IMPAIRED MACROPHAGE LISTERICIDAL AND CYTOKINE ACTIVITIES ARE RESPONSIBLE FOR THE RAPID DEATH OF LISTERIA MONOCYTOGENES-INFECTED IFN-GAMMA RECEPTOR-DEFICIENT MICE

IFN-gamma receptor-deficient (IFN-gamma R -/-) mice were used to study the innate immune responses during infection with Listeria monocytoge nes. Mutant mice were unable to limit bacterial growth and died of sep sis even with an infection dose of 70 Listeria. At day 2, they showed an exacerbated listeriosis and mice succumbed to infection before the onset of an effective specific immunity, demonstrating a defective inn ate immunity. Recruitment and extravasation of phagocytic cells to inf ected organs was present and dominated by neutrophils. However, during the early course of infection, mutant mice responded by an elevated i nflammatory type 1 cytokine response, as determined by IL-12, IFN-gamm a, TNF-alpha, and IL-1 alpha-specific RNA expression. Induction of ind ucible nitric oxide synthase was present and also increased in mutant mice. Interestingly, IFN-gamma R -/- neutrophils expressed substantial TNF-alpha- and IL-1 alpha-specific RNA, suggesting a substantial cont ribution in the overall inflammatory cytokine response. In contrast, I FN-gamma R -/- macrophages showed reduced MHC class II surface express ion levels and impaired TNF-alpha and IL-1 alpha but normal IL-6 produ ction after restimulation with heat-killed L. monocytogenes. Moreover, IFN-gamma R -/- macrophages showed defective listericidal activities. In contrast to normal macrophages, Listeria escaped rapidly from the phagosome in IFN-gamma R -/- macrophages to the cytoplasm, where they productively survived. In conclusion, these data suggest that IFN-gamm a R signaling activates yet unknown functions in macrophages, preventi ng Listeria-induced escape from the phagosome and consequent killing o f the invader. Together with the impaired cytokine responses, these ma crophage defects seem to be responsible for the dramatic susceptibilit y during innate immunity, whereas predominant neutrophil responses med iate limited protective role in mutant mice.