Septic arthritis /bacterial arthritis is a serious complication of rheumatoid arthritis (RA) and other forms of arthritis. It can also occur in seemingly normal joints. If it is not rapidly diagnosed and treated, it can lead to acute joint destruction, osteomyelitis, sepsis and even death. Staphylococcus aureus is the predominant organism invading the RA joints. Synovium of active RA joints contains many cytokines amongst which is the members of the IL-1 family namely, IL-l alpha, IL-1beta and IL-1 receptor antagonist(IL-Ira). We have observed and previously reported that S. aureus is able to use IL-1beta and IL-1ra as growth factors. Furthermore, these molecules specifically bind to the receptors on the surface of S. aureus (referred hereafter as IL-1R). A major and minor epitope on IL-1beta has been identified to reside in the amino acid residues 208-240 and 118-147 respectively. We hypothesize that specific epitopes in IL-1beta and IL-1 ra bind to IL-1 receptor as a first step in initiating receptor post-receptor mediated events which result in stimulation of replication of the bacterium.
Four specific aims will address this hypothesis as follows: 1) Isolate and characterize the S. aureus IL-1R; 2) Clone the S. aureus IL-1 R ; 3) Determine the structural requirements of IL-1beta for binding to S. aureus IL-1R and 4) Determine the structural requirements of IL-1ra necessary for binding to S. aureus IL-1R. This study identifies and characterizes a previously unknown mechanism by which S. aureus utilize members of the IL-1 family as growth factors to defeat the host defense response against infection and persistent inflammation. This particular study is very relevant to septic arthritis in RA and non-RA patients in whom the rapid diagnosis and appropriate treatment to protect the joint structures are very important. A better understanding of how bacteria such as S. aureus use IL-1 family of cytokines to replicate and defeat the host defense is highly relevant to the study of septic arthritis.
| Kanangat, Siva; Postlethwaite, Arnold; Cholera, Shaleen et al. (2007) Modulation of virulence gene expression in Staphylococcus aureus by interleukin-1beta: novel implications in bacterial pathogenesis. Microbes Infect 9:408-15 |
| Kanangat, Siva; Postlethwaite, Arnold; Hasty, Karen et al. (2006) Induction of multiple matrix metalloproteinases in human dermal and synovial fibroblasts by Staphylococcus aureus: implications in the pathogenesis of septic arthritis and other soft tissue infections. Arthritis Res Ther 8:R176 |
