Key Points
PGE2 induces immune exhaustion and promotes disease progression of BLV infection.
Dual blockade of PGE2 and PD-L1 invigorates antiviral immune response in cattle.
Abstract
Bovine leukemia virus (BLV) infection is a chronic viral infection of cattle and endemic in many countries, including Japan. Our previous study demonstrated that PGE2, a product of cyclooxygenase (COX) 2, suppresses Th1 responses in cattle and contributes to the progression of Johne disease, a chronic bacterial infection in cattle. However, little information is available on the association of PGE2 with chronic viral infection. Thus, we analyzed the changes in plasma PGE2 concentration during BLV infection and its effects on proviral load, viral gene transcription, Th1 responses, and disease progression. Both COX2 expression by PBMCs and plasma PGE2 concentration were higher in the infected cattle compared with uninfected cattle, and plasma PGE2 concentration was positively correlated with the proviral load. BLV Ag exposure also directly enhanced PGE2 production by PBMCs. Transcription of BLV genes was activated via PGE2 receptors EP2 and EP4, further suggesting that PGE2 contributes to disease progression. In contrast, inhibition of PGE2 production using a COX-2 inhibitor activated BLV-specific Th1 responses in vitro, as evidenced by enhanced T cell proliferation and Th1 cytokine production, and reduced BLV proviral load in vivo. Combined treatment with the COX-2 inhibitor meloxicam and anti-programmed death-ligand 1 Ab significantly reduced the BLV proviral load, suggesting a potential as a novel control method against BLV infection. Further studies using a larger number of animals are required to support the efficacy of this treatment for clinical application.
Footnotes
This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, by Research Project for Improving Animal Disease Prevention Technologies to Combat Antimicrobial Resistance 2017–2021 FY, and by grants from the Project of the NARO, Bio-oriented Technology Research Advancement Institution (Research Program on Development of Innovative Technology 26058 BC [to S.K.] and Special Scheme Project on Regional Developing Strategy, Grant 16817557 [to S.K.]). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The online version of this article contains supplemental material.
- Received April 1, 2019.
- Accepted June 28, 2019.
- Copyright © 2019 by The American Association of Immunologists, Inc.
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