Hepatitis C Virus Infection of Cultured Human Hepatoma Cells Causes Apoptosis and Pyroptosis in Both Infected and Bystander Cells

Abstract

Individuals infected with hepatitis C virus (HCV) are at high risk of developing progressive liver disease, including cirrhosis and hepatocellular carcinoma (HCC). How HCV infection causes liver destruction has been of significant interest for many years, and apoptosis has been proposed as one operative mechanism. In this study, we employed a tissue culture-adapted strain of HCV (JFH1T) to test effects of HCV infection on induction of programmed cell death (PCD) in Huh-7.5 cells. We found that HCV infection reduced the proliferation rate and induced caspase-3-mediated apoptosis in the infected cell population. However, in addition to apoptosis, we also observed infected cells undergoing caspase-1-mediated pyroptosis, which was induced by NLRP3 inflammasome activation. By co-culturing HCV-infected Huh-7.5 cells with an HCV-non-permissive cell line, we also demonstrated induction of both apoptosis and pyroptosis in uninfected cells. Bystander apoptosis, but not bystander pyroptosis, required cell-cell contact between infected and bystander cells. In summary, these findings provide new information on mechanisms of cell death in response to HCV infection. The observation that both apoptosis and pyroptosis can be induced in bystander cells extends our understanding of HCV-induced pathogenesis in the liver.

The intra‐ and extracellular functions of ASC specks

“…Uptake of extracellular specks and their escape from endosomes to nucleate further ASC polymerization may be an additional mode of amplifying inflammation that does not rely on other extracellular proteins. The spread of ASC specks between cells could also underlie the transference of pyroptosis to bystander cells co‐cultured with cells infected with HIV and hepatitis C virus . As mentioned above, the mechanisms for the uptake of extracellular ASC specks are unknown, as well as the main cellular types that would mediate their uptake and removal.…”

Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases

“…When co-cultured with lymphoid-derived CD4 + T cells, peripheral blood-derived CD4 + T cells become sensitized to HIV-1-induced pyroptosis (140), suggesting that pyroptosis is transmissible between different subsets of cells. Uninfected liver cells can also undergo caspase-1-dependent pyroptosis following infection of bystander cells with hepatitis C virus (HCV) (141). …”

Inflammasomes and their roles in the pathogenesis of viral hepatitis and their related complications: An updated systematic review

“…Due to the significant roles of ROS in the hepatitis pathogenesis [76], it appears that ROS uses inflammasomes to induce the complication as a crucial mechanism. HCV also induces pyroptosis in either infected or bystander liver cells via activation of NLRP3 inflammasome and then caspase-1 [77]. Pyroptosis is an essential main mechanism to induce inflammation, fibrosis and also HCC in the liver.…”

“…Sasaki et al, showed that HCV induces cysteine-cysteine chemokine ligand 5 (CCL5) secretion from macrophages, which leads to activation of inflammasomes in the HSCs and subsequently increases the risk of HCC [90]. However, another in vitro investigation presented contrasting results and reported that HCV infection of HCC cell lines is associated with increased apoptosis in the inflammasomes dependent manner [77]. Therefore, it seems that more in vitro and in vivo investigations need to be performed to determine the effects of HBV/ HCV interaction with the inflammasomes on the HCC progression.…”

“…Not applicable. [77] CCL5: cysteine-cysteine chemokine ligand 5, MHV: Mouse hepatitis virus, AIM2: Absent in Melanoma 2, NLRP1: Nucleotide binding and oligomerization domain-lLike rReceptor family Pyrin domain-containing, LPS: Lipopolysacharide, IRF7: IFN regulatory factor 7, TLR: Toll like receptor, NK cell: Natural Killer cell, SREBPs: Sterol regulatory element-binding proteins, ROS: Reactive oxygen species, HSCs: Hepatic stellate cells.…”