scholarly journals Type I and III IFNs produced by the nasal epithelia and dimmed inflammation are features of alpacas resolving MERS-CoV infection

2021 ◽  
Vol 17 (5) ◽  
pp. e1009229
Author(s):  
Nigeer Te ◽  
Jordi Rodon ◽  
Maria Ballester ◽  
Mónica Pérez ◽  
Lola Pailler-García ◽  
...  
Keyword(s):  
Immune Response ◽  
Respiratory Tract ◽  
Nasal Mucosa ◽  
Inflammatory Responses ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
Mononuclear Leukocytes ◽  
Post Inoculation ◽  
Type I ◽  
Anti Inflammatory

While MERS-CoV (Middle East respiratory syndrome Coronavirus) provokes a lethal disease in humans, camelids, the main virus reservoir, are asymptomatic carriers, suggesting a crucial role for innate immune responses in controlling the infection. Experimentally infected camelids clear infectious virus within one week and mount an effective adaptive immune response. Here, transcription of immune response genes was monitored in the respiratory tract of MERS-CoV infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III interferons (IFNs) were maximally transcribed only in the nasal mucosa of alpacas, while interferon stimulated genes (ISGs) were induced along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-κB control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, seems central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10.

scholarly journals Type I and III IFNs produced by the nasal epithelia and dimmed inflammation are key features of alpacas resolving MERS-CoV infection

2020 ◽  
Author(s):  
Nigeer Te ◽  
Jordi Rodon ◽  
Maria Ballester ◽  
Mónica Pérez ◽  
Lola Pailler-García ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Nasal Mucosa ◽  
Inflammatory Cytokine ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Responses ◽  
Interferon Stimulated Genes ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine

ABSTRACTWhile MERS-CoV (Middle East respiratory syndrome Coronavirus) provokes a lethal disease in humans, camelids, the main virus reservoir, are asymptomatic carriers, suggesting a crucial role for innate immune responses in controlling the infection. Experimentally infected camelids clear infectious virus within one week and mount an effective adaptive immune response. Here, transcription of immune response genes was monitored in the respiratory tract of MERS-CoV infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III interferons (IFNs) were maximally transcribed only in the nasal mucosa of alpacas, provoking the induction of interferon stimulated genes (ISGs) along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-κB control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, is central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10.IMPORTANCEMiddle East respiratory syndrome coronavirus (MERS-CoV) is the etiological agent of a respiratory disease causing high mortality in humans. In camelids, the main MERS-CoV reservoir host, viral infection leads to subclinical disease. Our study describes transcriptional regulations of innate immunological pathways underlying asymptomatic clinical manifestations of alpacas in response to MERS-CoV. Concomitant to the peak of infection, these animals elicited a strong transient interferon response and induction of the anti-inflammatory cytokine IL10 in the nasal mucosa. This was associated to a dimmed regulation of pro-inflammatory cytokines and induction of interferon stimulated genes along the whole respiratory mucosa, leading to the rapid clearance of the virus. Thus, innate immune responses occurring in the nasal mucosa appear to be the key in controlling MERS-CoV disease by avoiding a cytokine storm. Understanding on how asymptomatic host reservoirs counteract MERS-CoV infection will aid in the development of antiviral drugs and vaccines.

scholarly journals Type I and III IFNs produced by the nasal epithelia and dimmed inflammation are key features of alpacas resolving MERS-CoV infection

2020 ◽  
Author(s):  
Nigeer Te ◽  
Jordi Rodon ◽  
Maria Ballester ◽  
Mónica Pérez ◽  
Lola Pailler-García ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Nasal Mucosa ◽  
Inflammatory Cytokine ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Responses ◽  
Interferon Stimulated Genes ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine

