Cytokine Induction in Nipah Virus–Infected Primary Human and Porcine Bronchial Epithelial Cells

Elvert, Mareike; Sauerhering, Lucie; Maisner, Andrea

doi:10.1093/infdis/jiz455

Cited by 8 publications

(10 citation statements)

References 20 publications

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“…As the human airway cell line A549 is known to respond to viral infection with the upregulation of type I (IFN-α/β) and type III IFN (IFN-λ) [ 54 ], we quantified the IFN-β and IFN-λ expression. As shown in Figure 5 B, both IFNs were clearly induced, with IFN-λ being more efficiently upregulated, consistent with our earlier observations in human primary airway epithelial cell cultures [ 51 , 55 ]. IFN induction in NiV-infected cell cultures also led to the upregulation of several ISGs, as exemplified by PKR, OAS, ISG56 and MxA ( Figure 5 C).…”

Section: Resultssupporting

confidence: 91%

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Nipah Virus Impairs Autocrine IFN Signaling by Sequestering STAT1 and STAT2 into Inclusion Bodies

Becker

Maisner

2023

Viruses

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Nipah virus (NiV) is an emerging zoonotic paramyxovirus that causes fatal infections in humans. As with most disease-causing viruses, the pathogenic potential of NiV is linked to its ability to block antiviral responses, e.g., by antagonizing IFN signaling through blocking STAT proteins. One of the STAT1/2-binding proteins of NiV is the phosphoprotein (P), but its functional role in IFN antagonism in a full viral context is not well defined. As NiV P is required for genome replication and specifically accumulates in cytosolic inclusion bodies (IBs) of infected cells, we hypothesized that this compartmentalization might play a role in P-mediated IFN antagonism. Supporting this notion, we show here that NiV can inhibit IFN-dependent antiviral signaling via a NiV P-dependent sequestration of STAT1 and STAT2 into viral IBs. Consequently, the phosphorylation/activation and nuclear translocation of STAT proteins in response to IFN is limited, as indicated by the lack of nuclear pSTAT in NiV-infected cells. Blocking autocrine IFN signaling by sequestering STAT proteins in IBs is a not yet described mechanism by which NiV could block antiviral gene expression and provides the first evidence that cytosolic NiV IBs may play a functional role in IFN antagonism.

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Section: Resultssupporting

confidence: 91%

“…Quantitative PCR (qPCR) analysis was performed as described previously [ 50 , 51 ]. Total RNA was isolated from lysates of infected cells (RNeasy Kit, Qiagen, Venlo, Netherlands) and reverse-transcribed with oligo(dT) 18 primers (RevertAid First Strand cDNA Synthesis Kit, ThermoFisher).…”

Section: Methodsmentioning

confidence: 99%

Nipah Virus Impairs Autocrine IFN Signaling by Sequestering STAT1 and STAT2 into Inclusion Bodies

Becker

Maisner

2023

Viruses

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“…HAE retain the functional IFN signaling cascades that robustly induce type I and III IFNs in vivo in response to viral infections and have been used to model innate immune responses to viral infections, including respiratory syncytial virus (RSV), pneumovirus ( 38 , 39 ), influenza A virus ( 40 ), and SARS-CoV-2 ( 41 ), as well as other Paramyxoviridae family members such as Nipah virus ( 42 ) and parainfluenza viruses ( 43 ). Of note, RSV-infected HAE show increased antiviral cytokine and chemokine expression despite minimal induction of type I IFNs ( 38 , 39 ).…”

Section: Introductionmentioning

confidence: 99%

Interferon-independent processes constrain measles virus cell-to-cell spread in primary human airway epithelial cells

