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

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Abstract
Background: Mouse virulence assessments of certainMycobacterium tuberculosismutants have revealed an immunopathology defect in which high tissue CFU counts are observed but the tissue pathology and lethality are reduced.M. tuberculosismutants 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; theM. tuberculosisΔsigCmutant. Aerosol infection of DBA/2 and SCID mice with theM. tuberculosisΔsigCmutant, 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 ΔsigCmutant, 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 ΔsigCmutant strains but not in mice infected with the ΔsigCmutant. In addition, DBA/2 mice infected with the ΔsigCmutant had reduced levels of TNF-α, IL-1β, IL-6 and IFN-γ in the lungs. Similarly, there was a reduction in proinflammatory cytokines in the lungs of SCID mice. In contrast to the mouse model, the ΔsigCmutant had reduced initial growth in guinea pig lungs. A possible mechanism of attenuation in the ΔsigCmutant may be a reduction in neutrophilic-influx in the alveolar spaces of the lungs, and decreased proinflammatory cytokine secretion. In contrast to mouse data, theM. tuberculosisΔsigCmutant proliferates slowly in guinea pig lungs, a setting characterized by caseating necrosis.Conclusion: 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 containingM. tuberculosisdisease our study has shown that neutrophils may also play an important role in the containment of this organism.