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Title:   Author  item
                                            Schlink, Sarahitem
                                            Lager, Kellyitem
                                            Brockmeier, Susanitem
                                            Loving, Crystalitem
                                            Miller, Lauraitem
                                            Vorwald, Annitem
                                            YANG, HAN-CHUN - China Agricultural Universityitem
                                            Kehrli Jr, Marcusitem
                                            Faaberg, Kay
  Submitted to: Veterinary Immunology and Immunopathology
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 8/4/2016
                                    Publication  Date: 8/10/2016
                                    Citation: Schlink, S.N., Lager, K.M., Brockmeier, S.L., Loving, C.L., Miller, L.C., Vorwald, A.C., Yang, H., Kehrli, Jr., M.E., Faaberg, K.S. 2016. Enhancement of innate immunity with granulocyte colony-stimulating factor did not mitigate disease in pigs infected with a highly pathogenic Chinese PRRSV strain. Veterinary Immunology and Immunopathology. 179:70-76.Interpretive Summary: Porcine reproductive and respiratory syndrome virus (PRRSV) is responsible for one of the most economically important disease in swine worldwide. It causes reproductive failure in sows and pneumonia in pigs which predisposes them to secondary bacterial infections. Methods to control PRRSV and/or limit secondary bacterial infections are desired to reduce the impact of this virus on animal health. Part of the pig's natural immune response to a bacterial infection is to increase the production of neutrophils, a certain type of white blood cell that circulates in the blood. Neutrophils can migrate in the tissues as well to help defend the pig against invading bacteria. The growth and development of neutrophils is moderated by Granulocyte-Colony Stimulating Factor (G-CSF), a protein in the body that controls the production, differentiation and function of neutrophils. Recent work from our laboratory has shown that a single dose of porcine G-CSF given to pigs induced a significant increase in circulating neutrophils for more than two weeks. Secondary bacterial infection is a common occurrence following PRRSV infection in young pigs. The aim of the current study was to evaluate the effectiveness of a single dose of G-CSF to reduce secondary bacterial disease associated with PRRSV infection. Administration of G-CSF induced a significant increase in circulating neutrophils in pigs. However, between 1 and 2 days following PRRSV challenge, the number of circulating neutrophils decreased dramatically in the PRRSV infected group, but not the non-infected G-CSF treated group. Overall, there was no difference in the progression of disease between the G-CSF and control groups following PRRSV infection. It is not yet clear how the PRRSV infection affected the increased number of neutrophils. The use of G-CSF to help fight bacterial infections is still a possibility, but it may be that a single dose of this potential therapy will not work during a PRRSV infection. However, there is still potential for this strategy to work for other diseases, and with different formulations or dosing, it still may work in PRRSV infections.
                                Technical Abstract: Porcine reproductive and respiratory syndrome virus (PRRSV) is responsible for one of the most economically important diseases in swine worldwide. It causes reproductive failure in sows and pneumonia in pigs that predisposes them to secondary bacterial infections. Methods to control PRRSV and/or limit secondary bacterial infections are desired to reduce the impact of this virus on animal health. Neutrophils play a major role in combatting infection; they can act as phagocytes as well as produce and release lytic enzymes that have potent antimicrobial effects leading to the destruction and clearance of bacterial pathogens. Granulocyte-colony stimulating factor (G-CSF) is a cytokine that controls the production, differentiation and function of granulocytes (including neutrophils) from the bone marrow. Recent work from our laboratory has shown that encoding porcine G-CSF in a replication-defective adenovirus (Ad5-G-CSF) and delivering a single dose to pigs induced a neutrophilia lasting more than two weeks. As secondary bacterial infection is a common occurrence following PRRSV infection, particularly following challenge with highly pathogenic (HP)-PRRSV, the aim of the current study was to evaluate the effectiveness of a single prophylactic dose of adenovirus-encoded G-CSF to mitigate secondary bacterial disease associated with HP-PRRSV infection. Administration of the Ad5-G-CSF induced a significant increase in circulating neutrophils as expected. However, between 1 and 2 days following HP-PRRSV challenge the number of circulating neutrophils decreased dramatically in the HP-PRRSV infected group, but not the non-infected Ad5-G-CSF group. Ad5-G-CSF administration induced monocytosis as well, which was also effected by HP-PRRSV challenge. Overall, there was no difference in the progression of disease between the Ad5-G-CSF and Ad5-empty groups following HP-PRRSV challenge, with pneumonia and systemic bacterial infection occurring in both treatment groups. Given the impact of HP-PRRSV infection on the neutrophilia induced by the Ad5-G-CSF administration, additional studies are still warranted to evaluate the timing of Ad5-G-CSF induced neutrophilia and multiple G-CSF inoculations on protection against secondary bacterial infection following PRRSV infection. Nevertheless, this study may provide insight into the pathogenesis of HP-PRRSV.


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