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**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** PORCINE REPRODUCTIVE AND RESPIRATORY SYNDROME VIRUS (PRRSV)AND SWINE INFLUENZA A VIRUS (SIAV) INFECTIONS ARE TWO OF THE MOST IMPORTANT VIRAL DISEASES IN PIGS WITH MAJOR ECONOMIC IMPACT ON THE SWINE INDUSTRY AND SUSTAINED FOOD SUPPLY. SIAV CAUSES INFLUENZA OUTBREAKS IN PIGS, LEADING TO MAJOR ECONOMIC LOSSES FOR PIG PRODUCERS. FURTHERMORE, PIGS ARE A POTENTIAL SOURCE FOR EMERGENCE OF PANDEMIC INFLUENZA IN HUMANS FOR THEY CAN BE INFECTED WITH BOTH HUMAN AND PIG INFLUENZA VIRUSES. THEREFORE, CONTROLLING INFLUENZA INFECTION IN PIGS IS HIGHLY IMPORTANT FOR THE SWINE INDUSTRY AND THE PUBLIC HEALTH. PRRSV CAUSES REPRODUCTIVE PROBLEMS AND POST-WEANING MORTALITY IN PIGS, RESULTING IN SIGNIFICANT ECONOMIC LOSSES. SINCE CURRENTLY AVAILABLE VACCINES AND OTHER CONVENTIONAL METHODS ARE NOT EFFECTIVE AT CONTROLLING SIAV AND PRRSV INFECTIONS IN PIGS, DEVELOPMENT OF NOVEL METHODS TO MITIGATE THE BURDEN OF THESE VIRAL DISEASES IS EXPECTED TO GREATLY BENEFIT THE SWINE INDUSTRY AND THE PUBLIC HEALTH. IDENTIFYING HOST FACTORS THAT ARE CRUCIAL FOR BOTH VIRUSES IS AN IMPORTANT STEP TOWARDS THIS GOAL. WE HAVE FOUND THAT PROTEIN DISULFIDE ISOMERASES (PDIS), ESPECIALLY PDIA4, ARE REQUIRED FOR SIAV AND PRRSV IN NON-PORCINE ORIGINATED CELLS. PDIS ARE THE ENZYMES THAT ARE INVOLVED IN PROPER PROTEIN FOLDING IN THE CELLS. IN THIS PROJECT, WE WILL INVESTIGATE WHETHER VARIOUS STRAINS OF HUMAN INFLUENZA VIRUS AND SIAV AND PRRSV ARE DEPENDENT ON THE PDIS FOR THEIR REPLICATION IN THE PORCINE-ORIGINATED CELLS. TO DO THIS, WE WILL GENERATE PDIA4-DELETED (KNOCKOUT) PORCINE CELLS AND GROW HUMAN AND SWINE INFLUENZA VIRUSES AND PRRSV. SIGNIFICANTLY REDUCED VIRAL REPLICATION IN THE PDIA4-KNOCKOUT CELLS INDICATES THAT PDIA4 IS CRITICAL FOR THESE VIRUSES. THE RESULTS WILL BE CONFIRMED BY RESTORING THE EXPRESSION OF PDIA4 IN THE CELLS. THE MECHANISM BY WHICH PDIA4 KNOCKOUT INHIBITS VIRAL REPLICATION WILL BE STUDIED BY CONDUCTING AN ARRAY OF EXPERIMENTS. LASTLY, TRANSGENIC MICE WITH PDIA4 KNOCKOUT WILL BE INFECTED WITH INFLUENZA VIRUS TO STUDY WHETHER PDIA4 KNOCKOUT LEADS TO INCREASED RESISTANCE TO INFLUENZA VIRUS INFECTION. THIS PROOF-OF-CONCEPT STUDY USING A COMMERCIALLY AVAILABLE TRANSGENIC MOUSE MODEL WILL OFFER VALUABLE INSIGHT INTO THE FEASIBILITY OF USING PDIA4 TO PRODUCE TRANSGENIC PIGS WITH INCREASED RESISTANCE TO BOTH VIRAL DISEASES IN FUTURE STUDIES.

