Effects of a-1 antitrypsin augmentation therapy and a-1 antitrypsin deficiency in pneumococcal pneumonia in mice

Congenital AAT deficiency is an important genetic condition strongly increasing risk of severe pulmonary emphysema. Although AAT augmentation therapy is of major importance for the treatment of AAT deficiency-related emphysema, its impact on neutral serine protease-dependent lung antibacterial immunity is still poorly defined. In the current study, we examined the effect of AAT augmentation therapy versus AAT deficiency on bacterial clearance and inflammatory responses in WT and AAT KO mice challenged with S. pneumoniae (Spn). Treatment of Spn-infected WT mice with two plasma-purified AAT drugs (Prolastin® or Zemaira®) approved for patient treatment, led to significantly increased bacterial loads in both BAL fluids (BALF) and lung tissue on days 2 and 3 post-infection. No differences in BALF cellular profiles we found between AAT and vehicle-treated, Spn-infected mice. The AAT protein levels in BALF were higher in mice treated with AAT as compared to control mice. Remarkably, Spn-infected AAT KO mice on day 3 post-infection showed significantly increased bacterial loads in BALF and lung tissue compared to WT mice. We observed a significant depletion of alveolar macrophages in Spn-infected AAT KO as compared to WT mice. Collectively, our data suggest that increased levels of AAT within the bronchoalveolar space and congenital deficiency of AAT protein inversely affect lung antibacterial immunity in mice challenged with S. pneumoniae. This study illustrates the critical importance of tightly controlled AAT levels for regulation of lung antibacterial immunity and may provide a basis for refined AAT augmentation therapy in emphysema patients with congenital AAT deficiency.