Mechanical control of innate immune responses against viral infection revealed in a human Lung Alveolus Chip

ABSTRACTMechanical forces associated with breathing play a fundamental role in lung development and disease but the molecular pathways remain largely unknown. Here, we used a mechanically actuatable Human Lung Alveolus Chip that recapitulates human lung alveolar type I and type II cell differentiation, alveolar-capillary interface formation, and genome-wide gene expression profiles characteristic of the distal lung to investigate the role of physical forces associated with cyclic breathing motions in lung innate immune responses to viral infection. When the mechanically active Alveolus Chips are infected with the influenza H3N2 virus, a cascade of host responses is elicited on-chip, including increased production of cytokines and expression of inflammation-associated genes in pulmonary epithelial and endothelial cells, resulting in enhanced recruitment of circulating immune cells as occurs during viral infection in vivo. Surprisingly, studies carried out in parallel with static chips revealed that physiological breathing motions suppress viral replication by activating protective innate immune responses in epithelial and endothelial cells. This is mediated at least in part through upregulation of S100 calcium-binding protein A7 (S100A7), which binds to the Receptor for Advanced Glycation End Products (RAGE), an inflammatory mediator that is most highly expressed in the lung alveolus in vivo. This mechano-immunological control mechanism is further supported by the finding that existing RAGE inhibitor drugs can suppress the production of inflammatory cytokines in response to influenza virus infection in this model. S100A7-RAGE interactions and modulation of mechanical ventilation parameters could therefore serve as new targets for therapeutic intervention in patients infected with influenza and other potential pandemic viruses that cause life-threatening lung inflammation.

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Released Tryptophanyl-tRNA Synthetase Stimulates Innate Immune Responses against Viral Infection

Journal of Virology ◽

10.1128/jvi.01291-18 ◽

2018 ◽

Vol 93 (2) ◽

Cited By ~ 9

Author(s):

Hyun-Cheol Lee ◽

Eun-Seo Lee ◽

Md Bashir Uddin ◽

Tae-Hwan Kim ◽

Jae-Hoon Kim ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Viral Infection ◽

Innate Immune Response ◽

Trna Synthetase ◽

Innate Immune ◽

Full Length ◽

Type I ◽

Innate Immune Responses

ABSTRACT Tryptophanyl-tRNA synthetase (WRS) is one of the aminoacyl-tRNA synthetases (ARSs) that possesses noncanonical functions. Full-length WRS is released during bacterial infection and primes the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex to elicit innate immune responses. However, the role of WRS in viral infection remains unknown. Here, we show that full-length WRS is secreted by immune cells in the early phase of viral infection and functions as an antiviral cytokine. Treatment of cells with recombinant WRS protein promotes the production of inflammatory cytokines and type I interferons (IFNs) and curtails virus replication in THP-1 and Raw264.7 cells but not in TLR4−/− or MD2−/− bone marrow-derived macrophages (BMDMs). Intravenous and intranasal administration of recombinant WRS protein induces an innate immune response and blocks viral replication in vivo. These findings suggest that secreted full-length WRS has a noncanonical role in inducing innate immune responses to viral infection as well as to bacterial infection. IMPORTANCE ARSs are essential enzymes in translation that link specific amino acids to their cognate tRNAs. In higher eukaryotes, some ARSs possess additional, noncanonical functions in the regulation of cell metabolism. Here, we report a novel noncanonical function of WRS in antiviral defense. WRS is rapidly secreted in response to viral infection and primes the innate immune response by inducing the secretion of proinflammatory cytokines and type I IFNs, resulting in the inhibition of virus replication both in vitro and in vivo. Thus, we consider WRS to be a member of the antiviral innate immune response. The results of this study enhance our understanding of host defense systems and provide additional information on the noncanonical functions of ARSs.

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pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production

PLoS Pathogens ◽

10.1371/journal.ppat.1009733 ◽

2021 ◽

Vol 17 (7) ◽

pp. e1009733

Author(s):

Jiangnan Li ◽

Jie Song ◽

Li Kang ◽

Li Huang ◽

Shijun Zhou ◽

...

