scholarly journals Retinoic acid-inducible gene-I-like receptor (RLR)-mediated antiviral innate immune responses in the lower respiratory tract: Roles of TRAF3 and TRAF5

2015 ◽  
Vol 467 (2) ◽  
pp. 191-196 ◽  
Author(s):  
Yuki Chiba ◽  
Tomoh Matsumiya ◽  
Tsugumi Satoh ◽  
Ryo Hayakari ◽  
Ken Furudate ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Immune Responses ◽  
Respiratory Tract ◽  
Lower Respiratory Tract ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Inducible Gene

scholarly journals Human nasal and lung tissues infected ex vivo with SARS-CoV-2 provide insights into differential tissue-specific and virus-specific innate immune responses in the upper and lower respiratory tract

2021 ◽  
Author(s):  
Or Alfi ◽  
Arkadi Yakirevitch ◽  
Ori Wald ◽  
Ori Wandel ◽  
Uzi Izhar ◽  
...  
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Immune Responses ◽  
Respiratory Tract ◽  
Nasal Mucosa ◽  
Innate Immune Response ◽  
Lower Respiratory Tract ◽  
Influenza Virus Infection ◽  
Innate Immune ◽  
Innate Immune Responses

ABSTRACTThe nasal-mucosa constitutes the primary entry site for respiratory viruses including SARS-CoV-2. While the imbalanced innate immune response of end-stage COVID-19 has been extensively studied, the earliest stages of SARS-CoV-2 infection at the mucosal entry site have remained unexplored. Here we employed SARS-CoV-2 and influenza virus infection in native multi-cell-type human nasal turbinate and lung tissues ex vivo, coupled with genome-wide transcriptional analysis, to investigate viral susceptibility and early patterns of local-mucosal innate immune response in the authentic milieu of the human respiratory tract. SARS-CoV-2 productively infected the nasal turbinate tissues, predominantly targeting respiratory epithelial cells, with rapid increase in tissue-associated viral sub-genomic mRNA, and secretion of infectious viral progeny. Importantly, SARS-CoV-2 infection triggered robust antiviral and inflammatory innate immune responses in the nasal mucosa. The upregulation of interferon stimulated genes, cytokines and chemokines, related to interferon signaling and immune-cell activation pathways, was broader than that triggered by influenza virus infection. Conversely, lung tissues exhibited a restricted innate immune response to SARS-CoV-2, with a conspicuous lack of type I and III interferon upregulation, contrasting with their vigorous innate immune response to influenza virus. Our findings reveal differential tissue-specific innate immune responses in the upper and lower respiratory tract, that are distinct to SARS-CoV-2. The studies shed light on the role of the nasal-mucosa in active viral transmission and immune defense, implying a window of opportunity for early interventions, whereas the restricted innate immune response in early-SARS-CoV-2-infected lung tissues could underlie the unique uncontrolled late-phase lung damage of advanced COVID-19.IMPORTANCEIn order to reduce the late-phase morbidity and mortality of COVID-19, there is a need to better understand and target the earliest stages of SARS-CoV-2 infection in the human respiratory tract. Here we have studied the initial steps of SARS-CoV-2 infection and the consequent innate immune responses within the natural multicellular complexity of human nasal-mucosal and lung tissues. Comparing the global innate response patterns of nasal and lung tissues, infected in parallel with SARS-CoV-2 and influenza virus, we have revealed distinct virus-host interactions in the upper and lower respiratory tract, which could determine the outcome and unique pathogenesis of SARS-CoV-2 infection. Studies in the nasal-mucosal infection model can be employed to assess the impact of viral evolutionary changes, and evaluate new therapeutic and preventive measures against SARS-CoV-2 and other human respiratory pathogens.

scholarly journals Human nasal and lung tissues infected ex vivo with SARS-CoV-2 provide insights into differential tissue-specific and virus-specific innate immune responses in the upper and lower respiratory tract

2021 ◽  
Author(s):  
Or Alfi ◽  
Arkadi Yakirevitch ◽  
Ori Wald ◽  
Ori Wandel ◽  
Uzi Izhar ◽  
...  
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Immune Responses ◽  
Respiratory Tract ◽  
Nasal Mucosa ◽  
Innate Immune Response ◽  
Lower Respiratory Tract ◽  
Influenza Virus Infection ◽  
Innate Immune ◽  
Innate Immune Responses

