Complement resistance and acute lung injury during Klebsiella pneumoniae infection

About This Grant

PROJECT SUMMARY Hospital-acquired pneumonia caused by multidrug-resistant Klebsiella pneumoniae (KP) poses a significant challenge in clinical settings due to limited therapeutic options. Immunotherapy has emerged as a promising strategy against such infections. To inform the development of immunomodulatory therapies to target this pathogen, it is crucial to understand the specific interactions between the immune system and multidrug-resistant KP. The complement system is one of the first lines of defense against bacterial infection. The canonical mechanism by which KP evades complement-mediated killing is through prevention of complement deposition either by modifying its capsule composition to prevent complement deposition or producing more capsule to cover potential complement binding sites on the bacterial membrane. There have been reports, however, of clinical KP isolates that are able to evade complement-mediated lysis despite high levels of complement deposition. The clinical isolates reported to demonstrate this phenomenon belong to the sequence type 258 (ST258). KP ST258 is an epidemic lineage that has caused numerous outbreaks in hospitals around the world. The KP ST258 lineage has diverged into two clades, Clade 1 and Clade 2, that differ primarily in their capsule locus. Clade 2 isolates are found much more frequently in infections than Clade 1 isolates, suggesting that they are more successful pathogens. Notably, in preliminary studies, Clade 2 isolates were found to both bind more C3 complement protein and be more resistant to serum-mediated killing than Clade 1 isolates. This proposal will explore a novel mechanism used by KP to evade complement-mediated killing despite C3 deposition, and will examine if this mechanism results in increased lung injury. Aim 1 will utilize in vitro assays, comparative genomics, and genetic approaches to investigate the requirement for the KP ST258 Clade 2 capsule in this new mechanism of complement-mediated killing. Aim 2 will utilize an in vivo murine model of pneumonia to investigate whether increased complement activation also increases lung injury, and if this can be mitigated through blockade of complement anaphylatoxins. Overall, this proposal will provide new insights into a novel mechanism of complement evasion and will pave the way for the development of targeted immunotherapeutic interventions for pneumonia caused by multidrug-resistant KP. Completion of the proposed training plan under the mentorship of Dr. Daria Van Tyne and Dr. John Alcorn will enable the applicant to develop and refine a wide variety of technical, intellectual, and professional skills that will be instrumental in her future success as an independent investigator and physician scientist.