scholarly journals Porcine epidemic diarrhea virus inhibits HDAC1 expression to facilitate its replication via binding of its nucleocapsid protein to host transcription factor Sp1

2021 ◽  
Author(s):  
Jidong Xu ◽  
Junyong Mao ◽  
Xiao Han ◽  
Fushan Shi ◽  
Qin Gao ◽  
...  
Keyword(s):  
Immune Responses ◽  
Histone Deacetylases ◽  
Porcine Epidemic Diarrhea Virus ◽  
Innate Immune ◽  
Host Responses ◽  
Innate Immune Responses ◽  
N Protein ◽  
Diarrhea Virus ◽  
Neonatal Pigs ◽  
Porcine Epidemic Diarrhea

Porcine epidemic diarrhea virus (PEDV) is an enteric coronavirus causing acute intestinal infection in pigs, with high mortality often seen in neonatal pigs. The newborns rely on innate immune responses against invading pathogens because of lacking adaptive immunity. However, how PEDV disables the innate immunity of newborns towards severe infection remains unknown. We found that PEDV infection led to reduced expression of histone deacetylases (HDACs), especially HDAC1 in porcine IPEC-J2 cells. HDACs are considered as important regulators of innate immunity. We hypothesized that PEDV might interact with certain host factors to regulate HDAC1 expression in favor of its replication. We show that HDAC1 acted as a negative regulator of PEDV replication in IPEC-J2 cells, as shown by chemical inhibition, gene knockout and overexpression. A GC-box ( GCCCCACCCCC ) within the HDAC1 promoter region was identified for Sp1 binding in IPEC-J2 cells. Treatment of the cells with Sp1 inhibitor, mithramycin A, inhibited HDAC1 expression, indicating direct regulation of HDAC1 expression by Sp1. Of the viral proteins that were overexpressed in IPEC-J2 cells, the N protein was found to be present in the nuclei and more inhibitory to HDAC1 transcription. The putative NLS 261 PKKNKSR 267 contributed to its nuclear localization. The N protein interacted with Sp1 and interfered with its binding to the promoter region, thereby inhibiting its transcriptional activity for HDAC1 expression. Our findings reveal a novel mechanism of PEDV evasion of the host responses, offering implications for studying the infection processes of other coronaviruses. Importance The enteric coronavirus porcine epidemic diarrhea virus (PEDV) causes fatal acute intestinal infection in neonatal pigs that rely on innate immune responses. Histone deacetylases (HDACs) play important roles in innate immune regulation. Our study found PEDV suppresses HDAC1 expression via the interaction of its N protein and porcine Sp1, which identified a novel mechanism of PEDV evasion of the host responses to benefit its replication. This study suggests that other coronaviruses, including SARS-CoV and SARS-CoV-2, may also make use of their N proteins to intercept the host immune responses in favor of their infection.

scholarly journals Immunogenicity of Recombinant-Deficient Lactobacillus casei with Complementary Plasmid Expressing Alanine Racemase Gene and Core Neutralizing Epitope Antigen against Porcine Epidemic Diarrhea Virus

Vaccines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1084
Author(s):  
Fengsai Li ◽  
Xiaona Wang ◽  
Xiaolong Fan ◽  
Ling Sui ◽  
Hailin Zhang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Porcine Epidemic Diarrhea Virus ◽  
Lactobacillus Casei ◽  
Oral Vaccine ◽  
Mucosal Vaccine ◽  
Alanine Racemase ◽  
Main Function ◽  
Neutralizing Epitope ◽  
Diarrhea Virus ◽  
Porcine Epidemic Diarrhea

Porcine epidemic diarrhea (PED), which is caused by the porcine epidemic diarrhea virus (PEDV), has occurred worldwide and poses a serious threat to the pig industry. Intestine is the main function site of PEDV; therefore, it is important to develop an oral mucosal immunity vaccine against this virus infection. Most traditional plasmid delivery vectors use antibiotic genes as a selective marker, easily leading to antibiotic accumulation and gene contamination. In this study, to explore whether the alanine racemase gene (Alr) could be used as a screening marker and develop an efficient oral vaccine against PEDV infection, a recombinant strain was constructed using Lactobacillus casei with Alr deletion (L. casei ΔAlr W56) to deliver the Alr gene and a core-neutralizing epitope (COE) antigen. This recombinant bacterium efficiently induced secretory immunoglobulin A (SIgA)-based mucosal and immunoglobulin G (IgG)-based humoral immune responses via oral vaccination in mice. Compared to the other strains, the recombinant bacteria were able to grow without the addition of D-alanine, revealing that Alr in the plasmid could function normally in defective bacteria. This oral mucosal vaccine would provide a useful strategy to substitute the application of antibiotics in the future and induce efficient immune responses against PEDV infection.

scholarly journals Enterotoxigenic Escherichia coli Prevents Host NF-κB Activation by Targeting IκBα Polyubiquitination

