808:Sigma Factor / Q000235:genetics / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000473:pathology / Q000628:therapy
D001426:Bacterial Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D012808:Sigma Factor; C081467:sigC protein, Bacteria
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