Durnell,

Hippee,

Cattaneo

et al. 2023

Microbiol Spectr

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Amplification of measles virus (MeV) in human airway epithelia may contribute to its extremely high contagious nature. We use well-differentiated primary cultures of human airway epithelial cells (HAE) to model ex vivo how MeV spreads in human airways. In HAE, MeV spreads cell-to-cell for 3–5 days, but then, infectious center growth is arrested. What stops MeV spread in HAE is not understood, but interferon (IFN) is known to slow MeV spread in other in vitro and in vivo models. Here, we assessed the role of type I and type III IFN in arresting MeV spread in HAE. The addition of IFN-β or IFN-λ1 to the medium of infected HAE slowed MeV infectious center growth, but when IFN receptor signaling was blocked, infectious center size was not affected. In contrast, blocking type-I IFN receptor signaling enhanced respiratory syncytial virus spread. HAE were also infected with MeV mutants defective for the V protein. The V protein has been demonstrated to interact with both MDA5 and STAT2 to inhibit activation of innate immunity; however, innate immune reactions were unexpectedly muted against the V-defective MeV in HAE. Minimal innate immunity activation was confirmed by deep sequencing, quantitative RT-PCR, and single-cell RNA-seq analyses of the transcription of IFN and IFN-stimulated genes. We conclude that in HAE, IFN-signaling can contribute to slowing infectious center growth; however, IFN-independent processes are most important for limiting cell-to-cell spread. IMPORTANCE Fundamental biological questions remain about the highly contagious measles virus (MeV). MeV amplifies within airway epithelial cells before spreading to the next host. This final step likely contributes to the ability of MeV to spread host-to-host. Over the course of 3–5 days post-infection of airway epithelial cells, MeV spreads directly cell-to-cell and forms infectious centers. Infectious center formation is unique to MeV. In this study, we show that interferon (IFN) signaling does not explain why MeV cell-to-cell spread is ultimately impeded within the cell layer. The ability of MeV to spread cell-to-cell in airway cells without appreciable IFN induction may contribute to its highly contagious nature. This study contributes to the understanding of a significant global health concern by demonstrating that infectious center formation occurs independent of the simplest explanation for limiting viral transmission within a host.

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“…The Nipah virus (NiV) infects the respiratory tract of both humans and pigs. However, while NiV-infected pigs develop an acute and often severe inflammatory-mediated respiratory disease, symptoms are seen only in few NiV-infected human patients ( 13 ). Comparative studies using primary cultures of human and porcine bronchial epithelial cells infected with NiV revealed that both RECs responded to NiV infection by producing IFN-λ and antiviral factors ( OAS and ISG-56 ).…”

Section: Introductionmentioning

confidence: 99%

“…Comparative studies using primary cultures of human and porcine bronchial epithelial cells infected with NiV revealed that both RECs responded to NiV infection by producing IFN-λ and antiviral factors ( OAS and ISG-56 ). Human cells were more efficient than porcine cells to up-regulate IFN-λ and antiviral factors, which correlated with lower viral RNA content ( 13 ). Of note, while porcine bronchial epithelial cells had a reduced capacity to produce IFN-λ, they were capable to strongly express the proinflammatory cytokines IL-6 and IL-8 , which were suggested to contribute to inflammatory-pathology.…”

Section: Introductionmentioning

confidence: 99%

Establishment of a porcine bronchial epithelial cell line and its application to study innate immunity in the respiratory epithelium

Fukuyama,

Zhuang,

Toyoshi

et al. 2023

Front. Immunol.

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In vitro culture models that precisely mirror the porcine respiratory epithelium are needed to gain insight into how pathogens and host interact. In this study, a new porcine bronchial epithelial cell line, designated as PBE cells, was established from the respiratory tract of a neonatal pig. PBE cells assumed a cobblestone-epithelial like morphology with close contacts between the cells when they reached confluence. The PBE cell line was characterized in terms of its expression of pattern recognition receptors (PRRs) and its ability to respond to the activation of the Toll-like receptor 3 (TLR3) and TLR4 signaling pathways, which are key PRRs involved in the defense of the respiratory epithelium against pathogens. PBE cells stimulated with poly(I:C) were able to up-regulate the expression of IFN-β, IFN-λ1 (IL-29), IFN-λ3 (IL-28B), the antiviral factors Mx1, OAS1, and PKR, as well as the viral PRRs RIG-1 and MDA5. The expression kinetics studies of immune factors in PBE cells allow us to speculate that this cell line can be a useful in vitro tool to investigate treatments that help to potentiate antiviral immunity in the respiratory epithelium of the porcine host. In addition, poly(I:C) and LPS treatments increased the expression of the inflammatory cytokines TNF-α, IL-6, IL-8, and MCP-1/CCL2 and differentially modulated the expression of negative regulators of the TLR signaling pathways. Then, PBE cells may also allow the evaluation of treatments that can regulate TLR3- and TLR4-mediated inflammatory injury in the porcine airway, thereby protecting the host against harmful overresponses.

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Cytokine Induction in Nipah Virus–Infected Primary Human and Porcine Bronchial Epithelial Cells

Cited by 8 publications

References 20 publications

Nipah Virus Impairs Autocrine IFN Signaling by Sequestering STAT1 and STAT2 into Inclusion Bodies

Nipah Virus Impairs Autocrine IFN Signaling by Sequestering STAT1 and STAT2 into Inclusion Bodies

Interferon-independent processes constrain measles virus cell-to-cell spread in primary human airway epithelial cells

Establishment of a porcine bronchial epithelial cell line and its application to study innate immunity in the respiratory epithelium

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