Molecules involved in the NFκB signaling pathway are down regulated in neonatal alveolar macrophages resulting in reduced response to Pneumocystis infection (37.7)

Neonates are unable to clear Pneumocystis (PC) infection with the same efficiency as adults. The alveolar macrophage (AM) phenotype of neonates during infection varies from that of adults, leading to a delayed inflammatory response and a slower clearance of infection. Upon infection with PC, neonatal AMs appear to maintain an alternatively activated phenotype, where as adults tend to adopt a classical AM phenotype. Previous data from our lab has shown that an elevated expression of TGFβ in neonatal lungs suppresses the ability of AMs to respond to PC. Use of a conditional smad4 KO model in which TGFβ signaling is defective in macrophages allowed us to show that blocking the TGFβ signaling pathway improves clearance of PC in neonatal mice. To further examine the response of neonatal AMs, in vitro immunoflourescence assays were performed to examine NFκB translocation to the nucleus. We found that, while neonatal AMs translocate NFκB in response to zymosan, they remain unresponsive to PC cysts. This data suggests that the unresponsiveness of neonatal AMs to PC infection may be due in part to reduced response of macrophages to PC cysts, in addition to the immunosuppressed lung environment. We hypothesize that the down regulation of molecules involved with NFκB translocation to the nucleus results in the reduced response of AMs to PC.