Keyword(s):

Immune Responses ◽

Inflammatory Responses ◽

African Swine Fever Virus ◽

African Swine Fever ◽

Innate Immune ◽

Fever Virus ◽

Type I ◽

Type I Ifn ◽

Innate Immune Responses

Inflammatory factors and type I interferons (IFNs) are key components of host antiviral innate immune responses, which can be released from the pathogen-infected macrophages. African swine fever virus (ASFV) has developed various strategies to evade host antiviral innate immune responses, including alteration of inflammatory responses and IFNs production. However, the molecular mechanism underlying inhibition of inflammatory responses and IFNs production by ASFV-encoded proteins has not been fully understood. Here we report that ASFV infection only induced low levels of IL-1β and type I IFNs in porcine alveolar macrophages (PAMs), even in the presence of strong inducers such as LPS and poly(dA:dT). Through further exploration, we found that several members of the multigene family 360 (MGF360) and MGF505 strongly inhibited IL-1β maturation and IFN-β promoter activation. Among them, pMGF505-7R had the strongest inhibitory effect. To verify the function of pMGF505-7R in vivo, a recombinant ASFV with deletion of the MGF505-7R gene (ASFV-Δ7R) was constructed and assessed. As we expected, ASFV-Δ7R infection induced higher levels of IL-1β and IFN-β compared with its parental ASFV HLJ/18 strain. ASFV infection-induced IL-1β production was then found to be dependent on TLRs/NF-κB signaling pathway and NLRP3 inflammasome. Furthermore, we demonstrated that pMGF505-7R interacted with IKKα in the IKK complex to inhibit NF-κB activation and bound to NLRP3 to inhibit inflammasome formation, leading to decreased IL-1β production. Moreover, we found that pMGF505-7R interacted with and inhibited the nuclear translocation of IRF3 to block type I IFN production. Importantly, the virulence of ASFV-Δ7R is reduced in piglets compared with its parental ASFV HLJ/18 strain, which may due to induction of higher IL-1β and type I IFN production in vivo. Our findings provide a new clue to understand the functions of ASFV-encoded pMGF505-7R and its role in viral infection-induced pathogenesis, which might help design antiviral agents or live attenuated vaccines to control ASF.

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Proteolytic Disassembly of Viral Outer Capsid Proteins Is Crucial for Reovirus-Mediated Type-I Interferon Induction in Both Reovirus-Susceptible and Reovirus-Refractory Tumor Cells

BioMed Research International ◽

10.1155/2015/468457 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

Yuki Katayama ◽

Yuichi Terasawa ◽

Masashi Tachibana ◽

Hiroyuki Mizuguchi ◽

Fuminori Sakurai

Keyword(s):

Immune Responses ◽

Tumor Cells ◽

Human Tumor ◽

Innate Immune ◽

Capsid Proteins ◽

Type I ◽

Innate Immune Responses ◽

Outer Capsid ◽

Proapoptotic Gene

Oncolytic reovirus induces innate immune responses, which contribute to the antitumor activity of reovirus, followingin vivoapplication. Reovirus-induced innate immune responses have been relatively well characterized in immune cells and mouse embryonic fibroblasts cells; however, the mechanisms and profiles of reovirus-induced innate immune responses in human tumor cells have not been well understood. In particular, differences in reovirus-induced innate immune responses between reovirus-susceptible and reovirus-refractory tumor cells remain unknown, although the intracellular trafficking of reovirus differs between these tumor cells. In this study, we examined reovirus-induced upregulation of interferon- (IFN-)βand of the proapoptotic gene, Noxa, in reovirus-susceptible and -refractory tumor cells. IFN-βand Noxa were significantly induced by reovirusviathe IFN-βpromoter stimulator-1 (IPS-1) signaling in both types of tumor cells. Inhibition of cathepsins B and L, which are important for disassembly of reovirus outer capsid proteins and escape into cytoplasm, largely suppressed reovirus-induced upregulation of IFN-βand Noxa expression in not only reovirus-susceptible but also reovirus-refractory tumor cells. These results indicated that in both reovirus-susceptible and reovirus-refractory tumor cells, disassembly of the outer capsid proteins by cathepsins and the escape into the cytoplasm were crucial steps for reovirus-induced innate immunity.

