scholarly journals Unique and complementary suppression of cGAS-STING and RNA sensing- triggered innate immune responses by SARS-CoV-2 proteins

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Yajuan Rui ◽  
Jiaming Su ◽  
Si Shen ◽  
Ying Hu ◽  
Dingbo Huang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Nuclear Factor Κb ◽  
Innate Immune ◽  
Nuclear Accumulation ◽  
Innate Immune Responses ◽  
Structural Protein ◽  
Viral Protease ◽  
Downstream Signaling ◽  
Efficient Replication

AbstractThe emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic, leading to millions of infections and hundreds of thousands of human deaths. The efficient replication and population spread of SARS-CoV-2 indicates an effective evasion of human innate immune responses, although the viral proteins responsible for this immune evasion are not clear. In this study, we identified SARS-CoV-2 structural proteins, accessory proteins, and the main viral protease as potent inhibitors of host innate immune responses of distinct pathways. In particular, the main viral protease was a potent inhibitor of both the RLR and cGAS-STING pathways. Viral accessory protein ORF3a had the unique ability to inhibit STING, but not the RLR response. On the other hand, structural protein N was a unique RLR inhibitor. ORF3a bound STING in a unique fashion and blocked the nuclear accumulation of p65 to inhibit nuclear factor-κB signaling. 3CL of SARS-CoV-2 inhibited K63-ubiquitin modification of STING to disrupt the assembly of the STING functional complex and downstream signaling. Diverse vertebrate STINGs, including those from humans, mice, and chickens, could be inhibited by ORF3a and 3CL of SARS-CoV-2. The existence of more effective innate immune suppressors in pathogenic coronaviruses may allow them to replicate more efficiently in vivo. Since evasion of host innate immune responses is essential for the survival of all viruses, our study provides insights into the design of therapeutic agents against SARS-CoV-2.

scholarly journals RIG-I Signaling via MAVS Is Dispensable for Survival in Lethal Influenza Infection In Vivo

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Wenxin Wu ◽  
Xiaoqiu Wang ◽  
Wei Zhang ◽  
Lili Tian ◽  
J. Leland Booth ◽  
...  
Keyword(s):  
Immune Responses ◽  
Influenza A ◽  
Influenza Infection ◽  
Lavage Fluid ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Downstream Signaling ◽  
Cytokine Responses

Retinoic acid-inducible gene I (RIG-I) is an important regulator of virus-induced antiviral interferons (IFNs) and proinflammatory cytokines. It requires interaction with an adaptor molecule, mitochondrial antiviral-signaling protein (MAVS), to activate downstream signaling pathways. To elucidate the mechanism(s) by which RIG-I-dependent recognition of IAV infection in vivo triggers innate immune responses, we infected mutant mice lacking RIG-I or MAVS with influenza A virus (IAV) and measured their innate immune responses. As has previously been demonstrated with isolated deletion of the virus recognition receptors TLR3, TLR7, and NOD2, RIG-I or MAVS knockout (KO) did not result in higher mortality and did not reduce IAV-induced cytokine responses in mice. Infected RIG-I KO animals displayed similar lung inflammation profiles as did WT mice, in terms of the protein concentration, total cell count, and inflammatory cell composition in the bronchoalveolar lavage fluid. RNA-Seq results demonstrated that all types of mice exhibited equivalent antiviral and inflammatory gene responses following IAV infection. Together, the results indicated that although RIG-I is important in innate cytokine responses in vitro, individual deletion of the genes encoding RIG-I or MAVS did not change survival or innate responses in vivo after IAV infection in mice.

scholarly journals Immunologic Consequences of Hypoxia during Critical Illness

2016 ◽  
Vol 125 (1) ◽  
pp. 237-249 ◽  
Author(s):  
Harmke D. Kiers ◽  
Gert-Jan Scheffer ◽  
Johannes G. van der Hoeven ◽  
Holger K. Eltzschig ◽  
Peter Pickkers ◽  
...  
Keyword(s):  
Immune Responses ◽  
Signaling Pathways ◽  
Daily Practice ◽  
Innate Immune ◽  
Protective Effects ◽  
Innate Immune Responses ◽  
Downstream Signaling ◽  
Pathogen Clearance ◽  
Pharmacologic Modulation ◽  
Oxygen Status

