The requirement of tumour necrosis factor-alpha and interferon-gamma for the expression of protective immunity to secondary murine tularaemia depends on the size of the challenge inoculum

The present study was conducted to determine the extent to which the cytokines tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) are required to protect against primary or secondary murine tularaemia caused by the live vaccine strain of the facultative intracellular bacterium Francisella tularensis. It is shown that non-immune mice treated with neutralizing monoclonal antibodies (mAbs) against TNF-alpha and IFN-gamma are rendered defenceless against otherwise sublethal 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, spleens and lungs of non-immune mice to rapidly reach lethal numbers. By contrast, Francisella-immune mice treated with either of the mAbs remained capable of resolving secondary infection with 50-fold larger inocula. However, the need for TNF-alpha and IFN-gamma for controlling secondary tularaemia became critical when challenge inocula exceeded 10(6) c.f.u. Overall, the results imply that different defence mechanisms operate to control primary versus secondary murine tularaemia. Additionally, they show that the need for TNF-alpha and IFN-gamma to combat secondary infection depends on the size of the challenge inoculum.