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Published on: September 18, 2020
Macrophage Polarization Modulated by Porcine Circovirus Type 2 Facilitates Bacterial Coinfection
Wen Zhang1,2, Zhendong Fu1,2, Hongyan Yin1,2
1Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, China.
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.
Insights
Porcine circovirus type 2 (PCV2) infection shifts macrophages to a pro-inflammatory M1 state by inhibiting epigenetic regulators. This M1 polarization impairs host defense, increasing susceptibility to secondary bacterial infections.
Area of Science:
- Immunology
- Virology
- Epigenetics
Background:
- Macrophages are crucial for pathogen response, with polarization to M1 or M2 states dictating function.
- Porcine circovirus type 2 (PCV2) causes significant economic losses and is linked to increased susceptibility to other infections.
- The mechanisms by which PCV2 influences macrophage polarization and host defense remain unclear.
Purpose of the Study:
- To investigate how PCV2 infection affects macrophage polarization.
- To elucidate the molecular mechanisms underlying PCV2-induced macrophage reprogramming.
- To understand the contribution of PCV2-mediated macrophage polarization to secondary infections.
Main Methods:
- Analysis of macrophage gene expression profiles following PCV2 infection.
- Investigation of signaling pathways including NF-κB and JNK.
- Assessment of JMJD3 and IRF4 expression and their role in M2 polarization.
- In vitro assays to evaluate the impact of PCV2 infection on bacterial coinfection.
Main Results:
- PCV2 infection promotes M1 macrophage polarization by upregulating M1-associated genes via NF-κB and JNK pathways.
- PCV2 inhibits M2 macrophage polarization by suppressing JMJD3, a key epigenetic regulator.
- The PCV2 capsid protein directly represses JMJD3 transcription, leading to reduced IRF4 expression.
- PCV2-induced M1 polarization facilitates in vitro bacterial coinfection.
Conclusions:
- PCV2 infection induces M1 macrophage polarization through canonical signaling pathways and epigenetic modification.
- The suppression of M2 polarization by PCV2, mediated by JMJD3 inhibition, contributes to increased susceptibility to bacterial infections.
- These findings reveal a novel mechanism of viral pathogenesis involving immune cell reprogramming and highlight PCV2's role in facilitating coinfections.
