scholarly journals MERS-CoV infection is associated with downregulation of genes encoding Th1 and Th2 cytokines/chemokines and elevated inflammatory innate immune response in the lower respiratory tract

Cytokine ◽  
2020 ◽  
Vol 126 ◽  
pp. 154895 ◽  
Author(s):  
Bandar Alosaimi ◽  
Maaweya E. Hamed ◽  
Asif Naeem ◽  
Ali A. Alsharef ◽  
Saeed Y. AlQahtani ◽  
...  
Keyword(s):  
Immune Response ◽  
Respiratory Tract ◽  
Innate Immune Response ◽  
Lower Respiratory Tract ◽  
Innate Immune ◽  
Th2 Cytokines ◽  
Genes Encoding ◽  
Th1 And Th2 Cytokines ◽  
Th1 And Th2

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 The innate immune response to lower respiratory tract E. Coli infection and the role of the CCL2-CCR2 axis in neonatal mice

Cytokine ◽  
2017 ◽  
Vol 97 ◽  
pp. 108-116 ◽  
Author(s):  
Sharon A. McGrath-Morrow ◽  
Roland Ndeh ◽  
Joseph M. Collaco ◽  
Amy K. Poupore ◽  
Dustin Dikeman ◽  
...  
Keyword(s):  
Immune Response ◽  
Respiratory Tract ◽  
Innate Immune Response ◽  
Lower Respiratory Tract ◽  
Innate Immune ◽  
E Coli ◽  
Neonatal Mice

High content screening and computational prediction reveal viral genes that suppress innate immune response

2021 ◽  
Author(s):  
Tai L Ng ◽  
Erika J Olson ◽  
Tae Yeon Yoo ◽  
H. Sloane Weiss ◽  
Yukiye Koide ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Nuclear Transport ◽  
Computational Prediction ◽  
Viral Proteins ◽  
Innate Immune ◽  
Type I ◽  
Viral Genes ◽  
Genes Encoding

Suppression of the host innate immune response is a critical aspect of viral replication. Upon infection, viruses may introduce one or more proteins that inhibit key immune pathways, such as the type I interferon pathway. However, the ability to predict and evaluate viral protein bioactivity on targeted pathways remains challenging and is typically done on a single virus/gene basis. Here, we present a medium-throughput high-content cell-based assay to reveal the immunosuppressive effects of viral proteins. To test the predictive power of our approach, we developed a library of 800 genes encoding known, predicted, and uncharacterized human viral genes. We find that previously known immune suppressors from numerous viral families such as Picornaviridae and Flaviviridae recorded positive responses. These include a number of viral proteases for which we further confirmed that innate immune suppression depends on protease activity. A class of predicted inhibitors encoded by Rhabdoviridae viruses was demonstrated to block nuclear transport, and several previously uncharacterized proteins from uncultivated viruses were shown to inhibit nuclear transport of the transcription factors NF-kB and IRF3. We propose that this pathway-based assay, together with early sequencing, gene synthesis, and viral infection studies, could partly serve as the basis for rapid in vitro characterization of novel viral proteins.

The Role of Hox Proteins and Interferon Regulatory Factors in Myeloid Differentiation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-34-sci-34
Author(s):  
Elizabeth A. Eklund
Keyword(s):  
Immune Response ◽  
Transcription Factors ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Gene Encoding ◽  
Hox Proteins ◽  
Regulatory Factors ◽  
Interferon Regulatory Factors ◽  
Genes Encoding ◽  
Myeloid Progenitors