2012 ◽  
Vol 80 (12) ◽  
pp. 4417-4425 ◽  
Author(s):  
Xiaogang Wang ◽  
Philip R. Hardwidge
Keyword(s):  
Escherichia Coli ◽  
Immune Responses ◽  
Diarrheal Disease ◽  
Innate Immune ◽  
Host Cells ◽  
Enterotoxigenic Escherichia Coli ◽  
Host Responses ◽  
Innate Immune Responses ◽  
Content Type ◽  
Heat Stable

ABSTRACTThe NF-κB pathway regulates innate immune responses to infection. NF-κB is activated after pathogen-associated molecular patterns are detected, leading to the induction of proinflammatory host responses. As a countermeasure, bacterial pathogens have evolved mechanisms to subvert NF-κB signaling. EnterotoxigenicEscherichia coli(ETEC) causes diarrheal disease and significant morbidity and mortality for humans in developing nations. The extent to which this important pathogen subverts innate immune responses by directly targeting the NF-κB pathway is an understudied topic. Here we report that ETEC secretes a heat-stable, proteinaceous factor that blocks NF-κB signaling normally induced by tumor necrosis factor (TNF), interleukin-1β, and flagellin. Pretreating intestinal epithelial cells with ETEC supernatant significantly blocked the degradation of the NF-κB inhibitor IκBα without affecting IκBα phosphorylation. Data from immunoprecipitation experiments suggest that the ETEC factor functions by preventing IκBα polyubiquitination. Inhibiting clathrin function blocked the activity of the secreted ETEC factor, suggesting that this yet-uncharacterized activity may utilize clathrin-dependent endocytosis to enter host cells. These data suggest that ETEC evades the host innate immune response by directly modulating NF-κB signaling.

scholarly journals The papain-like protease of porcine epidemic diarrhea virus negatively regulates type I interferon pathway by acting as a viral deubiquitinase

2013 ◽  
Vol 94 (7) ◽  
pp. 1554-1567 ◽  
Author(s):  
Yaling Xing ◽  
Jianfei Chen ◽  
Jian Tu ◽  
Bailing Zhang ◽  
Xiaojuan Chen ◽  
...  
Keyword(s):  
Porcine Epidemic Diarrhea Virus ◽  
Innate Immune ◽  
Signalling Pathway ◽  
Type I ◽  
Polyubiquitin Chains ◽  
Diarrhea Virus ◽  
Ubiquitinated Proteins ◽  
Interferon Pathway ◽  
Porcine Epidemic Diarrhea ◽  
Swine Disease

Porcine epidemic diarrhea virus (PEDV) is the cause of an economically important swine disease. Previous studies suggested that PEDV does not elicit a robust IFN response, but the mechanism(s) used to evade or block this innate immune response was not known. In this study, we found that PEDV infection blocked synthetic dsRNA-induced IFN-β production by interfering with the activation of interferon regulatory factor 3 (IRF3). We identified PEDV replicase encoded papain-like protease 2 (PLP2) as an IFN antagonist that depends on catalytic activity for its function. We show that levels of ubiquitinated proteins are reduced during PEDV infection and that PEDV PLP2 has deubiquitinase (DUB) activity that recognizes and processes both K-48 and K-63 linked polyubiquitin chains. Furthermore, we found that PEDV PLP2 strongly inhibits RIG-I- and STING-activated IFN expression and that PEDV PLP2 can be co-immunoprecipitated with and deubiquitinates RIG-I and STING, the key components of the signalling pathway for IFN expression. These results show that PEDV infection suppresses production of IFN-β and provides evidence indicating that the PEDV papain-like protease 2 acts as a viral DUB to interfere with the RIG-I- and STING-mediated signalling pathway.

scholarly journals Host Factors Affecting Generation of Immunity Against Porcine Epidemic Diarrhea Virus in Pregnant and Lactating Swine and Passive Protection of Neonates

Pathogens ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 130 ◽  
Author(s):  
Stephanie N. Langel ◽  
Qiuhong Wang ◽  
Anastasia N. Vlasova ◽  
Linda J. Saif
Keyword(s):  
Immune Responses ◽  
Porcine Epidemic Diarrhea Virus ◽  
Host Factors ◽  
Diarrhea Virus ◽  
Maternal Immunization ◽  
Immunization Strategies ◽  
Suckling Piglets ◽  
Porcine Epidemic Diarrhea ◽  
Lactogenic Immunity ◽  
Highly Virulent

Porcine epidemic diarrhea virus (PEDV) is a highly virulent re-emerging enteric coronavirus that causes acute diarrhea, dehydration, and up to 100% mortality in neonatal suckling piglets. Despite this, a safe and effective PEDV vaccine against highly virulent strains is unavailable, making PEDV prevention and control challenging. Lactogenic immunity induced via the gut-mammary gland-secretory IgA (sIgA) axis, remains the most promising and effective way to protect suckling piglets from PEDV. Therefore, a successful PEDV vaccine must induce protective maternal IgA antibodies that passively transfer into colostrum and milk. Identifying variables that influence lymphocyte migration and IgA secretion during gestation and lactation is imperative for designing maternal immunization strategies that generate the highest amount of lactogenic immune protection against PEDV in suckling piglets. Because pregnancy-associated immune alterations influence viral pathogenesis and adaptive immune responses in many different species, a better understanding of host immune responses to PEDV in pregnant swine may translate into improved maternal immunization strategies against enteric pathogens for multiple species. In this review, we discuss the role of host factors during pregnancy on antiviral immunity and their implications for generating protective lactogenic immunity in suckling neonates.

