Endodontic infection of tooth root canals and pulp chambers are polymicrobial localized infections that can cause tissue destruction and bone loss, often resulting in tooth loss. Treatment of these infections remains inefficient, with up to a 30% failure rate. There is a strong need for novel approaches to control these infections. The detailed mechanism of the host response to these infections remains incompletely understood. Understanding these mechanisms will be critically important in their control, as well as the control of other polymicrobial infections such as those that are common in diabetic patients. The long term goal of this project is to develop novel effective and efficient treatment regimens for these infections. The objective of this application is to understand the role of the osteopontin (OPN)-integrin axis in the host response to endodontic infection. OPN is a secreted small integrin-binding protein that has a protective effect in a mouse model of endodontic infection, where mice lacking osteopontin (OPN) have significantly greater inflammatory response and bone loss than WT mice. The effect of OPN is likely to be on the innate immune system, which is the primary means of host defense against these infections. Osteopontin interacts with a series of integrins to enhance migration and/or function of myeloid cells including macrophages and neutrophils. The central hypothesis of this proposal is that OPN signals through ?v-containing integrins and/or the ?9?1 integrin to maximize migration and effector functions of myeloid cell types in response to bacterial infection. While the effect of OPN on migration of myeloid cells has been well established, the mechanism of this effect and the integrins with which it interacts are still poorly understood. Experiments described in this proposal are designed to answer these questions and to begin to describe the role of the OPN-binding integrins in endodontic infection.
In Specific Aim 1, a subcutaneous chamber infection model will be used to determine the early defects in myeloid cell accumulation and bacterial killing in mice lacking OPN.
In Aim 2, myeloid cells deficient for one or more of several OPN-binding integrins: the ?v, ?9, ?3 or ?5 integrin will be used in in vitro assays to define the integrins responsible fr the effects of OPN on migration and function. The novel hypothesis that the mechanism of action of OPN includes effects on endocytic recycling will be tested.
Aim 3 will determine the unique role of the OPN-binding integrins in the innate immune response to endodontic infection, using mice deficient for these integrins in all cells, or just in myeloid cells. This approach is innovative in exploring new mechanisms of action of OPN and elucidating the uncharacterized role of the OPN-binding integrins in the host response to polymicrobial infection. The project is especially significant since integrins and their ligands are potential extracellular targets for noel therapeutic interventions.
Control of infection, either in the oral cavity or elsewhere in the body can be challenging, especially in the age of antibiotic resistant organisms. This project will provide novel new information that will increase our understanding of the innate immune response to these infections. This increased understanding is important for the development of new therapeutic strategies to combat these infections.
|Johnston, Christopher D; Skeete, Chelsey A; Fomenkov, Alexey et al. (2017) Restriction-modification mediated barriers to exogenous DNA uptake and incorporation employed by Prevotella intermedia. PLoS One 12:e0185234|
|Singh, Rani; Hui, Tommy; Matsui, Aritsune et al. (2017) Modulation of infection-mediated migration of neutrophils and CXCR2 trafficking by osteopontin. Immunology 150:74-86|
|Wisitrasameewong, W; Kajiya, M; Movila, A et al. (2017) DC-STAMP Is an Osteoclast Fusogen Engaged in Periodontal Bone Resorption. J Dent Res 96:685-693|
|Rittling, S R; Singh, R (2015) Osteopontin in Immune-mediated Diseases. J Dent Res 94:1638-45|
|Hui, Tommy; Sørensen, Esben S; Rittling, Susan R (2015) Osteopontin binding to the alpha 4 integrin requires highest affinity integrin conformation, but is independent of post-translational modifications of osteopontin. Matrix Biol 41:19-25|
|Matsui, Aritsune; Stephens, Danielle; Kantarci, Alpdogan et al. (2015) Early Cytokine Response to Infection with Pathogenic vs Non-Pathogenic Organisms in a Mouse Model of Endodontic Infection. PLoS One 10:e0132752|
|Matsui, Aritsune; Jin, Jun-O; Johnston, Christopher D et al. (2014) Pathogenic bacterial species associated with endodontic infection evade innate immune control by disabling neutrophils. Infect Immun 82:4068-79|
|Diao, Hongyan; Liu, Xiangdong; Wu, Zhongwen et al. (2012) Osteopontin regulates interleukin-17 production in hepatitis. Cytokine 60:129-37|