Up-Regulation of Immune Checkpoints in the Thymus of PRRSV-1-Infected Piglets in a Virulence-Dependent Fashion.

Inés Ruedas-Torres,Fernanda Larenas-Muñoz,Silvia Guil-Luna,Francisco J Pallarés,Irene M Rodríguez-Gómez,Librado Carrasco,Jaime Gómez-Laguna,José María Sánchez-Carvajal

doi:10.3389/fimmu.2021.671743

Abstract

Virulent porcine reproductive and respiratory syndrome virus (PRRSV) strains, such as the Lena strain, have demonstrated a higher thymus tropism than low virulent strains. Virulent PRRSV strains lead to severe thymus atrophy, which could be related to marked immune dysregulation. Impairment of T-cell functions through immune checkpoints has been postulated as a strategy executed by PRRSV to subvert the immune response, however, its role in the thymus, a primary lymphoid organ, has not been studied yet. Therefore, the goal of this study was to evaluate the expression of selected immune checkpoints (PD1/PDL1, CTLA4, TIM3, LAG3, CD200R1 and IDO1) in the thymus of piglets infected with two different PRRSV-1 strains. Thymus samples from piglets infected with the low virulent 3249 strain, the virulent Lena strain and mock-infected were collected at 1, 3, 6, 8 and 13 days post-infection (dpi) to analyze PRRSV viral load, relative quantification and immunohistochemical staining of immune checkpoints. PD1/PDL1, CTLA4, TIM3, LAG3 and IDO1 immune checkpoints were significantly up-regulated in the thymus of PRRSV infected piglets, especially in those infected with the virulent Lena strain from 6 dpi onwards. This up-regulation was associated with disease progression, high viral load and cell death. Co-expression of these molecules can affect T-cell development, maturation and selection, negatively regulating the host immune response against PRRSV.

Highlights

Porcine reproductive and respiratory syndrome (PRRS) is caused by PRRS virus (PRRSV), an RNA virus which presents a huge genetic and antigenic variability, being classified into two different viral species, Betaarterivirus suid-1 and Betaarterivirus suid-2 within the order Nidovirales and family Arteriviridae [1]
T-cell dysfunction through immune checkpoints has been postulated as a strategy executed by PRRSV to subvert the immune response and escape from the host immune control [16]; the role of immune checkpoints in a target lymphoid organ, such as the thymus, has not been studied in PRRS yet, in animals infected with virulent PRRSV strains
We outline the expression of selected immune checkpoints (PD1/programmed cell death 1 ligand 1 (PDL1), cytotoxic T-lymphocyte associated protein 4 (CTLA4), TIM3, lymphocyte activating 3 (LAG3), CD200 receptor 1 (CD200R1) and IDO1) in the thymus of infected piglets during the early phase of PRRSV infection with strains of differing virulence

Summary

Introduction

Porcine reproductive and respiratory syndrome (PRRS) is caused by PRRS virus (PRRSV), an RNA virus which presents a huge genetic and antigenic variability, being classified into two different viral species, Betaarterivirus suid-1 (former PRRSV-1) and Betaarterivirus suid-2 (former PRRSV-2) within the order Nidovirales and family Arteriviridae [1]. The thymus, as primary lymphoid organ, gains special interest in the study of the immunopathogenesis of PRRS, because of its role in T-cell development and maturation [5], and, for being more affected by virulent PRRSV-1 strains, such as Lena or SU1-bel strains [6, 7] Such strains are capable of inducing high apoptosis rates in the thymic cortex, leading to a severe atrophy of the organ in comparison to low virulent strains [6,7,8]. These findings support the interest of studying the immunopathogenesis of PRRS in the thymus of pigs infected with strains of different virulence

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