Research Areas

Late onset Alzheimer’s disease (AD), a progressive irreversible senile dementia, is the 6th-leading cause of death in elderly, with an estimated 5.7 million Americans afflicted by this debilitating disorder. These numbers are expected to double in the next 20 years, presenting a significant emotional and economic burden. While AD research continues to be a priority, little headway has been made in slowing disease progression, let alone curing it. Early hypotheses into the development of AD included infectious paradigms, but these ideas were largely discarded. However, new data has led researchers to once again suggest that infections may play a developmental and or accelerating role in AD progression. Among infectious organisms, Chlamydia (C.) pneumoniae has been identified as the leading candidate for a pathogenic role in AD. C. pneumoniae, a common cause of community acquired pneumonia, has been linked with many chronic inflammatory diseases, including atherosclerosis, asthma and lung cancer, as well as AD. In addition to anti-C. pneumoniae antibody titer associations with AD, several studies have identified C. pneumoniae in the brains of AD patients. Our expertise in C. pneumoniae infection and immune responses, in combination with our co-investigator’s expertise in AD (Maya Koronyo-Hamaoui, PhD), allows us a unique opportunity to investigate the relationship between C. pneumoniae infection and AD in mouse models of AD. Additionally, we will investigate effect of antibiotic treatment on C. pneumoniae-accelerated AD as well as the role of the NLRP3 inflammasome. The data obtained from these studies will provide the foundation for future in-depth investigations into the relationship between AD and C. pneumoniae, which may lead to new therapeutic avenues.

We have recently published that receptor interacting protein 2 (RIP2) in T-cells regulated pathogenic polarization of Th17 T-cells. New data in the Crother Lab suggests that this pathway may critically control small intestinal inflammation in inflammatory bowel disease (IBD). In the TNBS model of IBD, RIP2 deficient mice developed extensive ileitis in addition to colitis, while wild type mice only developed colitis. This ileal inflammation was accompanied by an influx of Th17/Th1 T-cells, which are considered to be highly pathogenic. We are currently investigating if RIP2 specifically in T-cells is the key factor that regulates this ileal involvement. Additionally, our data suggests that the RIP2 CARD domain may critically control pathogenic Th17 development, and expression of this CARD domain skews Th17 cells towards a more homeostatic phenotype and away from a pathogenic phenotype. Thus, the RIP2 caspase recruitment domain may be a target for a therapeutic approach to Th17 diseases.

The respiratory pathogen, C. pneumoniae, is an obligate intracellular bacteria that causes atypical pneumonia. I have been interested in determining the innate immune mechanisms by which C. pneumoniae is detected during lung infection, and what role each pathway plays in the host response to the infection. To this end, we use various knockout mice in order to dissect out the contributions of toll-like receptors, MYD88, the Nod/Rip2 signaling pathway and the NLRP3 inflammasome/IL-1β signaling pathway. 

We recently made the novel discovery that RIP2 plays a critical role in controlling IL-17 mediated chronic inflammation associated with C. pneumoniae infection. We are interested in defining the regulatory pathways and molecular mechanism by which this occurs, as well as determining the contribution of IL-17 signaling to chronic pulmonary inflammation.

We have also found that plasmacytoid dendritic cells, typically known for their potent antiviral responses, are required for an effective innate immune response to C. pneumoniae infection and are interested in determining this mechanism. Interestingly, these responses do not require type I interferon. Additionally, we are interested in other infectious organisms such as Staphylococcus aureus, Klebsiella pneumoniae and influenza viral infections.

Our lab is interested in how various innate immunity pathways regulate the development and exacerbation of asthma. We have previously investigated how bacterial lung infections can induce or prevent allergic airway inflammation depending on the severity and timing of the initial infection. More recently, we have been investigating house dust mite mouse models of allergic airway sensitization. The Crother Lab is also interested in how gut microbial dysbiosis affects asthma development.