Modeling senecavirus a replication in immortalized porcine alveolar macrophages triggers a robust interferon-mediated immune response that conversely constrains viral replication

Wen, Dandan; Li, Tao; Xu, Fan; Wang, Yannan; Yang, Fan; Zheng, Haixue

doi:10.1016/j.virol.2022.12.001

Cited by 3 publications

(3 citation statements)

References 34 publications

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“…Extending this inquiry to other viral 3C-like proteases yielded a surprising result: none were capable of cleaving Pro-IL-1β. This specificity suggests that SVV 3C is currently the only viral protease capable of cleaving Pro-IL-1β, which explains why SVV infection causes a stronger inflammatory response [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Species-specific IL-1β is an inflammatory sensor of Seneca Valley Virus 3C Protease

Huang,

Zhao,

Zhu

et al. 2024

PLoS Pathog

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Inflammasomes play pivotal roles in inflammation by processing and promoting the secretion of IL-1β. Caspase-1 is involved in the maturation of IL-1β and IL-18, while human caspase-4 specifically processes IL-18. Recent structural studies of caspase-4 bound to Pro-IL-18 reveal the molecular basis of Pro-IL-18 activation by caspase-4. However, the mechanism of caspase-1 processing of pro-IL-1β and other IL-1β-converting enzymes remains elusive. Here, we observed that swine Pro-IL-1β (sPro-IL-1β) exists as an oligomeric precursor unlike monomeric human Pro-IL-1β (hPro-IL-1β). Interestingly, Seneca Valley Virus (SVV) 3C protease cleaves sPro-IL-1β to produce mature IL-1β, while it cleaves hPro-IL-1β but does not produce mature IL-1β in a specific manner. When the inflammasome is blocked, SVV 3C continues to activate IL-1β through direct cleavage in porcine alveolar macrophages (PAMs). Through molecular modeling and mutagenesis studies, we discovered that the pro-domain of sPro-IL-1β serves as an ’exosite’ with its hydrophobic residues docking into a positively charged 3C protease pocket, thereby directing the substrate to the active site. The cleavage of swine IL-1β (sIL-1β) generates a monomeric and active form of sIL-1β, initiating the downstream signaling. Thus, these studies provide IL-1β is an inflammatory sensor that directly detects viral protease through an independent pathway operating in parallel with host inflammasomes.

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Section: Discussionmentioning

confidence: 99%

Species-specific IL-1β is an inflammatory sensor of Seneca Valley Virus 3C Protease

Huang,

Zhao,

Zhu

et al. 2024

PLoS Pathog

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“…SVA-eGFP constructed by our laboratory ( 52 ) was used to determine the effects of STAT1 and STAT2 mutants on SVA. In brief, HEK-293T cells were transfected with STAT1/STAT2 or its mutants for 24 h, and the cells were inoculated with SVA-eGFP at an MOI of 0.1 for 12 h. Fluorescent intensity of eGFP was measured and visualized by inverted fluorescence microscopy (10× magnification using EVOS5000).…”

Section: Methodsmentioning

confidence: 99%

Impaired interferon response in senecavirus A infection and identification of 3C ^pro as an antagonist

