The suppression of innate immune response by human rhinovirus C

doi:10.1016/j.bbrc.2017.05.169

Biochemical and Biophysical Research Communications

Volume 490, Issue 1, 12 August 2017, Pages 22-28

https://doi.org/10.1016/j.bbrc.2017.05.169 Get rights and content

Highlights

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RV-C did not induce robust IFN-β antiviral response in differentiated HBE cells.
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RV-C 3C^pro down-regulates the expression of RIG-I in a caspase-dependent manner.
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RV-C 3C^pro cleaved MAVS at 148 Q/A.

Abstract

Rhinovirus C (RV-C), a newly identified group of human rhinoviruses (RVs), is associated with exacerbation of severe asthma. The type I interferon (IFN) response induced by this virus and the mechanisms of evasion of IFN-mediated innate immunity for RV-C remain unclear. In this study, we constructed a full-length cDNA clone of RV-C (LZ651) from a clinical sample. IFN-β mRNA and protein levels were not elevated in differentiated Human bronchial epithelial (HBE) cells at the air-liquid interface infected with RV-C, except in the early stage of infection. The ability to attenuate IFN-β activation was ascribed to 3C^pro of RV-C, and the 40-His site of 3C^pro played an important role. Furthermore, RIG-I was degraded by 3C^pro in a caspase-dependent manner and 3C^pro cleaved MAVS at 148 Q/A, which inhibited IFN signaling. Taken together, our results demonstrate the mechanism by which RV-C circumvents the production of type I IFN in infected cells.

Introduction

Human rhinovirus (RV), belonging to the genus Enterovirus in the family Picornaviridae, is the most frequent etiological agent of the common cold in humans [1]. Recent studies have shown that rhinovirus infection is also a major source of asthma exacerbation and lower respiratory tract illness [2]. In addition to RV-A and RV-B, RV-C strains were recently discovered using molecular techniques [3]. Clinical data suggest that RV-C strains are more virulent than RV-A and RV-B strains [4], [5], [6]. RV-A and RV-C cause more severe illness in infancy than RV-B [4]. RV-C is present in the majority of children with acute asthma and is associated with more severe asthma than other species [7], [8], [9].

The pathogenic mechanisms of asthma exacerbation caused by RV remain unclear. A cytokine imbalance with a deficient Th1 response to rhinovirus is associated with degrees of asthma severity, suggesting that impaired antiviral responses may be associated [10]. The interferon (IFN) response plays an important role in virus-associated respiratory disease. One abnormal feature of the asthma induced by rhinovirus is the impaired expression of IFNs [11], [12], [13]. RV-C can be grown in the organ cultures of human sinus epithelium and human airway epithelial cells that are differentiated at the air-liquid interface (ALI), but to date, it has not been propagated in immortalized cell lines [14], [15]. The IFN responses to RV-C infection remain largely unknown.

Virus infection activates the innate immune system, which recognizes viral components through pattern-recognition receptors (PRRs). PRRs that sense RNA virus infections include Toll-like receptors (TLRs) and the cytoplasmic RNA helicases RIG-I-like receptors (RLRs), such as retinoid acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). After transmission of serial signals, IFNs and cytokines are produced in response to viral infection. Studies on RV-A have indicated roles for TLR3, RIG-I, and MDA5 in the induction of IFNs following RV infection [16], [17], [18]. Many picornaviruses attenuate the production of IFN-β to evade innate immune responses. Reports have suggested that mitochondrial antiviral signaling protein (MAVS, also known as IPS-1, VISA, or Cardif) is cleaved during HRV1a infection [19]. The mechanisms of innate immune evasion by rhinovirus (particularly RV-C) have not been investigated comprehensively.

Section snippets

Viruses and cells

LZ651 is a clinical RV-C sample (GenBank: JF317016.1). Sendai virus was a gift from Professor Li-shu Zheng (China CDC, Beijing, China). Bronchial tissue was obtained from Nanjing Children's Hospital (Nanjing, China). The protocol was approved by the Ethical Committee of the National Institute for Viral Disease Prevention and Control (China CDC) and Nanjing Children's Hospital. The use of patient specimens in this study was approved by the Ethics Committee of the National Institute for Viral

RV-C infection does not induce a robust IFN-β response in human differentiated bronchial epithelial cells

To explore the IFN responses to RV-C, we developed differentiated primary HBE cells at the ALI with a pseudostratified morphology to infect and propagate RV-C (Supplementary Fig. 1). We constructed a full-length cDNA clone of LZ651 from a clinical RV-C sample (Supplementary Fig. 2). After transcription in vitro, the full-length genome of LZ651 was transfected into HeLa cells and the differentiated HBE cells were infected with the LZ651 virus. As shown in Fig. 1A, following inoculation with

Discussion

Previous studies have reported distinct IFN responses against rhinoviruses. Rhinovirus RV13, RV20, and RV14 did not induce significant amounts of type I IFN in HeLa and A549 cells [11], [21]. Khaitov et al. [22] showed that RV1B and RV16 infected BEAS-2B cells and peripheral blood mononuclear cells, which resulted in induction interferon. To explore the interaction of RV-C and the innate immune pathways, we determined whether RV-C infection stimulated the expression of type I IFN in HBE cells

Conflict of interest

None.

Acknowledgments

We thank Prof. Yury A. Bochkov for assistance with HBE culture at ALI and Prof. Dong-yan Jin for assistance with experiments. This work was supported by Grants from the National Natural Science Foundation of China (Grant No. 81601813) and the China Mega-Project for Infectious Disease (Grant No. 2013ZX10004).

