Abstract
Marek’s disease virus (MDV), an avian alphaherpesvirus, infects chickens, transforms CD4+ T cells, and induces immunosuppression early during infection. However, the exact mechanisms involved in MDV-induced immunosuppression are yet to be identified. Here, our results demonstrate that MDV infection in vitro and in vivo induces activation of cyclooxygenase-2 (COX-2) and production of prostaglandin E2 (PGE2). This exerts its inhibitory effects on T cell proliferation at day 21 post infection via PGE2 receptor 2 (EP2) and receptor 4 (EP4). Impairment of the MDV-induced T cell proliferation was associated with downregulation of IL-2 and transferrin uptake in a COX-2/PGE2 dependent manner in vitro. Interestingly, oral administration of a COX-2 inhibitor, meloxicam, during MDV infection inhibited COX-2 activation and rescued T cell proliferation at day 21 post infection. Taken together, our results reveal a novel mechanism that contributes to immunosuppression in the MDV-infected chickens.
Highlights
Several viruses that establish chronic infections have evolved mechanisms to escape immune control
The results showed that the chemical inhibitors of the COX-2/Prostaglandin E2 (PGE2) pathway; TG4-155 (EP2 blocker), ER-819762 (EP4 blocker) and SC-236 (COX-2 inhibitor) inhibited impairment of T cell proliferation induced by the recombinant PGE2 (Figures 4E, F), the soluble factors released from Marek’s disease virus (MDV)-infected cells (Figures 4E, G) and soluble factors released from MDV-transformed T cell lines (265L sup.) (Figures 4E, H)
In vitro infection of chicken embryonated fibroblasts with virulent strain of MDV activates COX-2/PGE2 pathway which is involved in efficient replication of MDV via Ep2 and EP4 receptors which are upregulated in MDV infected cells [15]
Summary
Several viruses that establish chronic infections have evolved mechanisms to escape immune control. MDV-Induced COX-2 Pathway Suppresses T Cell Proliferation In Vitro and In Vivo virus replication and modulate both anti-viral innate and adaptive immune system. We had previously shown that in vitro infection of chicken embryonic fibroblasts (CEFs) with virulent MDV activates COX-2/PGE2 pathway, which is involved in MDV replication [15]. It was unclear whether MDV can activate COX2/PGE2 pathway in vivo and very little was known about the effects of MDV-induced PGE2 on function of immune cells. The in vitro and in vivo results demonstrate that the virulent MDV, but not Rispens-CVI988, activates the COX-2/PGE2 pathway which modulates T cell proliferation in EP2 and EP4 dependent manner. Oral administration of a COX-2 inhibitor downregulated MDV-induced COX-2 activation and restored T cell proliferation at 21-day post infection in the MDVinfected chickens
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