PRRSV-1 induced lung lesion is associated with an imbalance between costimulatory and coinhibitory immune checkpoints

Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV) induces a dysregulation on the innate and adaptive immune responses. T-cell activation requires a proper interaction and precise balance between costimulatory and coinhibitory molecules, commonly known as immune checkpoints. This study aims to evaluate the expression of immune checkpoints in lung and tracheobronchial lymph node from piglets infected with two PRRSV-1 strains of different virulence during the early stage of infection. Seventy 4-week-old piglets were grouped into three experimental groups: (i) control, (ii) 3249-infected group (low virulent strain), and (iii) Lena-infected group (virulent strain) and were euthanized at 1, 3, 6, 8, and 13 days post-infection (dpi). Lung and tracheobronchial lymph node were collected to evaluate histopathological findings, PRRSV viral load and mRNA expression of costimulatory (CD28, CD226, TNFRSF9, SELL, ICOS, and CD40) and coinhibitory (CTLA4, TIGIT, PD1/PDL1, TIM3, LAG3, and IDO1) molecules through RT-qPCR. Our findings highlight a mild increase of costimulatory molecules together with an earlier and stronger up-regulation of coinhibitory molecules in both organs from PRRSV-1-infected animals, especially in the lung from virulent Lena-infected animals. The simultaneous expression of coinhibitory immune checkpoints could work in synergy to control and limit the inflammation-induced tissue damage. Further studies should be addressed to determine the role of these molecules in later stages of PRRSV infection.

Integrative transcriptomic profiling of mRNA, miRNA, circRNA, and lncRNA in alveolar macrophages isolated from PRRSV-infected porcine

“…This might be indicative of the commencement of recovery mechanisms in pigs from PRRS, suggesting a potential temporal modulation of these genes during the infection’s progression. These findings align with three other investigations, which report CTLA4 upregulation during PRRSV-1 or PRRSV-2 infection ( 59 – 61 ), lending further credence to the prolonged immune suppressive effect of PRRSV. We also observed the upregulation of another gene, SAMHD1 (SAM domain and HD domain-containing protein 1), known for its antiviral properties triggered by interferon, and its capacity to restrain the proliferation of numerous RNA or DNA viruses ( 62 , 63 ).…”

The scene of lung pathology during PRRSV-1 infection

“…Furthermore, recently, it has been published that PRRSV-1 may induce an imbalance between costimulatory and coinhibitory immune checkpoints at lung level during the acute phase of infection ( 110 ). Thus, it was reported that a modest increase in costimulatory molecules was accompanied by an earlier and more robust upregulation of coinhibitory molecules, particularly in the lungs of those infected with the virulent Lena strain ( 110 ).…”

“…Furthermore, recently, it has been published that PRRSV-1 may induce an imbalance between costimulatory and coinhibitory immune checkpoints at lung level during the acute phase of infection ( 110 ). Thus, it was reported that a modest increase in costimulatory molecules was accompanied by an earlier and more robust upregulation of coinhibitory molecules, particularly in the lungs of those infected with the virulent Lena strain ( 110 ). The concurrent expression of these coinhibitory immune checkpoints, as evidenced by the strong correlations observed among them, implies a synergistic action of these molecules, likely aimed at modulating the heightened inflammatory response and mitigating associated lung tissue damage.…”

The DC–T cell axis is an effective target for the treatment of non‐small cell lung cancer

“…The interaction involving MHCs, antigens, and TCRs triggers the activation of T cells, which initiates downstream signals through the immune receptor tyrosine‐based activation motif 66 . The second signal can be classified into co‐stimulatory and co‐inhibitory molecules based on their distinct effects 67,68 . CD28, inducible co‐stimulator, tumor necrosis factor receptor superfamily member 4 (OX40), and CD40L are co‐stimulatory molecules.…”

“…66 The second signal can be classified into co-stimulatory and coinhibitory molecules based on their distinct effects. 67,68 CD28, inducible co-stimulator, tumor necrosis factor receptor superfamily member 4 (OX40), and CD40L are co-stimulatory molecules. All these pivotal signaling molecules are accountable for the activation, differentiation, and survival of T cells.…”