AbstractWhile MERS-CoV (Middle East respiratory syndrome Coronavirus) provokes a lethal disease in humans, camelids, the main virus reservoir, are asymptomatic carriers, suggesting a crucial role for innate immune responses in controlling the infection. Experimentally infected camelids clear infectious virus within one week and mount an effective adaptive immune response. Here, transcription of immune response genes was monitored in the respiratory tract of MERS-CoV infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III interferons (IFNs) were maximally transcribed only in the nasal mucosa of alpacas, provoking the induction of interferon stimulated genes (ISGs) along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-κB control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, is central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10.Author summaryMiddle East respiratory syndrome coronavirus (MERS-CoV) is the etiological agent of a respiratory disease causing high mortality in humans. In camelids, the main MERS-CoV reservoir host, viral infection leads to subclinical disease. Our study describes transcriptional regulations of innate immunological pathways underlying asymptomatic clinical manifestations of alpacas in response to MERS-CoV. Concomitant to the peak of infection, these animals elicited a strong transient interferon response and induction of the anti-inflammatory cytokine IL10 in the nasal mucosa. This was associated to a dimmed regulation of pro-inflammatory cytokines and induction of interferon stimulated genes along the whole respiratory mucosa, leading to the rapid clearance of the virus. Thus, innate immune responses occurring in the nasal mucosa appear to be the key in controlling MERS-CoV disease by avoiding a cytokine storm. Understanding on how asymptomatic host reservoirs counteract MERS-CoV infection will aid in the development of antiviral drugs and vaccines.

SLPI and elafin: one glove, many fingers

2005 ◽  
Vol 110 (1) ◽  
pp. 21-35 ◽  
Author(s):  
Steven E. Williams ◽  
Thomas I. Brown ◽  
Ali Roghanian ◽  
Jean-Michel Sallenave
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Immune Responses ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Type I ◽  
Adaptive Immune ◽  
Pathological Conditions ◽  
Related Proteins

Elafin and SLPI (secretory leucocyte protease inhibitor) have multiple important roles both in normal homoeostasis and at sites of inflammation. These include antiprotease and antimicrobial activity as well as modulation of the response to LPS (lipopolysaccharide) stimulation. Elafin and SLPI are members of larger families of proteins secreted predominantly at mucosal sites, and have been shown to be modulated in multiple pathological conditions. We believe that elafin and SLPI are important molecules in the controlled functioning of the innate immune system, and may have further importance in the integration of this system with the adaptive immune response. Recent interest has focused on the influence of inflamed tissues on the recruitment and phenotypic modulation of cells of the adaptive immune system and, indeed, the local production of elafin and SLPI indicate that they are ideally placed in this regard. Functionally related proteins, such as the defensins and cathelicidins, have been shown to have direct effects upon dendritic cells with potential alteration of their phenotype towards type I or II immune responses. This review addresses the multiple functions of elafin and SLPI in the inflammatory response and discusses further their roles in the development of the adaptive immune response.

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 Deletion of Irf3 and Irf7 Genes in Mice Results in Altered Interferon Pathway Activation and Granulocyte-Dominated Inflammatory Responses to Influenza A Infection

2016 ◽  
Vol 9 (2) ◽  
pp. 145-161 ◽  
Author(s):  
Bastian Hatesuer ◽  
Hang Thi Thu Hoang ◽  
Peggy Riese ◽  
Stephanie Trittel ◽  
Ingo Gerhauser ◽  
...  
Keyword(s):  
Immune Response ◽  
Knockout Mice ◽  
Influenza A ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Adaptive Immune Response ◽  
Strong Increase ◽  
Type I ◽  
Influenza A Viruses ◽  
Double Knockout

The interferon (IFN) pathway plays an essential role in the innate immune response following viral infections and subsequent shaping of adaptive immunity. Infections with influenza A viruses (IAV) activate the IFN pathway after the recognition of pathogen-specific molecular patterns by respective pattern recognition receptors. The IFN regulatory factors IRF3 and IRF7 are key players in the regulation of type I and III IFN genes. In this study, we analyzed the role of IRF3 and IRF7 for the host response to IAV infections in Irf3-/-, Irf7-/-, and Irf3-/-Irf7-/- knockout mice. While the absence of IRF3 had only a moderate impact on IFN expression, deletion of IRF7 completely abolished IFNα production after infection. In contrast, lack of both IRF3 and IRF7 resulted in the absence of both IFNα and IFNβ after IAV infection. In addition, IAV infection of double knockout mice resulted in a strong increase of mortality associated with a massive influx of granulocytes in the lung and reduced activation of the adaptive immune response.

scholarly journals Biomaterials-Mediated Regulation of Macrophage Cell Fate

2020 ◽  
Vol 8 ◽  
Author(s):  
Yining Liu ◽  
Tatiana Segura
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Cell Fate ◽  
Innate Immune Response ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Adaptive Immune Response ◽  
Material Design ◽  
Innate Immune ◽  
Macrophage Phenotype

