Porcine reproductive and respiratory syndrome virus infection upregulates negative immune regulators and T-cell exhaustion markers

Jayeshbhai Chaudhari, Chia Sin Liew, Jean Jack M. Riethoven, Sarah Sillman, Hiep L.X. Vu

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Porcine alveolar macrophage (PAM) is one of the primary cellular targets for porcine reproductive and respiratory syndrome virus (PRRSV), but less than 2% of PAMs are infected with the virus during the acute stage of infection. To comparatively analyze the host transcriptional response between PRRSV-infected PAMs and bystander PAMs that remained uninfected but were exposed to the inflammatory milieu of an infected lung, pigs were infected with a PRRSV strain expressing green fluorescent protein (PRRSV-GFP), and GFP1 (PRRSV infected) and GFP2 (bystander) cells were sorted for RNA sequencing (RNA-seq). Approximately 4.2% of RNA reads from GFP1 and 0.06% reads from GFP2 PAMs mapped to the PRRSV genome, indicating that PRRSV-infected PAMs were effectively separated from bystander PAMs. Further analysis revealed that inflammatory cytokines, interferon-stimulated genes, and antiviral genes were highly upregulated in GFP1 compared to GFP2 PAMs. Importantly, negative immune regulators, including NF-kB inhibitors (NFKBIA, NFKBID, NFKBIZ, and TNFAIP3) and T-cell exhaustion markers (programmed death ligand-1 [PD-L1], PD-L2, interleukin-10 [IL-10], IDO1, and transforming growth factor b2 [TGFB2]) were highly upregulated in GFP1 cells compared to GFP2 cells. By using an in situ hybridization assay, RNA transcripts of tumor necrosis factor (TNF) and NF-kB inhibitors were detected in PRRSV-infected PAMs cultured ex vivo and lung sections of PRRSV-infected pigs during the acute stage of infection. Collectively, the results suggest that PRRSV infection upregulates expression of negative immune regulators and T-cell exhaustion markers in PAMs to modulate the host immune response. Our findings provide further insight into PRRSV immunopathogenesis. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) is widespread in many swine-producing countries, causing substantial economic losses to the swine industry. Porcine alveolar macrophage (PAM) is considered the primary target for PRRSV replication in pigs. However, less than 2% of PAMs from acutely infected pigs are infected with the virus. In the present study, we utilized a PRRSV strain expressing green fluorescent protein to infect pigs and sorted infected and bystander PAMs from the pigs during the acute stage of infection for transcriptome analysis. PRRSV-infected PAMs showed a distinctive gene expression profile and contained many uniquely activated pathways compared to bystander PAMs. Interestingly, upregulated expression of NF-kB signaling inhibitors and T-cell exhaustion molecules were observed in PRRSV-infected PAMs. Our findings provide additional knowledge on the mechanisms that PRRSV employs to modulate the host immune system.

Original languageEnglish (US)
Article numbere01052-21
JournalJournal of virology
Volume95
Issue number21
DOIs
StatePublished - Nov 2021

Keywords

  • NF-kB inhibitors
  • NF-kB inhibitors
  • PRRSV
  • RNA-seq
  • T-cell exhaustion
  • Transcriptome

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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