scholarly journals Porcine Epidemic Diarrhea Virus and the Host Innate Immune Response

Pathogens ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 367 ◽  
Author(s):  
Shasha Li ◽  
Jinping Yang ◽  
Zixiang Zhu ◽  
Haixue Zheng
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Porcine Epidemic Diarrhea Virus ◽  
Innate Immune ◽  
Viral Rna ◽  
Watery Diarrhea ◽  
Economic Losses ◽  
Diarrhea Virus ◽  
Host Innate Immune Response ◽  
Porcine Epidemic Diarrhea

Porcine epidemic diarrhea virus (PEDV), a swine enteropathogenic coronavirus (CoV), is the causative agent of porcine epidemic diarrhea (PED). PED causes lethal watery diarrhea in piglets, which has led to substantial economic losses in many countries and is a great threat to the global swine industry. Interferons (IFNs) are major cytokines involved in host innate immune defense, which induce the expression of a broad range of antiviral effectors that help host to control and antagonize viral infections. PEDV infection does not elicit a robust IFN response, and some of the mechanisms used by the virus to counteract the host innate immune response have been unraveled. PEDV evades the host innate immune response by two main strategies including: 1) encoding IFN antagonists to disrupt innate immune pathway, and 2) hiding its viral RNA to avoid the exposure of viral RNA to immune sensors. This review highlights the immune evasion mechanisms employed by PEDV, which provides insights for the better understanding of PEDV-host interactions and developing effective vaccines and antivirals against CoVs.

scholarly journals Porcine Epidemic Diarrhea Virus 3C-Like Protease Regulates Its Interferon Antagonism by Cleaving NEMO

2015 ◽  
Vol 90 (4) ◽  
pp. 2090-2101 ◽  
Author(s):  
Dang Wang ◽  
Liurong Fang ◽  
Yanling Shi ◽  
Huan Zhang ◽  
Li Gao ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cysteine Protease ◽  
Porcine Epidemic Diarrhea Virus ◽  
Protease Activity ◽  
The United States ◽  
Watery Diarrhea ◽  
Type I ◽  
Diarrhea Virus ◽  
Cysteine Protease Activity ◽  
Porcine Epidemic Diarrhea

ABSTRACTPorcine epidemic diarrhea virus (PEDV) is an enteropathogenic coronavirus causing lethal watery diarrhea in piglets. Since 2010, a PEDV variant has spread rapidly in China, and it emerged in the United States in 2013, posing significant economic and public health concerns. The ability to circumvent the interferon (IFN) antiviral response, as suggested for PEDV, promotes viral survival and regulates pathogenesis of PEDV infections, but the underlying mechanisms remain obscure. Here, we show that PEDV-encoded 3C-like protease, nsp5, is an IFN antagonist that proteolytically cleaves the nuclear transcription factor kappa B (NF-κB) essential modulator (NEMO), an essential adaptor bridging interferon-regulatory factor and NF-κB activation. NEMO is cleaved at glutamine 231 (Q231) by PEDV, and this cleavage impaired the ability of NEMO to activate downstream IFN production and to act as a signaling adaptor of the RIG-I/MDA5 pathway. Mutations specifically disrupting the cysteine protease activity of PEDV nsp5 abrogated NEMO cleavage and the inhibition of IFN induction. Structural analysis suggests that several key residues outside the catalytic sites of PEDV nsp5 probably impact NEMO cleavage by modulating potential interactions of nsp5 with their substrates. These data show that PEDV nsp5 disrupts type I IFN signaling by cleaving NEMO. Previously, we and others demonstrated that NEMO is also cleaved by 3C or 3C-like proteinases of picornavirus and artertivirus. Thus, NEMO probably represents a prime target for 3C or 3C-like proteinases of different viruses.IMPORTANCEThe continued emergence and reemergence of porcine epidemic diarrhea virus (PEDV) underscore the importance of studying how this virus manipulates the immune responses of its hosts. During coevolution with its hosts, PEDV has acquired mechanisms to subvert host innate immune responses for its survival advantage. At least two proteins encoded by PEDV have been identified as interferon (IFN) antagonists, papain-like protease (PLP) and N protein. Here, we report that the PEDV nsp5 gene, which encodes the 3C-like protease of PEDV, is another IFN antagonist. Mechanistically, the cysteine protease activity of PEDV nsp5 mediates proteolysis of NEMO, the key adaptor for IFN synthesis, and NEMO is cleaved at glutamine 231 (Q231). The new molecular details and determinants impacting NEMO scission by PEDV nsp5 delineated in this study are fundamental to our understanding of critical virus-host interactions that determine PEDV pathogenesis.

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