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Regulation of TRIF-mediated innate immune response by K27-linked polyubiquitination and deubiquitination

Nature Communications ◽

10.1038/s41467-019-12145-1 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 9

Author(s):

Xin Wu ◽

Caoqi Lei ◽

Tian Xia ◽

Xuan Zhong ◽

Qing Yang ◽

...

Keyword(s):

Immune Responses ◽

Adaptor Protein ◽

Innate Immune ◽

Negative Regulator ◽

Type I Interferons ◽

Poly I:C ◽

Type I ◽

Innate Immune Responses

Abstract TIR domain-containing adaptor inducing interferon-β (TRIF) is an essential adaptor protein required for innate immune responses mediated by Toll-like receptor (TLR) 3- and TLR4. Here we identify USP19 as a negative regulator of TLR3/4-mediated signaling. USP19 deficiency increases the production of type I interferons (IFN) and proinflammatory cytokines induced by poly(I:C) or LPS in vitro and in vivo. Usp19-/- mice have more serious inflammation after poly(I:C) or LPS treatment, and are more susceptible to inflammatory damages and death following Salmonella typhimurium infection. Mechanistically, USP19 interacts with TRIF and catalyzes the removal of TRIF K27-linked polyubiquitin moieties, thereby impairing the recruitment of TRIF to TLR3/4. In addition, the RING E3 ubiquitin ligase complex Cullin-3-Rbx1-KCTD10 catalyzes K27-linked polyubiquitination of TRIF at K523, and deficiency of this complex inhibits TLR3/4-mediated innate immune signaling. Our findings thus reveal TRIF K27-linked polyubiquitination and deubiquitination as a critical regulatory mechanism of TLR3/4-mediated innate immune responses.

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Yin Yang 1 Dynamically Regulates Antiviral Innate Immune Responses During Viral Infection

Cellular Physiology and Biochemistry ◽

10.1159/000485116 ◽

2017 ◽

Vol 44 (2) ◽

pp. 607-617 ◽

Cited By ~ 10

Author(s):

Jie Zan ◽

Hao Zhang ◽

Ai-Ping Gu ◽

Kai-Lun Zhong ◽

Min-Yi Lu ◽

...

Keyword(s):

Immune Responses ◽

Viral Infection ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Expression Levels ◽

Interferon Stimulated Genes ◽

Yin Yang 1 ◽

Yin Yang ◽

Interfering Rna

Background/Aims: Type I interferon (IFN-1) production and IFN-1 signaling play critical roles in the host antiviral innate immune responses. Although transcription factor Yin Yang 1 (YY1) has been reported to have a dual activator/repressor role during the regulation of interferon beta (IFN-β) promoter activity, the roles of YY1 in the regulation of upstream signaling pathways leading to IFN-1 induction and IFN-1 signaling during viral infection remain to be elucidated. Methods: The roles of YY1 in IFN-1 production and IFN-1 signaling were investigated using immunoblotting, real-time PCR, small interfering RNA (siRNA)-mediated YY1 knockdown, YY1 overexpression by transient transfection, and co-immunoprecipitation, using mouse cells. Results: YY1 was shown to interact with STAT1 in the absence of viral infection. Following viral infection, YY1 protein expression levels were decreased. YY1 knockdown led to a considerable downregulation of phosphorylated (p) TBK1 and pIRF3 expressions, while YY1 overexpression significantly upregulated pTBK1 and pIRF3 expression levels and promoted virus-induced IFN-β production. Additionally, YY1 knockdown led to a significant upregulation of pSTAT1, pSTAT2 and antiviral interferon-stimulated genes, and inhibited viral replication. Conclusion: We demonstrated here that YY1 interacts with STAT1 and dynamically regulates the induction of IFN-1 production and activation of IFN-1 signaling in different stages during viral infection.