The nasal-mucosa constitutes the primary entry site for respiratory viruses including SARS-CoV-2. While the imbalanced innate immune response of end-stage COVID-19 has been extensively studied, the earliest stages of SARS-CoV-2 infection at the mucosal entry site have remained unexplored. Here we employed SARS-CoV-2 and influenza virus infection in native multi-cell-type human nasal turbinate and lung tissues ex vivo, coupled with genome-wide transcriptional analysis, to investigate viral susceptibility and early patterns of local-mucosal innate immune response in the authentic milieu of the human respiratory tract. SARS-CoV-2 productively infected the nasal turbinate tissues, predominantly targeting respiratory epithelial cells, with rapid increase in tissue-associated viral sub-genomic mRNA, and secretion of infectious viral progeny. Importantly, SARS-CoV-2 infection triggered robust antiviral and inflammatory innate immune responses in the nasal mucosa. The upregulation of interferon stimulated genes, cytokines and chemokines, related to interferon signaling and immune-cell activation pathways, was broader than that triggered by influenza virus infection. Conversely, lung tissues exhibited a restricted innate immune response to SARS-CoV-2, with a conspicuous lack of type I and III interferon upregulation, contrasting with their vigorous innate immune response to influenza virus. Our findings reveal differential tissue-specific innate immune responses in the upper and lower respiratory tract, that are distinct to SARS-CoV-2. The studies shed light on the role of the nasal-mucosa in active viral transmission and immune defense, implying a window of opportunity for early interventions, whereas the restricted innate immune response in early-SARS-CoV-2-infected lung tissues could underlie the unique uncontrolled late-phase lung damage of advanced COVID-19. IMPORTANCE In order to reduce the late-phase morbidity and mortality of COVID-19, there is a need to better understand and target the earliest stages of SARS-CoV-2 infection in the human respiratory tract. Here we have studied the initial steps of SARS-CoV-2 infection and the consequent innate immune responses within the natural multicellular complexity of human nasal-mucosal and lung tissues. Comparing the global innate response patterns of nasal and lung tissues, infected in parallel with SARS-CoV-2 and influenza virus, we have revealed distinct virus-host interactions in the upper and lower respiratory tract, which could determine the outcome and unique pathogenesis of SARS-CoV-2 infection. Studies in the nasal-mucosal infection model can be employed to assess the impact of viral evolutionary changes, and evaluate new therapeutic and preventive measures against SARS-CoV-2 and other human respiratory pathogens.

scholarly journals Innate immune responses at the asymptomatic stage of influenza A viral infections of Streptococcus pneumoniae colonized and non-colonized mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fabian Cuypers ◽  
Alexander Schäfer ◽  
Sebastian B. Skorka ◽  
Surabhi Surabhi ◽  
Lea A. Tölken ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Immune Responses ◽  
Respiratory Tract ◽  
Influenza A ◽  
Innate Immune ◽  
Upper Respiratory Tract ◽  
Innate Immune Responses ◽  
Local Inflammatory Response ◽  
Inflammatory Monocytes ◽  
Asymptomatic Stage

AbstractSeasonal Influenza A virus (IAV) infections can promote dissemination of upper respiratory tract commensals such as Streptococcus pneumoniae to the lower respiratory tract resulting in severe life-threatening pneumonia. Here, we aimed to compare innate immune responses in the lungs of healthy colonized and non-colonized mice after IAV challenge at the initial asymptomatic stage of infection. Responses during a severe bacterial pneumonia were profiled for comparison. Cytokine and innate immune cell imprints of the lungs were analyzed. Irrespective of the colonization status, mild H1N1 IAV infection was characterized by a bi-phasic disease progression resulting in full recovery of the animals. Already at the asymptomatic stage of viral infection, the pro-inflammatory cytokine response was as high as in pneumococcal pneumonia. Flow cytometry analyses revealed an early influx of inflammatory monocytes into the lungs. Neutrophil influx was mostly limited to bacterial infections. The majority of cells, except monocytes, displayed an activated phenotype characterized by elevated CCR2 and MHCII expression. In conclusion, we show that IAV challenge of colonized healthy mice does not automatically result in severe co-infection. However, a general local inflammatory response was noted at the asymptomatic stage of infection irrespective of the infection type.

scholarly journals Modulation of T Cell and Innate Immune Responses by Retinoic Acid

2014 ◽  
Vol 192 (7) ◽  
pp. 2953-2958 ◽  
Author(s):  
Mathilde Raverdeau ◽  
Kingston H. G. Mills
Keyword(s):  
Retinoic Acid ◽  
T Cell ◽  
Immune Responses ◽  
Innate Immune ◽  
Innate Immune Responses

scholarly journals Picornavirus 3C proteins inhibit RIG-I-mediated innate immune responses by reducing TRIM25 expression

