Projects
PATHOGENESIS OF EXACERBATED PNEUMONIA IN PRRSV-BACTERIAL CO-INFECTIONS
Summary
Non Technical Summary
Respiratory viral infections are often accompanied by secondary bacterial infections that make the disease produced by the same virus or the bacteria alone much worse. In swine, over 60% of pneumonias resulting from the infection of pigs with porcine reproductive and respiratory syndrome virus (PRRSV) become complicated with secondary infections by commensal pathogenic bacteria. PRRSV-bacterial co-infections produce heightened pneumonia which is accompanied by an intense pulmonary inflammatory response resulting in an increased severity of the disease and often death. The aim of this project is to test the hypothesis that the activation of endoplasmic reticulum stress sensor kinase IRE-1alpha, which becomes activated in alveolar macrophages (AMø) infected with PRRSV is involved in the development of exacerbated pneumonia and enhanced morbidity that occurs in pigs afflicted with a PRRSV and bacterial co-infection. To test this hypothesis, we will use inhibitors of this kinase to directly examine the role of IRE-1alpha in the development of a pro-inflammatory cytokine response of AMø infected with PRRSV as well its role in the development of exacerbated pneumonia during a PRRSV bacterial co-infections. The goal is to identify novel targets for alternative therapeutic intervention for disease reduction in swine afflicted with a PRRSV-bacterial co-infection as an alternative to antimicrobial therapy.
Objectives & Deliverables
Goals / Objectives
In swine, infection of the lower respiratory tract with porcine and reproductive syndrome virus (PRRSV) is often associated with secondary bacterial infections, resulting in an exacerbated pneumonia that can be lethal. The heightened pneumonia is associated with an excessive inflammatory response in the lung, however the mechanisms responsible for this virus-bacterial synergy is unknown. The aim of this project is to test the hypothesis that activation of endoplasmic reticulum stress sensor kinase IRE-1alpha, which becomes activated in alveolar macrophages (AMø) infected with porcine reproductive and respiratory syndrome virus (PRRSV), plays a role in promoting the heightened pneumonia and intense inflammatory response that occurs in the lungs of pigs afflicted with a PRRSV-bacterial co-infection. We propose to: 1) Identify specific regions of PRRSV genome associated with the synergistic TNF-alpha response of PRRSV-infected AMø to bacterial molecules recognized by cells of the innate immune system. 2) Determine the effect of IRE-1alpha in the development of exacerbated pneumonia in PRRSV bacterial co-infections. The goal is to identify novel targets for alternative therapeutic intervention for disease reduction in swine afflicted with a PRRSV-bacterial co-infection as an alternative to antimicrobial therapy, an aim of priority code A1221.
Challenges
Project Methods
To accomplish our goal, we will test the pro-inflammatory cytokine response of AMø that have been infected with either of a number of strains of PRRSV and examine the intensity of the activation of IRE-1alpha and the extent of the synergistic pro-inflammatory response to bacterial products. We expect to find differences between the responses triggered by the different strains, which would lead to the identification of the region of the viral genome responsible for the stress response to the viral infection. We will test the ability of an inhibitor of IRE-1alpha to ameliorate the severity of the respiratory syndrome triggered by a PRRSV-bacterial co-infection. Reduction in the severity of the syndrome would indicate that IRE-1alpha kinase is involved in the pathogenesis of this syndrome.
Principle Investigator(s)
Planned Completion date: 14/06/2022
Effort: $460,000.00
Project Status
COMPLETE
Principal Investigator(s)
National Institute of Food and Agriculture
Researcher Organisations
Recipient Organization UNIVERSITY OF ILLINOIS 2001 S. Lincoln Ave. URBANA,IL 61801
United Kingdom