$472,017FY2019National Institute of Food and AgricultureUSDA

Kansas State University, Manhattan KS

Investigators

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**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** PORCINE REPRODUCTIVE AND RESPIRATORY SYNDROME VIRUS (PRRSV)AND SWINE INFLUENZA A VIRUS (SIAV) INFECTIONS ARE TWO OF THE MOST IMPORTANT VIRAL DISEASES IN PIGS WITH MAJOR ECONOMIC IMPACT ON THE SWINE INDUSTRY AND SUSTAINED FOOD SUPPLY. SIAV CAUSES INFLUENZA OUTBREAKS IN PIGS, LEADING TO MAJOR ECONOMIC LOSSES FOR PIG PRODUCERS. FURTHERMORE, PIGS ARE A POTENTIAL SOURCE FOR EMERGENCE OF PANDEMIC INFLUENZA IN HUMANS FOR THEY CAN BE INFECTED WITH BOTH HUMAN AND PIG INFLUENZA VIRUSES. THEREFORE, CONTROLLING INFLUENZA INFECTION IN PIGS IS HIGHLY IMPORTANT FOR THE SWINE INDUSTRY AND THE PUBLIC HEALTH. PRRSV CAUSES REPRODUCTIVE PROBLEMS AND POST-WEANING MORTALITY IN PIGS, RESULTING IN SIGNIFICANT ECONOMIC LOSSES. SINCE CURRENTLY AVAILABLE VACCINES AND OTHER CONVENTIONAL METHODS ARE NOT EFFECTIVE AT CONTROLLING SIAV AND PRRSV INFECTIONS IN PIGS, DEVELOPMENT OF NOVEL METHODS TO MITIGATE THE BURDEN OF THESE VIRAL DISEASES IS EXPECTED TO GREATLY BENEFIT THE SWINE INDUSTRY AND THE PUBLIC HEALTH. IDENTIFYING HOST FACTORS THAT ARE CRUCIAL FOR BOTH VIRUSES IS AN IMPORTANT STEP TOWARDS THIS GOAL. WE HAVE FOUND THAT PROTEIN DISULFIDE ISOMERASES (PDIS), ESPECIALLY PDIA4, ARE REQUIRED FOR SIAV AND PRRSV IN NON-PORCINE ORIGINATED CELLS. PDIS ARE THE ENZYMES THAT ARE INVOLVED IN PROPER PROTEIN FOLDING IN THE CELLS. IN THIS PROJECT, WE WILL INVESTIGATE WHETHER VARIOUS STRAINS OF HUMAN INFLUENZA VIRUS AND SIAV AND PRRSV ARE DEPENDENT ON THE PDIS FOR THEIR REPLICATION IN THE PORCINE-ORIGINATED CELLS. TO DO THIS, WE WILL GENERATE PDIA4-DELETED (KNOCKOUT) PORCINE CELLS AND GROW HUMAN AND SWINE INFLUENZA VIRUSES AND PRRSV. SIGNIFICANTLY REDUCED VIRAL REPLICATION IN THE PDIA4-KNOCKOUT CELLS INDICATES THAT PDIA4 IS CRITICAL FOR THESE VIRUSES. THE RESULTS WILL BE CONFIRMED BY RESTORING THE EXPRESSION OF PDIA4 IN THE CELLS. THE MECHANISM BY WHICH PDIA4 KNOCKOUT INHIBITS VIRAL REPLICATION WILL BE STUDIED BY CONDUCTING AN ARRAY OF EXPERIMENTS. LASTLY, TRANSGENIC MICE WITH PDIA4 KNOCKOUT WILL BE INFECTED WITH INFLUENZA VIRUS TO STUDY WHETHER PDIA4 KNOCKOUT LEADS TO INCREASED RESISTANCE TO INFLUENZA VIRUS INFECTION. THIS PROOF-OF-CONCEPT STUDY USING A COMMERCIALLY AVAILABLE TRANSGENIC MOUSE MODEL WILL OFFER VALUABLE INSIGHT INTO THE FEASIBILITY OF USING PDIA4 TO PRODUCE TRANSGENIC PIGS WITH INCREASED RESISTANCE TO BOTH VIRAL DISEASES IN FUTURE STUDIES. · GrantIndex