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The Sp1-Responsive microRNA-15b Negatively Regulates Rhabdovirus-Triggered Innate Immune Responses in Lower Vertebrates by Targeting TBK1

Frontiers in Immunology ◽

10.3389/fimmu.2020.625828 ◽

2021 ◽

Vol 11 ◽

Author(s):

Renjie Chang ◽

Qing Chu ◽

Weiwei Zheng ◽

Lei Zhang ◽

Tianjun Xu

Keyword(s):

Immune Response ◽

Immune Responses ◽

Innate Immune ◽

Infection Model ◽

Regulation Mechanism ◽

Type I ◽

Innate Immune Responses ◽

Positive Role ◽

Siniperca Chuatsi ◽

Antiviral Immune Response

As is known to all, the production of type I interferon (IFN) plays pivotal roles in host innate antiviral immunity, and its moderate production play a positive role in promoting the activation of host innate antiviral immune response. However, the virus will establish a persistent infection model by interfering with the production of IFN, thereby evading the organism inherent antiviral immune response. Therefore, it is of great necessity to research the underlying regulatory mechanisms of type I IFN appropriate production under viral invasion. In this study, we report that a Sp1–responsive miR-15b plays a negative role in siniperca chuatsi rhabdovirus (SCRV)-triggered antiviral response in teleost fish. We found that SCRV could dramatically upregulate miiuy croaker miR-15b expression. Enhanced miR-15b could negatively regulate SCRV-triggered antiviral genes and inflammatory cytokines production by targeting TANK-binding kinase 1 (TBK1), thereby accelerating viral replication. Importantly, we found that miR-15b feedback regulates antiviral innate immune response through NF-κB and IRF3 signaling pathways. These findings highlight that miR-15b plays a crucial role in regulating virus–host interactions, which outlines a new regulation mechanism of fish’s innate immune responses.

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Novel Functions of IFI44L as a Feedback Regulator of Host Antiviral Responses

Journal of Virology ◽

10.1128/jvi.01159-19 ◽

2019 ◽

Vol 93 (21) ◽

Cited By ~ 9

Author(s):

Marta L. DeDiego ◽

Luis Martinez-Sobrido ◽

David J. Topham

Keyword(s):

Immune Responses ◽

Nuclear Factor Kappa B ◽

Virus Production ◽

Innate Immune ◽

Type I ◽

Nuclear Factor ◽

Innate Immune Responses ◽

Virus Infections ◽

Nuclear Factor Kappa ◽

Ifn Treatment

ABSTRACT We describe a novel function for the interferon (IFN)-induced protein 44-like (IFI44L) gene in negatively modulating innate immune responses induced after virus infections. Furthermore, we show that decreasing IFI44L expression impairs virus production and that IFI44L expression negatively modulates the antiviral state induced by an analog of double-stranded RNA (dsRNA) or by IFN treatment. The mechanism likely involves the interaction of IFI44L with cellular FK506-binding protein 5 (FKBP5), which in turn interacts with kinases essential for type I and III IFN responses, such as inhibitor of nuclear factor kappa B (IκB) kinase alpha (IKKα), IKKβ, and IKKε. Consequently, binding of IFI44L to FKBP5 decreased interferon regulatory factor 3 (IRF-3)-mediated and nuclear factor kappa-B (NF-κB) inhibitor (IκBα)-mediated phosphorylation by IKKε and IKKβ, respectively. According to these results, IFI44L is a good target for treatment of diseases associated with excessive IFN levels and/or proinflammatory responses and for reduction of viral replication. IMPORTANCE Excessive innate immune responses can be deleterious for the host, and therefore, negative feedback is needed. Here, we describe a completely novel function for IFI44L in negatively modulating innate immune responses induced after virus infections. In addition, we show that decreasing IFI44L expression impairs virus production and that IFI44L expression negatively modulates the antiviral state induced by an analog of dsRNA or by IFN treatment. IFI44L binds to the cellular protein FKBP5, which in turn interacts with kinases essential for type I and III IFN induction and signaling, such as the kinases IKKα, IKKβ, and IKKε. IFI44L binding to FKBP5 decreased the phosphorylation of IRF-3 and IκBα mediated by IKKε and IKKβ, respectively, providing an explanation for the function of IFI44L in negatively modulating IFN responses. Therefore, IFI44L is a candidate target for reducing virus replication.

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