Postdoc Research Scientist Columbia University FORT LEE, New Jersey, United States
Abstract Text: Autosomal-dominant Hyper IgE syndrome due to dominant-negative mutations in STAT3 (STAT3DN) leads to infections, atopy, and connective tissue abnormalities. In addition to recurrent pyogenic pneumonia, especially due to Staphylococcus aureus, AD-HIES patients demonstrate evidence of abnormal wound healing, which includes development of pneumatoceles following infection, unexplained spontaneous bowel perforations, and non-inflammatory vascular aneurysms. Here, we developed a mouse model of infection-induced abscess and pneumatocele generation via intratracheal infection of transgenic Stat3DN Mut mice and littermate controls with S. aureus (USA300). We found that one to two weeks following infection, the Stat3DN Mut mice develop a higher rate of lung parenchymal abscesses compared to WT mice and these abscesses are more severe and larger (7/20 vs. 1/16). 4-8 weeks after l infection, large cavitary lung lesions were observed via CT only in STAT3DN mice (2/6 vs. 0/8). Moreover, S. aureus growth was significantly higher when cultured with STAT3DN fibroblasts, implying increased bacterial adhesion to cells/extracellular matrix. RNA-seq of STAT3DN dermal fibroblasts following Staphylococcal co-culture showed alterations in the expression of disintegrins and metalloproteinases involved in proteoglycan remodeling and structure of basement membranes(decreased expression of NTN4). Mice with STAT3 loss of function mutations provide a novel model for infection-induced pneumatocele formation, and STAT3 loss of function in fibroblasts creates a permissive environment for S. aureus growth, tissue adhesion, and impaired extracellular matrix and basement membrane remodeling. These findings may help shed light on the consequences and tissue targets of genetic and pharmaceutical alterations of the STAT3 pathway.
