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Principal Investigator: Dr. Julia Flaminio
Contact Information: E-mail: mbf6@cornell.edu - Phone: 607-253-3119
Sponsor: Harry M. Zweig Memorial Fund for Equine Research
Grant Number: N/A
Title: How does the Immune System of the Foal Fight Against Rhodococcus equi Infection?
Annual Direct Cost: $41,232
Project Period: 01/01/06-12/31/07
Description (provided by applicant): Our hypothesis is that dendritic cells of adult horses but not of young foals are capable of becoming mature to activate and support the effector cells of the acquired immune system. Our main objective is to investigate the role of dendritic cells in the development of a protective response against R. equi.
Our specific aims are to: a) investigate the potential of R. equi-infected dendritic cells to activate the acquired immune system by measuring the expression of cell surface molecules involved in antigen presentation (MHC class I and class II) and co-stimulation (CD86), and the expression of cytokines (IL-12, IFNa) that stimulate a Thl type immune response from lymphocytes. b) compare the effect of virulent versus avirulent R. equi in the parameters described above; c) compare the dendritic cell response to macrophage response; d) compare adult horse cell response to cells from foals of different ages. e) gather preliminary data in the dendritic cell capability of killing R. equi organism by measuring bacterial intracellular survival (bacterial count).
Foals younger than 5 months of age, but not older, are susceptible to Rhodococcus equi (Meijer and Prescott, 2004). R. equi is a Gram positive facultative intracellular organism capable of multiplying in macrophages, including alveolar macrophages (Hietala and Ardans, 1987b). This pathogen is ubiquitous in the horse environment (soil) and causes severe and often fatal granulomatous pneumonia, caseous abscessation of the lymph nodes of the intestine and occasionally osteomyelitis in young foals (Giguere and Prescott, 1997). It is also an opportunistic organism in immunocompromised human patients, including patients infected with the human immunodeficiency virus (Harvey and Sunstrom, 1991; Mosser and Hondalus, 1996). Taken together, those observations suggest that the young foal present an impaired immune mechanism in the clearance and protection against R. equi infection.
Dendritic cells are professional antigen presenting cells. Similarly to macrophages, those cells encounter pathogens or antigens in the tissues, phagocytose, and process them for presentation to cells belonging to the acquired immune system (e.g. lymphocytes). The effect of R. equi on dendritic cells has been poorly studied. However, it is possible that those cells may recognize R. equi via toll-like receptors (TLRs), and process the bacterium similarly to or more efficiently than macrophages. Also, it is possible that dendritic cells of foals may not process R. equi as efficiently as adult horses; if so, the susceptibility of young foals to R. equi may be associated with age-dependent maturation of the antigen presenting cells in presenting processed antigen to and priming of lymphocytes, which are the effect0r cells in protection. That possibility is supported by our preliminary data.
The rationale of this proposed study is that dendritic cells and macrophages of adult horses, but not young foals, phagocytose VapA+ R. equi, and express high levels of IFNtt and ILl2. Macrophages and dendritic cells of young foals infected with VapA+ R. equi may have impaired expression of MHC class II and cytokine production due to age-dependent cell function. VapA- R. equi will be used as a control to evaluate for immunosuppressor factors associated with the pathogen versus age-dependent maturation of the immune system of the foal.
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