During myelopoiesis, differentiating phagocytes develop functional competence and undergo proliferation arrest and eventual programmed cell death. This process involves transcriptional regulation of genes which mediate the innate immune response, mitotic arrest, and apoptosis. A number of transcription factor families play important roles in regulating such genes, including Hox proteins and interferon regulatory factors (IRFs). Disordered expression of Hox proteins is associated with myeloid leukemogenesis. Hox proteins are homeodomain transcription factors that are organized in four paralog groups (A–D). Expression of HoxA7-11 (the ABD-HOXA genes) is characteristic of myeloid progenitors. ABD-HOXA transcription decreases with CD34+ to CD34− progression, and persistent expression of these genes is found in poor prognosis leukemia. Abd Hox proteins regulate genes that are involved in multiple aspects of myelopoiesis. For example, HoxA10 represses transcription of the genes encoding gp91phox and p67phox in myeloid progenitors (the CYBB and NCF2 genes, respectively). In contrast, HoxA9 activates transcription of these genes as differentiation proceeds. Since these are the rate-limiting NADPH oxidase components, HoxA proteins influence the innate immune response. HoxA10 activates transcription of the gene encoding Beta3 integrin, thereby further facilitating NADPH oxidase activation and influencing adhesion. HoxA10 also activates transcription of DUSP4, the gene encoding MAP kinase phosphatase 2 (Mkp2). Mkp2 antagonizes the activity of c-Jun N-terminal kinases (Jnk). Since HoxA10-activation of DUSP4 decreases during myelopoiesis, decreased Mkp2 expression in mature phagocytes facilitates apoptosis via Jnk. Interferon regulatory factors (IRF) also regulate multiple aspects of myelopoiesis. IRF1 and ICSBP/IRF8 activate transcription of the CYBB and NCF2 genes in cooperation with the ets protein PU.1. ICSBP/IRF8 also contributes to phagocyte function by activating genes encoding TLR4, IL12, and Nramp. Additionally, IRF proteins regulate cell cycle progression and proliferation. IRF2, ICSBP/IRF8, and PU.1 activate transcription of gene encoding Neurofibromin 1, thereby downregulating the proliferative response to cytokines such as GM-CSF, M-CSF, and G-CSF. ICSBP/IRF8 and PU.1 also activate the gene encoding Ink4b, thereby also influencing proliferation. In myeloid progenitors, ICSBP/IRF8 influences cell survival by repressing transcription of PTPN13, the gene encoding Fas-associated phosphatase 1 (Fap1), a Fas-antagonist. Decreased ICSBP/IRF8-induced PTPN13 repression during myelopoiesis increases susceptibility of mature phagocytes to Fas-induced apoptosis. Such studies reveal that multiple aspects of myelopoiesis are regulated by common sets of transcription factors. This may suggest therapeutic targets for myeloid leukemias or other disorders of myeloid development.

scholarly journals Role of Th1 and Th2 Cytokines in Immune Response to Uncomplicated Plasmodium falciparum Malaria

2002 ◽  
Vol 9 (2) ◽  
pp. 348-351 ◽  
Author(s):  
Donato Torre ◽  
Filippo Speranza ◽  
Massimo Giola ◽  
Alberto Matteelli ◽  
Roberto Tambini ◽  
...  
Keyword(s):  
Immune Response ◽  
Plasmodium Falciparum ◽  
Interleukin 12 ◽  
Th2 Cytokines ◽  
Th1 And Th2 Cytokines ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Th1 Cytokines ◽  
Th1 And Th2

ABSTRACT The relative balance between Th1 and Th2 cytokines appears crucial, since the role of cytokines has been evaluated in several studies by comparison of clinically heterogeneous groups of patients. The aim of this study is to determine the role of proinflammatory Th1 cytokines, interleukin-12 (IL-12) and gamma interferon (IFN-γ), and anti-inflammatory Th2 cytokines, IL-4 and IL-10, in a homogeneous group of patients with uncomplicated Plasmodium falciparum malaria. Levels of IL-12, IFN-γ, Il-4, and IL-10 in serum for 20 adult patients and 15 healthy control subjects were determined by an immunoenzymatic assay. Serum levels of Th1 cytokines, IL-12 (8.6 ± 2.8 pg/ml; controls, 3.2 ± 0.7 pg/ml) and IFN-γ (39.2 ± 67.6 pg/ml; controls, 8.4 ± 6.3 pg/ml), were significantly increased at admission; 3 days later, levels of IL-12 in serum remained significantly high (8.8 ± 2.6 pg/ml), whereas IFN-γ levels returned to control values. The anti-inflammatory response of Th2 cytokines (IL-10 and IL-4) was distinct. Levels of IL-10 in serum were not significantly increased at day 0 and day 3 (306.6 ± 200.4 pg/ml and 56.6 ± 38.4 pg/ml, respectively; controls, 17.4 ± 9.0 pg/ml). In contrast, levels of IL-4 in serum were not increased on admission (3.4 ± 1.2 pg/ml; controls, 2.4 ± 0.8 pg/ml), but at day 3 a moderate and significant increase of IL-4 levels was observed (4.5 ± 1.7 pg/ml). In conclusion, the increase of Th1 cytokine IL-12 and IFN-γ levels during the acute phase of uncomplicated P. falciparum malaria may reflect an early and effective immune response regulated by proinflammatory Th1 cytokines, and in particular IFN-γ may play a role in limiting progression from uncomplicated malaria to severe and life-threatening complications.

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