Fatal granuloma necrosis without exacerbated mycobacterial growth in tumornecrosis factor receptor p55 gene-deficient mice intravenously infected with Mycobacterium avium

The pathogenesis of mycobacterial infections is associated with the formati on of granulomas in which both antibacterial protection and tissue damage t ake place concomitantly. We used murine Mycobacterium avium infection to co mpare the development of granulomatous lesions in intravenously infected tu mor necrosis factor receptor p55 (TNFRp55) gene deficient (p55(-/-)) mice t o the development of granulamatous lesions in M. avium-infected syngeneic C 57BL/6 (p55(+/+)) mice. Up to 5 weeks after infection with either the highl y virulent M. avium strain TMC724 or the intermediately virulent M. avium s train SE01, bacterial counts in the liver, spleen, and lung of p55(-/-) mic e were identical to or lower than those in infected p55(+/+) mice. However, the formation of mononuclear cell foci in the liver was delayed by approxi mately 2 to 3 weeks in p55(-/-) mice compared to the results obtained for i nfected p55(+/+) mice. Despite comparable bacterial loads, granulomas in p5 5(-/-) mice underwent progressive necrosis, causing damage to the surroundi ng liver tissue. The appearance of necrotizing granulomas was associated wi th the death of all infected p55(-/-) mice, regardless of the virulence of the M. avium strain used for infection. Granulomatous lesions in the liver contained three times as many CD3(+) cells in p55(-/-) mice yet appeared mo re diffuse than in p55(+/+) mice. Semiquantitative reverse transcription-PC R studies revealed that prior to mouse death, interleukin-12 (IL-12) and ga mma interferon mRNA levels were up regulated in the livers of infected p55( -/-) mice, while mRNA levels for tumor necrosis factor, the inducible isofo rm of nitric-oxide synthase (iNOS), and IL-10 were similar to those found i n infected p55(+/+) mice. In response to persistent mycobacterial infection , the absence of TNFRp55 causes the disregulation of T-cell-macrophage inte ractions and results in fatal granuloma necrosis even when adequate antibac terial functions are maintained.