Human Parvovirus Infection of Human Airway Epithelia Induces Pyroptotic Cell Death by Inhibiting Apoptosis

Abstract

Human bocavirus 1 (HBoV1) is a human parvovirus that causes acute respiratory tract infections in young children. In this study, we confirmed that, when polarized/well-differentiated human airway epithelia are infected with HBoV1 , they develop damage characterized by barrier function disruption and cell hypotrophy. Cell death mechanism analyses indicated that the infection induced pyroptotic cell death characterized by caspase-1 activation. Unlike infections with other parvoviruses, HBoV1 infection did not activate the apoptotic or necroptotic cell death pathway. When the NLRP3-ASC-caspase-1 inflammasome-induced pathway was inhibited by short hairpin RNA (shRNA), HBoV1-induced cell death dropped significantly; thus, NLRP3 mediated by ASC appears to be the pattern recognition receptor driving HBoV1 infection-induced pyroptosis. HBoV1 infection induced steady increases in the expression of interleukin 1α (IL-1α) and IL-18. HBoV1 infection was also associated with the marked expression of the antiapoptotic genes and When the expression of and/or was inhibited by shRNA, the infected cells underwent apoptosis rather than pyroptosis, as indicated by increased cleaved caspase-3 levels and the absence of caspase-1. and/or gene inhibition also significantly reduced HBoV1 replication. Thus, HBoV1 infection of human airway epithelial cells activates antiapoptotic proteins that suppress apoptosis and promote pyroptosis. This response may have evolved to confer a replicative advantage, thus allowing HBoV1 to establish a persistent airway epithelial infection. This is the first report of pyroptosis in airway epithelia infected by a respiratory virus. Microbial infection of immune cells often induces pyroptosis, which is mediated by a cytosolic protein complex called the inflammasome that senses microbial pathogens and then activates the proinflammatory cytokines IL-1 and IL-18. While virus-infected airway epithelia often activate NLRP3 inflammasomes, studies to date suggest that these viruses kill the airway epithelial cells via the apoptotic or necrotic pathway; involvement of the pyroptosis pathway has not been reported previously. Here, we show for the first time that virus infection of human airway epithelia can also induce pyroptosis. Human bocavirus 1 (HBoV1), a human parvovirus, causes lower respiratory tract infections in young children. This study indicates that HBoV1 kills airway epithelial cells by activating genes that suppress apoptosis and thereby promote pyroptosis. This strategy appears to promote HBoV1 replication and may have evolved to allow HBoV1 to establish persistent infection of human airway epithelia.

A CRISPR Activation Screen Identifies Genes That Protect against Zika Virus Infection

“…IFI6 and IFN-2 activation inhibits cell death in ZIKV-infected cells. IFI6 was previously reported to inhibit apoptosis in DENV-infected cells (31,32), in the context of parvovirus infection (37), and in cancer cells (38)(39)(40). Our results ( Fig.…”

More Than Just a Barrier: The Immune Functions of the Airway Epithelium in Asthma Pathogenesis

“…Consequently, those viruses should be able to luminally infect airway epithelial cells as long as their receptor is present on the apical side. Little is known about receptor distribution in vivo but at least on cultured airway epithelial cells apical receptor expression and/or infectivity has been demonstrated for both viruses (60)(61)(62)(63). Larger particles of about 100 nm and above, on the other hand, are efficiently blocked by the PCL (53).…”

“…Another possibility is the preceding action of a door-opener such as HBoV1 which may pave the way for further viral infections. HBoV1 was shown to persist for several months in the human airway epithelium (72) and causes pyroptotic cell death, epithelial cell hypertrophy, loss of cilia and disruption of the tight junction barrier (60,61). Such a predamaged epithelial barrier may then readily fall victim to an influenza, parainfluenza or HPMV infection.…”

The involvement of regulated cell death forms in modulating the bacterial and viral pathogenesis

“…Whereas, virus triggered inflammasome activation is a common event, inflammasome induced pyroptosis cannot be observed in all circumstances. Nevertheless, inflammasome dependent pyroptosis has been reported in response to infection by several viral pathogens, including HIV, DV (Tan and Chu, 2013), IAV , Coxsacivirus (CV) , Parvovirus (Deng et al, 2017), hepatitis C virus (Kofahi et al, 2016), and Enterovirus 71 (EV71) Zhu et al, 2018). An in vivo study on attenuated Rabies strain provides evidence for the beneficial role of pyroptosis against viral infections.…”