Abstract
Swine enteric coronaviruses (SECoVs) including porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), and porcine deltacoronavirus (PDCoV), account for the majority of lethal watery diarrhea in neonatal pigs and pose significant economic and public health burdens in the world. While the three SECoVs primarily infect intestinal epithelia in vivo and cause similar clinical signs, there are evident discrepancies in their cellular tropism and pathogenicity. However, the underlying mechanisms to cause the differences remain unclear. Herein, we employed porcine enteroids that are a physiologically relevant model of the intestine to assess the host epithelial responses following infection with the three SECoVs (PEDV, TGEV, and PDCoV). Although SECoVs replicated similarly in jejunal enteroids, a parallel comparison of transcriptomics datasets uncovered that PEDV and TGEV infection induced similar transcriptional profiles and exhibited a more pronounced response with more differentially expressed genes (DEGs) in jejunal enteroids compared with PDCoV infection. Notably, TGEV and PDCoV induced high levels of type I and III IFNs and IFN-stimulated gene (ISG) responses, while PEDV displayed a delayed peak and elicited a much lesser extent of IFN responses. Furthermore, TGEV and PDCoV instead of PEDV elicited a substantial upregulation of antigen-presentation genes and T cell-recruiting chemokines in enteroids. Mechanistically, we demonstrated that IFNs treatment markedly elevated the expression of NOD-like receptor (NLR) family NLRC5 and major histocompatibility complex class I (MHC-I) molecules. Together, our results indicate unique and common viral strategies for manipulating the global IFN responses and antigen presentation utilized by SECoVs, which help us a better understanding of host-SECoVs interactions.
Highlights
Swine enteric coronaviruses (SECoVs), including porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), as well as recent emergent porcine deltacoronavirus (PDCoV), have been major causative pathogens of lethal watery diarrhea in piglets [1, 2]
We initially analyzed the transcriptional profiles of type I and III IFNs in jejunal enteroids after infection with SECoVs, and the results showed that the levels of type I IFNB1 and type III IFNs (IFN-L1 and IFN-L3) in enteroids were notably upregulated by TGEV infection, followed by PDCoV; whereas PEDV infection only induced a minor expression of type I and III IFNs (Figure 5A)
To explore whether the expression of pattern recognition receptors (PRRs) and nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) determines the differential ability of SECoVs to manipulate the IFN responses, we investigated the transcriptional expression of PRRs and NLRs in enteroids following SECoVs infection, including RIG-I-like receptors (RLRs) and toll-like receptors (TLRs), which are mainly responsible for sensing RNA virus infection [33], as well as NLRs, which largely mediate the activation of rapid inflammatory responses and restriction of pathogen replication [34]
Summary
Swine enteric coronaviruses (SECoVs), including porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), as well as recent emergent porcine deltacoronavirus (PDCoV), have been major causative pathogens of lethal watery diarrhea in piglets [1, 2]. Whereas PDCoV, another newly discovered deltacoronavirus in 2014, causes about 40% mortality in neonatal piglets and is less pathogenic compared with PEDV and TGEV [6]. All the three SECoVs primarily infect intestinal epithelia and cause enterocyte loss, atrophy of villi, which is manifested by clinical acute, watery diarrhea and vomiting, resulting in dehydration and body weight loss [1, 2]. Except for the economic impact on the swine industry, PDCoV can use aminopeptidase N (APN) from multiple species to enter cells and have the ability to infect cells of avian and mammalian species including feline and humans, which emphasizes the potential zoonotic of SECoVs and their potential spillover to humans [7–9]. A better understanding of host intestinal epithelial responses to SECoVs is critical to elucidate the pathogenesis and immunobiology of these coronaviruses and prepare for the emerging and reemerging coronaviruses diseases in the future
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