Macrophage Polarization Modulated by Porcine Circovirus Type 2 Facilitates Bacterial Coinfection.

Wen Zhang,Yingli Shang,Qingbing Han,Hongyan Yin,Wenhui Fan,Fangkun Wang,Zhendong Fu

doi:10.3389/fimmu.2021.688294

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.

Highlights

Host organisms are generally exposed to multiple pathogens simultaneously in a natural environment [1]
We found that porcine circovirus type 2 (PCV2) infection strikingly induced expression of a subset of M1-associated genes including CXCL10, SOCS3, iNOS, IL12B and STAT1 whereas decreased expression of multiple M2-associated genes such as IRF4, KLF4, PPARg and CCR2 (Figure 1B), indicating that PCV2 infection likely reprograms the macrophage transcription phenotype
To further determine the result obtained by RNA-seq analysis, we tested the expression of M1 and M2 macrophage-associated genes in bone marrow-derived macrophages (BMDMs) infected with PCV2 for various times or with different doses of PCV2. Quantitative Real-Time PCR (qPCR) analysis showed that PCV2 infection promoted the expression of key M1 macrophageassociated genes and suppressed the expression of M2 macrophage phenotype genes (Figures 1C, D and Supplementary Figures 1A–C in Supplementary Material), which indicated that PCV2 infection induced M1 macrophages polarization state in BMDMs

Summary

Introduction

Host organisms are generally exposed to multiple pathogens simultaneously in a natural environment [1]. Polymicrobial infection or coinfection are common in the infectious diseases that can lead to severity and complications in clinical treatment. Many well-recognized instances involving coinfection of viruses and secondary bacteria are known in both human and animals [2, 3]. PCV2 Infection Modulates Macrophage Polarization deadly infection in human cases [1, 4,5,6]. Swine viruses such as porcine reproductive and respiratory syndrome virus (PRRSV) or PCV2 infection often predisposes pigs to bacterial coinfection [7,8,9,10,11,12]. How the host immune responses to one pathogen alters the immune response to another infectious agent in host-pathogen interactions remain largely unclear

Methods

Results

Conclusion