Endogenous regeneration aims to rebuild and reinstate tissue function through enlisting natural self-repairing processes. Promoting endogenous regeneration by reducing tissue-damaging inflammatory responses while reinforcing self-resolving inflammatory processes is gaining popularity. In this approach, the immune system is recruited as the principal player to deposit a pro-reparative matrix and secrete pro-regenerative cytokines and growth factors. The natural wound healing cascade involves many immune system players (neutrophils, macrophages, T cells, B cells, etc.) that are likely to play important and indispensable roles in endogenous regeneration. These cells support both the innate and adaptive arms of the immune system and collectively orchestrate host responses to tissue damage. As the early responders during the innate immune response, macrophages have been studied for decades in the context of inflammatory and foreign body responses and were often considered a cell type to be avoided. The view on macrophages has evolved and it is now understood that macrophages should be directly engaged, and their phenotype modulated, to guide the timely transition of the immune response and reparative environment. One way to achieve this is to design immunomodulating biomaterials that can be placed where endogenous regeneration is desired and actively direct macrophage polarization. Upon encountering these biomaterials, macrophages are trained to perform more pro-regenerative roles and generate the appropriate environment for later stages of regeneration since they bridge the innate immune response and the adaptive immune response. This new design paradigm necessitates the understanding of how material design elicits differential macrophage phenotype activation. This review is focused on the macrophage-material interaction and how to engineer biomaterials to steer macrophage phenotypes for better tissue regeneration.

scholarly journals Rat respiratory coronavirus infection: replication in airway and alveolar epithelial cells and the innate immune response

2009 ◽  
Vol 90 (12) ◽  
pp. 2956-2964 ◽  
Author(s):  
C. Joel Funk ◽  
Rizwan Manzer ◽  
Tanya A. Miura ◽  
Steve D. Groshong ◽  
Yoko Ito ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Intratracheal Instillation ◽  
Innate Immune ◽  
Alveolar Epithelial Cells ◽  
Immunofluorescent Staining ◽  
Alveolar Type ◽  
Post Inoculation ◽  
Type I ◽  
Respiratory Coronavirus

The rat coronavirus sialodacryoadenitis virus (SDAV) causes respiratory infection and provides a system for investigating respiratory coronaviruses in a natural host. A viral suspension in the form of a microspray aerosol was delivered by intratracheal instillation into the distal lung of 6–8-week-old Fischer 344 rats. SDAV inoculation produced a 7 % body weight loss over a 5 day period that was followed by recovery over the next 7 days. SDAV caused focal lesions in the lung, which were most severe on day 4 post-inoculation (p.i.). Immunofluorescent staining showed that four cell types supported SDAV virus replication in the lower respiratory tract, namely Clara cells, ciliated cells in the bronchial airway and alveolar type I and type II cells in the lung parenchyma. In bronchial alveolar lavage fluid (BALF) a neutrophil influx increased the population of neutrophils to 45 % compared with 6 % of the cells in control samples on day 2 after mock inoculation. Virus infection induced an increase in surfactant protein SP-D levels in BALF of infected rats on days 4 and 8 p.i. that subsided by day 12. The concentrations of chemokines MCP-1, LIX and CINC-1 in BALF increased on day 4 p.i., but returned to control levels by day 8. Intratracheal instillation of rats with SDAV coronavirus caused an acute, self-limited infection that is a useful model for studying the early events of the innate immune response to respiratory coronavirus infections in lungs of the natural virus host.

scholarly journals Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 675
Author(s):  
Samira Elmanfi ◽  
Mustafa Yilmaz ◽  
Wilson W. S. Ong ◽  
Kofi S. Yeboah ◽  
Herman O. Sintim ◽  
...  
Keyword(s):  
Immune Response ◽  
Periodontal Disease ◽  
Innate Immune ◽  
Host Cells ◽  
Type I Interferons ◽  
Type I ◽  
Vaccine Adjuvants ◽  
Cyclic Dinucleotides ◽  
Sting Pathway

Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides—including c-di-GMP, c-di-AMP, and cGAMP—of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms “STING”, “TBK 1”, “IRF3”, and “cGAS”—alone, or together with “periodontitis”. Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.

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