Tammy Kielian, PhD

Staphylococcal biofilm and disease (Bayles, Fey, Kielian)
This is a newly funded multi-investigator program project grant from the National Institutes of Health (NIH) that seeks to provide a broader understanding of the mechanisms of S. aureus biofilm development and dispersal, and how these processes interface with the host immune response.

Bacterial infections of the brain
Bacterial infections remain a constant source of morbidity and, depending on the causative agent, can result in significant mortality rates. For the past ten years, my laboratory has investigated various aspects related to bacterial infections in the brain. In particular, we have developed a mouse model of abscess formation in the brain caused by S. aureus, an organism that is acquiring resistance to multiple antibiotics at an alarming rate. These infections can arise from many sources, the most common of which is the spread of bacteria from another site of infection in the body, i.e. lung or heart, into the brain. Other means by which bacteria can gain access to the brain is through chronic sinus, tooth, or middle ear infections. The latter situation places children at risk due to the high incidence of ear infections in this patient population. If we are able to decipher the complex interplay between S. aureus and the immune response in the brain this information could lead to the development of novel therapeutic approaches to stop/interfere with bacterial growth in the brain. Brain abscesses are especially serious because individuals suffering from these infections typically experience long-term side effects that endure throughout life, which can include seizures, mental decline, and/or paralysis. Therefore, therapies aimed at reducing the extent of brain damage following infection could lead to significant improvements in clinical outcomes and quality of life for patients recovering from brain abscesses.

Our laboratory currently receives funding from the NIH to study questions related to these devastating brain infections. We have targeted numerous molecules that our studies have shown are involved in bacterial survival in the brain. One target is a receptor that is expressed on various immune and brain cell types called toll-like receptor 2 (TLR2). This receptor plays a pivotal role in recognizing S. aureus as foreign and results in a strong inflammatory response that serves to eliminate bacteria. Especially concerning from this perspective is the fact that mutations in this receptor have been identified in the human population and this has been linked to increased risk for infections. Importantly, our laboratory has the tools to understand how TLR2 is regulated and contributes to a protective anti-bacterial response through the use of specialized mice that lack this receptor. We use these mice to mimic what happens when S. aureus cannot be efficiently recognized. Our recent studies have demonstrated that in this case, the immune response compensates by over-expressing other molecules in an attempt to protect against death. These results are exciting because they have uncovered a previously unappreciated role for redundant pathways in bacterial recognition during brain infections.

Another area of active research relates to how brain abscess infections are contained. During infection, a wall forms around the lesion, which is the brain's attempt to protect surrounding tissue from destruction. However, this protective response does not happen until approximately ten days following S. aureus infection, which is sufficient time for irreparable harm to occur in the brain. We have recently identified a compound that significantly accelerates the formation of the abscess wall. Importantly, novel studies in our mouse model of infection using MRI have demonstrated that this correlates with a significant reduction in abscess size. Therefore, this drug may prove beneficial, in combination with conventional antibiotics, for the treatment of brain abscess patients by inducing rapid infection containment, effectively limiting S. aureus spread within normal brain tissue. Other interests include identifying the cell type(s) that are responsible for forming the fibrotic brain abscess capsule, which serves to spare surrounding tissue from destruction during bacterial infection.

S. aureus is also a frequent etiological agent of biofilm infections on both medical devices such as indwelling catheters and artificial joints, as well as natural body surfaces such as the heart and bladder. Biofilms are communities of bacteria that form a slime-like protective covering that effectively prevents killing by antibiotics and the immune response. In related work, we are actively investigating how S. aureus skews the immune response to favor bacterial survival. Our molecular targets in this study are anti-inflammatory molecules that we propose are induced by S. aureus to evade killing mechanisms. We have a mouse model that mimics biofilm infections observed in humans and envision that the information that we learn could be exploited to devise novel ways to activate the immune response to effectively recognize and kill bacteria associated with biofilm infections.