Macrophage Polarization Modulated by Porcine Circovirus Type 2 Facilitates Bacterial Coinfection

Abstract

Polarization of macrophages to different functional states is important for mounting responses against pathogen infections. Macrophages are the major target cells of porcine circovirus type 2 (PCV2), which is the primary causative agent of porcine circovirus–associated disease (PCVAD) leading to immense economic losses in the global swine industry. Clinically, PCV2 is often found to increase risk of other pathogenic infections yet the underlying mechanisms remain to be elusive. Here we found that PCV2 infection skewed macrophages toward a M1 status through reprogramming expression of a subset of M1-associated genes and M2-associated genes. Mechanistically, induction of M1-associated genes by PCV2 infection is dependent on activation of nuclear factor kappa B (NF-κB) and c-jun N-terminal kinase (JNK) signaling pathways whereas suppression of M2-associated genes by PCV2 is via inhibiting expression of jumonji domain containing-3 (JMJD3), a histone 3 Lys27 (H3K27) demethylase that regulates M2 activation of macrophages. Finally, we identified that PCV2 capsid protein (Cap) directly inhibits JMJD3 transcription to restrain expression of interferon regulatory factor (IRF4) that controls M2 macrophage polarization. Consequently, sustained infection of PCV2 facilitates bacterial infection in vitro. In summary, these findings showed that PCV2 infection functionally modulated M1 macrophage polarization via targeting canonical signals and epigenetic histone modification, which contributes to bacterial coinfection and virial pathogenesis.

Pseudorabies virus tegument protein UL13 recruits RNF5 to inhibit STING-mediated antiviral immunity

“…Cells were maintained in Dulbecco’s minimal essential medium (DMEM) (Gibco, USA) containing 10% fetal bovine serum (FBS) (Biological Industries, Israel) and 1% penicillin-streptomycin (Gibco) at 37°C and 5% CO 2 . IFNAR-deficient BMDMs were provided by Dr. Feng Ma (SuZhou Institute of Systems Medicine, SuZhou, China) and were cultured as previously described [ 55 ]. All cells were tested negative for mycoplasma.…”

Pseudorabies Virus Tegument Protein UL13 Suppresses RLR-Mediated Antiviral Innate Immunity through Regulating Receptor Transcription

“…For blocking of NF-κB and MAPK signals, specific chemical inhibitors were applied as described previously [ 28 ]. Briefly, cells were pretreated with the NF-κB inhibitor Bay11-7082 (Bay11, 10 µM), JNK inhibitor SP600125 (SP, 10 µM), MEK/ERK inhibitor U0126 (10 µM), or p38 MAPK inhibitor SB203580 (SB, 10 µM) for 1 h prior to poly(I:C) (InvivoGen, San Diego, CA, USA) transfection.…”

Modulation of Macrophage Polarization by Viruses: Turning Off/On Host Antiviral Responses

“…Moreover, the reduced production of IL-18 impairs the antibacterial activity of NK cells and then suppresses the production of IFN-γ, NO, and TNF-α. In contrast, the capsid protein (Cap) of porcine circovirus type 2 (PCV2) suppresses the expression of interferon regulatory factor 4 (IRF4) by inhibiting the transcription of jumonji domain-containing 3 (JMJD3), thus promoting M1 macrophage polarization and bacterial engulfment (Zhang W. et al, 2021).…”