IMMUNOLOGIC CONSEQUENCES OF M TUBERCULOSIS VIRULENCE

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The proposed experiments are based on the premise that all virulent strains of M. tuberculosis (Mtb) are capable of persisting and causing progressive disease in the lungs of mice in the face of a mechanism of T cell-mediated immunity capable of resolving infection in other organs. It is proposed to document the virulence of some standard reference strains of Mtb and some recently isolated strains in mice. Virulence will be assessed in terms of (a) the doubling times of the strains in the lungs, (b) their ability to grow progressively and cause progressive pathology in the lungs, and (c) the time it takes them to kill their hosts. It will be determined whether virulence ranking determined after inoculating Mtb strains iv applies when the strains are given by aerosol. It will also be determined whether BCG-vaccinated mice are more capable of dealing with Mtb strains of low virulence than strains of higher virulence. The identity of the T cells that mediate immunity will be investigated to determine whether CD4+ T cells are predominantly responsible, and whether they can mediate immunity alone. With this information in hand, experiments will be performed with a view to determining why the immunity mediated by CD4+ T cells in the lung fails to completely control infection in this organ. This will involve attempts to determine whether Mtb- specific CD4+ T cells accumulate at sites of Mtb infection in the lungs in smaller numbers than they accumulate at sites of BCG infection, and whether unsuccessful expression of immunity is associated with the production of lower quantities of cytokines characteristic of T helper 1 cells.