Full length articleROS induced by spring viraemia of carp virus activate the inflammatory response via the MAPK/AP-1 and PI3K signaling pathways
Introduction
Spring viraemia of carp virus (SVCV), designated as carp sprivivirus by the International Committee on Taxonomy of Viruses in 2018, is a single-stranded negative-strand RNA virus that belonging to the genus Sprivivirus in the family Rhabdoviridae. The genome of SVCV is approximately 11 kb in length and encodes five proteins, including nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and viral RNA-dependent RNA polymerase (L). SVCV is the etiological agent of spring viraemia of carp (SVC), which causes a high mortality in cyprinids, mainly common carp (Cyprinus carpio) [1]. Currently, no drugs or vaccines can control SVCV infection. Therefore, a better understanding the host response during SVCV infection is needed to develop strategies against this viral infection.
Viral infection with viruses such as hepatitis C virus (HCV), human papillomavirus, red-spotted grouper nervous necrosis virus, and grass carp reovirus can produce large amounts of reactive oxygen species (ROS) and induce oxidative stress [[2], [3], [4], [5]]. ROS can elicit extreme biological damage to the host if redox homeostasis is not properly maintained. For example, ROS have been shown to cause DNA damage and apoptosis in a Trichoplusia Tn5B1-4 cell model [6]. However, ROS also have been demonstrated to play important roles in the immune response of different models including mouse, zebrafish, and Caenorhabditis elegans [[7], [8], [9]]. For instance, hydrogen peroxide (H2O2) acts as a long-range signaling molecule that is important for attracting leukocytes to wound sites in zebrafish [7], and mitochondrial ROS play an important role in anti-bacterial immunity and wound healing in C. elegans [8].
Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, and irritants. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult or the inflammatory process, and initiate tissue repair [10]. ROS generated during viral infection are signaling mediators that are important for activation of the phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF-κB) pathways, resulting in the expression of the inflammatory factors tumor necrosis factor (TNF)-α and interleukin (IL)-8 [7,11,12]. As an important component of ROS, H2O2 can induce an inflammatory response through the MAPK and NF-κB pathways thus increasing cyclooxygenase (COX)-2 and inducible nitric oxide synthase expression [13,14]. In mammals, the NLRP3 inflammasome pathway is also involved in ROS-induced inflammation [15].
Oxidative stress is one of the pathogenic mechanisms of SVCV [[16], [17], [18]]. Our previous studies have shown that SVCV infection induces oxidative stress, causes H2O2 accumulation, and, simultaneously, down-regulates the expression of heme oxygenase-1 (HO-1) [16,17]. In addition, we have confirmed that SVCV impairs the function of mitochondrial complex III, resulting in the accumulation of H2O2 [18]. Furthermore, fish infected by SVCV show lethal hemorrhagic swim-bladder inflammation and peritonitis [1], but the detailed mechanism is not well understood. Here, we aimed to explore the relationship between H2O2 accumulation and inflammation upon SVCV infection. Moreover, the effect of ROS induced by SVCV infection on the MAPK/AP-1 and PI3K pathways. These findings will provide new insights into the mechanism of inflammation upon SVCV infection and may contribute to the control of SVCV.
Section snippets
Materials and methods
Cell cultures and reagents. Epithelioma papulosum cyprini (EPC; ATCC: CRL-2872) cells are SVCV-sensitive and were cultured in Eagle's minimum essential medium (Invitrogen, Carlsbad, CA) supplemented with 10% fetal bovine serum (Gibco, Thermo Fisher) at 28 °C in a humidified 5% CO2 atmosphere. SVCV (ATCC: VR-1390) was a kind gift from Professor Yuanan Lu (University of Hawaii at Manoa). N-acetyl-l-cysteine (NAC) was purchased from the Beyotime Institute of Biotechnology (China). SP600125, U0126,
SVCV infection induces the inflammatory response in EPC cells
To determine whether the inflammatory response was occurred following SVCV infection, the expression levels of the pro-inflammatory factors including TNF-α, (COX)-2, and IL-8 as well as the anti-inflammatory factor IL-10 were measured in EPC cells. The RT-qPCR results showed that the expression levels of TNF-ɑ and COX-2 in SVCV-infected cells were significantly increased by 6.54–38.6-fold and 2.34–16.02-fold, respectively, compared with the mock-infected group (Fig. 1). Similar observations
Discussion
SVCV causes lethal hemorrhagic swim-bladder inflammation and peritonitis as well as a high mortality in cyprinids, suggesting the importance of inflammation in its pathogenicity [1]. This study demonstrated that SVCV could activate the expression of molecules associated with inflammation and that ROS induced by SVCV infection could mediate the inflammatory response via the MAPK/AP-1 and PI3K pathways (Fig. 7).
Previous studies have shown that SVCV induces oxidative stress in EPC cells and
CRediT authorship contribution statement
Jie Sun: Investigation, Writing - original draft. Jingwen Wang: Methodology. Lijuan Li: Writing - review & editing. Zhixin Wu: Methodology. Xiaoxuan Chen: Methodology. Junfa Yuan: Conceptualization, Writing - review & editing.
Declaration of competing interest
The authors declare no financial or commercial conflicts of interest.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (31872598) and the Fundamental Research Funds for the Central Universities (2662017PY041).
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