TNF receptor 1 and 2 contribute in different ways to resistance to Legionella pneumophila-induced mortality in mice.

Legionella pneumophila is one of the most important pathogens which cause community-acquired pneumonia. Although TNF-alpha is considered to play an important role in response to bacteria, the role of the TNF-alpha receptor on L. pneumophila infection remains to be elucidated. To investigate this, we infected TNF receptor deficient mice with L. pneumophila. L. pneumophila was inoculated intranasally into TNF receptor (TNFR)-1-knock-out mice or TNFR2-knock-out mice. The mortality rate, histology of the lung, bacterial growth in the lung, and bronchoalveolar lavage (BAL) fluids were investigated. The bacterial growth of L. pneumophila in the macrophages was also studied. Almost all the mice survived after an intranasal inoculation of 1x10(6)CFU/head of L. pneumophila, but more than 90% mice were killed after inoculation of 1x10(8)CFU/head of L. pneumophila. In the case of TNFR1-knock-out mice and TNFR2-knock-out mice, a high mortality rate was observed after inoculation of 1x10(7)CFU/head of L. pneumophila in comparison to wild-type mice. The lung histology from both the TNFR1-knock-out mice documented severe lung injury at day 3 after inoculation. The clearance of L. pneumophila in the lung of the TNFR1-knock-out mice was slower than those from both the TNFR2-knock-out mice and the wild-type mice. Moreover, L. pneumophila growth in the peritoneal macrophages from the TNFR1-knock-out mice was observed. Interestingly, a lack of neutrophils accumulation in the BAL fluids and a dysregulation of cytokines (IFN-gamma, interleukin-12, and TNF-alpha) were observed in the TNFR1-knock-out mice. On the contrary, large accumulation of neutrophils in BAL fluids was observed in TNFR2-knock-out mice. These data suggested that a TNFR1 deficiency led to a compromise of the innate immunity against L. pneumophila, while a TNFR2 deficiency induced an excessive inflammatory response and resulted in death. The present study confirmed that TNFR1 and TNFR2 play a crucial, but different role in the control of L. pneumophila-induced mortality.