THE REQUIREMENT OF TUMOR-NECROSIS-FACTOR-ALPHA AND INTERFERON-GAMMA FOR THE EXPRESSION OF PROTECTIVE IMMUNITY TO SECONDARY MURINE TULAREMIADEPENDS ON THE SIZE OF THE CHALLENGE INOCULUM

The present study was conducted to determine the extent to which the c ytokines tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) are required to protect against primary or secondary muri ne tularaemia caused by the live vaccine strain of the facultative int racellular bacterium Francisella tularensis. It is shown that non-immu ne mice treated with neutralizing monoclonal antibodies (mAbs) against TNF-alpha and IFN-gamma are rendered defenceless against otherwise su blethal intravenous inocula of the bacterium. Treatment with either of the anti-cytokine mAbs resulted in even a very small inoculum of 500 c.f.u. of the pathogen multiplying unrestrictedly in the livers, splee ns and lungs of non-immune mice to rapidly reach lethal numbers. By co ntrast, Francisella-immune mice treated with either of the mAbs remain ed capable of resolving secondary infection with 50-fold larger inocul a. However, the need for TNF-alpha and IFN-gamma for controlling secon dary tularaemia became critical when challenge inocula exceeded 10(6) c.f.u. Overall, the results imply that different defence mechanisms op erate to control primary versus secondary murine tularaemia. Additiona lly, they show that the need for TNF-alpha and IFN-gamma to combat sec ondary infection depends on the size of the challenge inoculum.