In this Administrative supplement (PA-18-591) to supplement an existing NIH RO1 to investigate Alzheimer?s Disease, the original parent RO1 investigates the role of IL-17 signaling during Chlamydia Pneumonia (CP) infection and chronic lung inflammation. In this administrative supplement, we will investigate the role of Chlamydia pneumoniae infection in accelerating disease progression in Alzheimer's Disease (AD) utilizing the AD mouse model ( APPSWE/PS1?E9 mice). We also propose to determine the role and relevance of the Rip2/IL- 17 axis in Alzheimer's Disease as well as CP infection-mediated acceleration of Alzheimer's Disease using the experimental model of AD, APPSWE/PS1?E9 mice. Alzheimer's Disease (AD), a progressive irreversible senile dementia, is the sixth 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. 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 pneumoniae has been identified as the leading candidate for a pathogenic role in AD. CP, a common cause of community acquired pneumonia, has been linked with many chronic inflammatory diseases, including atherosclerosis, asthma, lung cancer, as well as AD. Studies also suggest that IL-17 inflammatory cytokine may play a detrimental role in Neuroinflammatory diseases, including AD, but the specific role of IL-17 in AD pathogenesis is not known. Based on the large amount of data in the published literature presented above, we hypothesize that Chlamydia pneumonia infection plays a role in progression and or development of Alzheimer's Disease and that IL-17 induction and the IL-17 induced neuroinflammation may be responsible for Chlamydia pneumonia infection-mediated acceleration of AD. Our expertise in CP infections and immune responses such as IL-17 induced inflammation, in combination with our collaborator?s world-wide expertise in AD and Ad mouse models, allows us a unique opportunity to investigate the relationship between Chlamydia pneumoniae infection and Alzheimer?s Disease progression using a well-accepted and relevant experimental murine model of AD. We hypothesize that CP infection plays a role in progression and or development of Alzheimer's Disease and that IL-17 induction by this infection is the mechanism by which the CP infection accelerates the brain pathology of AD. The two specific aims proposed are;
Aim 1 : To determine the role of Chlamydia pneumoniae infection in accelerating disease progression in Alzheimer's Disease in a murine model of AD ( APPSWE/PS1?E9 mice).
Aim 2 : To determine the role and relevance of the Rip2/IL-17 axis in Alzheimer's Disease as well as CP infection-mediated acceleration of Alzheimer's Disease using the APPSWE/PS1?E9 mice.
Alzheimer?s Disease is an irreversible neurodegenerative disorder which leads to dementia and eventual death. An estimated 5.7 million Americans and nearly 50 million worldwide are diagnosed with AD, and the human suffering, economic as well as emotional burden on families are substantial problems. In this application we will investigate if a common community acquired pneumoniae infection plays any role in accelerating Alzheimer?s disease using experimental mouse model of the disease.
| Shimada, Kenichi; Porritt, Rebecca A; Markman, Janet L et al. (2018) T-Cell-Intrinsic Receptor Interacting Protein 2 Regulates Pathogenic T Helper 17 Cell Differentiation. Immunity 49:873-885.e7 |
| Tumurkhuu, Gantsetseg; Dagvadorj, Jargalsaikhan; Porritt, Rebecca A et al. (2018) Chlamydia pneumoniae Hijacks a Host Autoregulatory IL-1? Loop to Drive Foam Cell Formation and Accelerate Atherosclerosis. Cell Metab 28:432-448.e4 |
| Chen, Shuang; Shimada, Kenichi; Crother, Timothy R et al. (2018) Chlamydia and Lipids Engage a Common Signaling Pathway That Promotes Atherogenesis. J Am Coll Cardiol 71:1553-1570 |
| Noval Rivas, Magali; Crother, Timothy R; Arditi, Moshe (2016) The microbiome in asthma. Curr Opin Pediatr 28:764-771 |