2020 ◽  
Author(s):  
Huimin Xiao ◽  
Jingliang Li ◽  
Xu Yang ◽  
Zhaolong Li ◽  
Yajuan Rui ◽  
...  
Keyword(s):  
Immune Responses ◽  
Innate Immune ◽  
Luciferase Reporter ◽  
Type I ◽  
Innate Immune Responses ◽  
Protease Cleavage ◽  
Structural Conformation ◽  
Reporter Assays ◽  
Retinoid Acid ◽  
Inducible Gene

Abstract Background：Enterovirus (EV) 3C proteins suppress type I interferon (IFN) responses mediated by retinoid acid-inducible gene I (RIG-I). An E3 ubiquitin ligase, tripartite motif protein 25 (TRIM25)-mediated RIG-I ubiquitination is essential for RIG-I antiviral activity. However, whether the effect of EV 3C on RIG-I is associated with TRIM25 remains unknown.Methods：In this study，luciferase reporter assays was used to detected the activity of IFN-β. Western Blot was used to detected the expression of proteins. Real-time PCR are used to detect that the mRNAs expression. And the co-immunoprecipitation assay was used to detect the interaction between TRIM25 and 3C protein.Results：Here, we demonstrated that 3C proteins of EV71 and CVB3 reduced the expression of RIG-I and TRIM25 through protease cleavage activities. Overexpression of TRIM25 restored RIG-I expression and IFN production reduced by 3C proteins. Further investigation confirmed that the two amino acids in TRIM25 required for RIG-I ubiquitination and structural conformation of TRIM25 were essential for RIG-I recovery. Moreover, we observed that TRIM25 could rescue RIG-I expression reduced by CVA6and EVD68 but not CVA16 3C.Conclusions：Our findings provide an insightful interpretation of 3C protein-mediated host innate immune suppression and support TRIM25 as an attractive target against EV infection.

scholarly journals Heightened Innate Immune Responses in the Respiratory Tract of COVID-19 Patients

2020 ◽  
Vol 27 (6) ◽  
pp. 883-890.e2 ◽  
Author(s):  
Zhuo Zhou ◽  
Lili Ren ◽  
Li Zhang ◽  
Jiaxin Zhong ◽  
Yan Xiao ◽  
...  
Keyword(s):  
Immune Responses ◽  
Respiratory Tract ◽  
Innate Immune ◽  
Innate Immune Responses

scholarly journals RNF39 mediates K48-linked ubiquitination of DDX3X and inhibits RLR-dependent antiviral immunity

2021 ◽  
Vol 7 (10) ◽  
pp. eabe5877
Author(s):  
Wenwen Wang ◽  
Mutian Jia ◽  
Chunyuan Zhao ◽  
Zhongxia Yu ◽  
Hui Song ◽  
...  
Keyword(s):  
Immune Responses ◽  
Ubiquitin Ligase ◽  
Rna Virus ◽  
Innate Immune ◽  
Regulatory Mechanisms ◽  
Innate Immune Responses ◽  
Dead Box ◽  
Rna Sensors ◽  
Antiviral Innate Immunity ◽  
Inducible Gene

Retinoic acid–inducible gene-I (RIG-I)–like receptors (RLRs) are major cytosolic RNA sensors and play crucial roles in initiating antiviral innate immunity. Furthermore, RLRs have been implicated in multiple autoimmune disorders. Thus, RLR activation should be tightly controlled to avoid detrimental effects. “DEAD-box RNA helicase 3, X-linked” (DDX3X) is a key adaptor in RLR signaling, but its regulatory mechanisms remain unknown. Here, we show that the E3 ubiquitin ligase RNF39 inhibits RLR pathways through mediating K48-linked ubiquitination and proteasomal degradation of DDX3X. Concordantly, Rnf39 deficiency enhances RNA virus–triggered innate immune responses and attenuates viral replication. Thus, our results uncover a previously unknown mechanism for the control of DDX3X activity and suggest RNF39 as a priming intervention target for diseases caused by aberrant RLR activation.

scholarly journals Innate immune responses during respiratory tract infection with a bacterial pathogen induce allergic airway sensitization

2008 ◽  
Vol 122 (3) ◽  
pp. 595-602.e5 ◽  
Author(s):  
Nicolas W.J. Schröder ◽  
Timothy R. Crother ◽  
Yoshikazu Naiki ◽  
Shuang Chen ◽  
Michelle H. Wong ◽  
...  
Keyword(s):  
Tract Infection ◽  
Immune Responses ◽  
Respiratory Tract ◽  
Respiratory Tract Infection ◽  
Bacterial Pathogen ◽  
Innate Immune ◽  
Innate Immune Responses
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