Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-alpha/beta

To understand how Virulent mycobacteria subvert host immunity and establish disease, we examined the differential response of mice to infection with v arious human outbreak Mycobacterium tuberculosis clinical isolates. One cli nical isolate, HN878, was found to be hypervirulent, as demonstrated by unu sually early death of infected immune-competent mice, compared with infecti on with other clinical isolates. The differential effect on survival requir ed lymphocyte function because severe combined immunodeficiency (SCID) mice infected with HN878 or other clinical isolates all died at the same rate. The hypervirulence of HN878 was associated with failure to induce M. tuberc olosis-specific proliferation and lFN-gamma production by spleen and lymph node cells from infected mice. In addition, 2- to 4-fold lower levels of tu mor necrosis factor-cu (TNF-alpha), IL-6, IL-12, and IFN-gamma mRNAs were o bserved in lungs of HN878-infected mice. IL-10, IL-4, and IL-5 mRNA levels were not significantly elevated in lungs of HN878 infected mice. In contras t, IFN-a mRNA levels were significantly higher in lungs of these mice. To f urther investigate the role of Type 1 IFNs, mice infected with HN878 were t reated intranasally with purified IFN-alpha/beta. The treatment resulted in increased lung bacillary loads and even further reduced survival. These re sults suggest that the hypervirulence of HN878 may be due to failure of thi s strain to stimulate Th1 type immunity. In addition, the lack of developme nt of Th1 immunity in response to HN878 appears to be associated with incre ased induction of Type 1 IFNs.