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The induction and suppression of type I and type III interferons by human group H rotavirus
2023, Virology
Group H Rotavirus (RVH) is associated with human diarrhea gastroenteritis. The interferon (IFN) response induced by RVH remains unclear. In this study, we first studied the characteristic feature of RVH and found J19 strain of RVH grew less efficiently compared with the G6P1 strain of RVA. Next, we found that infection with the J19 virus resulted in the secretion of IFN-λ1, but not IFN-β, while both IFN-β and IFN-λ1 could inhibit J19 replication significantly in Caco-2 cells. NSP1 played an important role in the suppression of type I and type III IFN response, and NSP5 protein significantly inhibited activation of IFN-λ1. J19 NSP1 suppressed the induction of IFN-β obviously than G6P1 NSP1, while G6P1 NSP1 reduced IFN-λ1 induction to the greatest extent compared with G9P8, Wa, and J19 NSP1s. Our studies reveal the propagation feature of RVH and interferon induction and suppression by group H rotavirus.
Rhinovirus diversity and virulence factors
2019, Rhinovirus Infections: Rethinking the Impact on Human Health and Disease
The rhinovirus (RV) genus is highly diverse, consisting of three species and more than 167 subtypes, utilizing three different receptors for cell entry. This diversity has been an obstacle to the development of effective cross-reactive antiviral treatments or vaccine strategies. Accumulating research suggests a possible association of virus species/subtypes with illness severity presenting the possibility for antiviral approaches targeting specific subtypes instead of all RVs. To facilitate such an approach, identification of the underlying molecular mechanism and the viral factor/s that mediate disease is required. Recent literature shows a clear species/subtype associated divergence in the host cell directed activity of RV proteases. Whether these differences correlate with the subtype-specific differences in illness severity remains to be confirmed. In this chapter, we bring together current knowledge of the association of RV species/subtypes with illness and explore the possible role of RV proteases as the main virulence factors associated with illness severity.
Interferon lambda receptor 1 (IFNL1R) transcript is highly expressed in rhinovirus bronchiolitis and correlates with disease severity
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Citation Excerpt :
Our previous studies documented a higher production of type III IFNs, ISGs and pattern recognition receptors in RSV-positive infants than in those with HRV infections [28,32,33], in line with the assumption that the IFN-mediated response might participate in the typical inflammation signature related to RSV infection. Moreover, HRV has been found to induce epidermal growth factor receptor (EGFR) activation, suppress IFN regulatory factor (IRF) 1-induced IFNλ production and innate immune response [34,35]. All these findings might suggest that increased levels of IFNLR1 could allow HRV-positive infants to mount an effective antiviral response despite a reduced IFNλs production [28].
As the expression of type III IFN receptor is restricted to the mucosal surfaces, its evaluation could be crucial to characterize the role of IFNλs during bronchiolitis.
This study was designed to investigate airway type III IFN receptor (IFNLR1/IL10RB) expression during respiratory syncytial virus (RSV) or human rhinovirus (HRV) bronchiolitis.
Seventy-one 1–6 month old infants hospitalized with their first episode of acute RSV or HRV bronchiolitis were selected for this study. Expression of IFNLR1, IL10RB and IFN-stimulated genes (ISGs) MxA and ISG56 in cells of nasopharyngeal washings taken within the first 48 h of admission were determined by a real-time hydrolysis probe RT-PCR assay. The ability of types I and III IFNs to induce the expression of both IFNLR1 and IL10RB in vitro was also evaluated.
Airway IFNLR1 transcript levels were significantly higher in HRV bronchiolitis infants compared to those with RSV bronchiolitis. No differences were recorded for IL10RB-mRNA between RSV or HRV infection. IFNLR1 mRNA levels increased significantly in infants infected with the C species of HRV and in those with a higher clinical score index and with an eosinophil count >3%. There were no correlations in vivo between type III IFN receptors and those of ISGs and neither IFNLR1 nor IL10RB were induced in vitro by IFNs.
These results suggest that IFNLR1 are increased in HRV-infected infants with more severe bronchiolitis and blood eosinophilia and in those infected with the HRVC species.
The Main Protease of Middle East Respiratory Syndrome Coronavirus Induces Cleavage of Mitochondrial Antiviral Signaling Protein to Antagonize the Innate Immune Response
2024, Viruses
MAVS-Based Reporter Systems for Real-Time Imaging of EV71 Infection and Antiviral Testing
2023, Viruses
Host mitochondria: more than an organelle in SARS-CoV-2 infection
2023, Frontiers in Cellular and Infection Microbiology

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The suppression of innate immune response by human rhinovirus C

Highlights

Abstract

Introduction

Section snippets

Viruses and cells

RV-C infection does not induce a robust IFN-β response in human differentiated bronchial epithelial cells

Discussion

Conflict of interest

Acknowledgments

official Publ. Pan Am. Soc. Clin. Virol.

J. allergy Clin. Immunol.

Virology

Cell

Frequent detection of human rhinoviruses, paramyxoviruses, coronaviruses, and bocavirus during acute respiratory tract infections

J. Med. Virol.

Human rhinovirus species and season of infection determine illness severity

Am. J. Respir. Crit. care Med.

Clinical spectrum of human rhinovirus infections in hospitalized Hong Kong children

Pediatr. Infect. Dis. J.

Novel human rhinoviruses and exacerbation of asthma in children

Emerg. Infect. Dis.

Association between human rhinovirus C and severity of acute asthma in children

Eur. Respir. J.

A novel group of rhinoviruses is associated with asthma hospitalizations

J. allergy Clin. Immunol.

Human rhinovirus group C infection in children with lower respiratory tract infection

Emerg. Infect. Dis.

Rhinovirus-induced interferon-gamma and airway responsiveness in asthma

Am. J. Respir. Crit. care Med.