Mechanisms of natural resistance to mouse typhoid

The early, innate resistance phase in mouse typhoid is largely controlled by a single gene (unlike the later, polygenic immune phase), designated Ity, which may be identical to those controlling resistance to Leishmania (Lsh) and mycobacteria (Bcg). The gene product and its function are unknown. Athymic (nu/nu) mice showed greater early resistance to salmonella infection than euthymic littermates, but only if they were already naturally resistant CBA (Ityr). Athymic susceptible Balb/c (Itys) were not different from the controls. The Ity mechanism is highly radio-resistant: 800 R whole body irradiation does not modify the early Ity phenotype in Balb/c and A/J mice, as measured by early in vivo net bacterial growth; this, however, increases sharply on day 3-4, when growth curves plateau in controls (immune response). Bone marrow radiation chimeras infected 3 months after the transfer confirm that, while the donor genotype determines the Ity recipient phenotype in single chimeras, double chimeras (Itys + Ityr) leads to Ityr are susceptible or intermediate in both semiallogeneic and syngeneic models. The typhoid relapse following cessation of antibiotic therapy was greater in susceptible than in resistant mice. In lethally infected mice, ampicillin decreased the bacterial load twice as fast in susceptible Balb/c than in resistant (B10 X A/J)F1 mice, but they required much more prolonged treatment to develop effective immunity. Considered collectively, the present data is consistent with the view that early resistance is thymus independent and relies on innate mechanisms present in radioresistant bone marrow derived cells that in some way provide an environment which favours a more rapid in vivo division rate of the organism in susceptible mice.