Zhang,

Li,

Chen

et al. 2024

J Virol

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Senecavirus A (SVA), a picornavirus, causes vesicular diseases and epidemic transient neonatal losses in swine, resulting in a multifaceted economic impact on the swine industry. SVA counteracts host antiviral response through multiple strategies facilitatng viral infection and transmission. However, the mechanism of how SVA modulates interferon (IFN) response remains elusive. Here, we demonstrate that SVA 3C protease (3C pro ) blocks the transduction of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway to antagonize type I IFN response. Mechanistically, 3C pro selectively cleaves and degrades STAT1 and STAT2 while does not target JAK1, JAK2, and IRF9, through its protease activity. Notably, SVA 3C pro cleaves human and porcine STAT1 on a Leucine (L)-Aspartic acid (D) motif, specifically L693/D694. In the case of STAT2, two cleavage sites were identified: glutamine (Q) 707 was identified in both human and porcine, while the second cleavage pattern differed, with residues 754–757 (Valine-Leucine-Glutamine-Serine motifs) in human STAT2 and Q758 in porcine STAT2. These cleavage patterns by SVA 3C pro partially differ from previously reported classical motifs recognized by other picornaviral 3C pro , highlighting the distinct characteristics of SVA 3C pro . Together, these results reveal a mechanism by which SVA 3C pro antagonizes IFN-induced antiviral response but also expands our knowledge about the substrate recognition patterns for picornaviral 3C pro . IMPORTANCE Senecavirus A (SVA), the only member in the Senecavirus genus within the Picornaviridae family, causes vesicular diseases in pigs that are clinically indistinguishable from foot-and-mouth disease (FMD), a highly contagious viral disease listed by the World Organization for Animal Health (WOAH). Interferon (IFN)-mediated antiviral response plays a pivotal role in restricting and controlling viral infection. Picornaviruses evolved numerous strategies to antagonize host antiviral response. However, how SVA modulates the JAK-STAT signaling pathway, influencing the type I IFN response, remains elusive. Here, we identify that 3C pro , a protease of SVA, functions as an antagonist for the IFN response. 3C pro utilizes its protease activity to cleave STAT1 and STAT2, thereby diminishing the host IFN response to promote SVA infection. Our findings underscore the significance of 3C pro as a key virulence factor in the antagonism of the type I signaling pathway during SVA infection.

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“…However, there are compelling data that it can overcome immune checkpoint inhibitor (ICI) resistance (i.e., PD-1/PD-L1 and CTLA4 antibodies) in pancreatic cancer murine models, thereby converting immunologically "cold" tumors via systemic anti-tumor immune responses with increased T-cell infiltration [35,36]. It had previously been shown to colonize porcine macrophage PAM-Tang [37] and 3D4/21 [38] cell lines.…”

Section: Pre-clinical Datamentioning

confidence: 99%

TEM8 in Oncogenesis: Protein Biology, Pre-Clinical Agents, and Clinical Rationale

Kareff,

Corbett,

Hallenbeck

et al. 2023

Cells

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The TEM8 protein represents an emerging biomarker in many solid tumor histologies. Given the various roles it plays in oncogenesis, including but not limited to angiogenesis, epithelial-to-mesenchymal transition, and cell migration, TEM8 has recently served and will continue to serve as the target of novel oncologic therapies. We review herein the role of TEM8 in oncogenesis. We review its normal function, highlight the additional roles it plays in the tumor microenvironment, and synthesize pre-clinical and clinical data currently available. We underline the protein’s prognostic and predictive abilities in various solid tumors by (1) highlighting its association with more aggressive disease biology and poor clinical outcomes and (2) assessing its associated clinical trial landscape. Finally, we offer future directions for clinical studies involving TEM8, including incorporating pre-clinical agents into clinical trials and combining previously tested oncologic therapies with currently available treatments, such as immunotherapy.

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Modeling senecavirus a replication in immortalized porcine alveolar macrophages triggers a robust interferon-mediated immune response that conversely constrains viral replication

Cited by 3 publications

References 34 publications

Species-specific IL-1β is an inflammatory sensor of Seneca Valley Virus 3C Protease

Species-specific IL-1β is an inflammatory sensor of Seneca Valley Virus 3C Protease

Impaired interferon response in senecavirus A infection and identification of 3C ^pro as an antagonist

TEM8 in Oncogenesis: Protein Biology, Pre-Clinical Agents, and Clinical Rationale

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Modeling senecavirus a replication in immortalized porcine alveolar macrophages triggers a robust interferon-mediated immune response that conversely constrains viral replication

Cited by 3 publications

References 34 publications

Species-specific IL-1β is an inflammatory sensor of Seneca Valley Virus 3C Protease

Species-specific IL-1β is an inflammatory sensor of Seneca Valley Virus 3C Protease

Impaired interferon response in senecavirus A infection and identification of 3C pro as an antagonist

TEM8 in Oncogenesis: Protein Biology, Pre-Clinical Agents, and Clinical Rationale

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Impaired interferon response in senecavirus A infection and identification of 3C ^pro as an antagonist