Abstract Hypoxia and immunity are highly intertwined at clinical, cellular, and molecular levels. The prevention of tissue hypoxia and modulation of systemic inflammation are cornerstones of daily practice in the intensive care unit. Potentially, immunologic effects of hypoxia may contribute to outcome and represent possible therapeutic targets. Hypoxia and activation of downstream signaling pathways result in enhanced innate immune responses, aimed to augment pathogen clearance. On the other hand, hypoxia also exerts antiinflammatory and tissue-protective effects in lymphocytes and other tissues. Although human data on the net immunologic effects of hypoxia and pharmacologic modulation of downstream pathways are limited, preclinical data support the concept of tailoring the immune response through modulation of the oxygen status or pharmacologic modulation of hypoxia-signaling pathways in critically ill patients.

scholarly journals High-Resolution Profiling of Innate Immune Responses by Porcine Dendritic Cell Subsets in vitro and in vivo

2020 ◽  
Vol 11 ◽  
Author(s):  
Gaël Auray ◽  
Stephanie C. Talker ◽  
Irene Keller ◽  
Sylvie Python ◽  
Markus Gerber ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
High Resolution ◽  
Immune Responses ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Dendritic Cell Subsets

194 A Non-Gluten Component of Wheat is a Strong Stimulator of Innate Immune Responses In Vitro and In Vivo and Acts via Toll Like Receptor 4

2010 ◽  
Vol 138 (5) ◽  
pp. S-36
Author(s):  
Yvonne Junker ◽  
Donatella Barisani ◽  
Daniel A. Leffler ◽  
Towia Libermann ◽  
Simon T. Dillon ◽  
...  
Keyword(s):  
Immune Responses ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals APOε4 is associated with enhanced in vivo innate immune responses in human subjects

2014 ◽  
Vol 134 (1) ◽  
pp. 127-134.e9 ◽  
Author(s):  
Stephen C. Gale ◽  
Li Gao ◽  
Carmen Mikacenic ◽  
Susette M. Coyle ◽  
Nicholas Rafaels ◽  
...  
Keyword(s):  
Immune Responses ◽  
Human Subjects ◽  
Innate Immune ◽  
Innate Immune Responses

scholarly journals Polysaccharides derived from Yamoa™ (Funtumia elastica) prime γδ T cells in vitro and enhance innate immune responses in vivo

2009 ◽  
Vol 9 (11) ◽  
pp. 1313-1322 ◽  
Author(s):  
Jill C. Graff ◽  
Emily M. Kimmel ◽  
Brett Freedman ◽  
Igor A. Schepetkin ◽  
Jeff Holderness ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Γδ T Cells ◽  
Innate Immune ◽  
Innate Immune Responses

scholarly journals IFNα and IFNγ Impede Marek’s Disease Progression

Viruses ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1103 ◽  
Author(s):  
Luca D. Bertzbach ◽  
Olof Harlin ◽  
Sonja Härtle ◽  
Frank Fehler ◽  
Tereza Vychodil ◽  
...  
Keyword(s):  
Immune Responses ◽  
Disease Onset ◽  
Antiviral Effect ◽  
Lymphoproliferative Disease ◽  
Innate Immune ◽  
Marek's Disease ◽  
Marek’S Disease ◽  
Innate Immune Responses

Marek’s disease virus (MDV) is an alphaherpesvirus that causes Marek’s disease, a malignant lymphoproliferative disease of domestic chickens. While MDV vaccines protect animals from clinical disease, they do not provide sterilizing immunity and allow field strains to circulate and evolve in vaccinated flocks. Therefore, there is a need for improved vaccines and for a better understanding of innate and adaptive immune responses against MDV infections. Interferons (IFNs) play important roles in the innate immune defenses against viruses and induce upregulation of a cellular antiviral state. In this report, we quantified the potent antiviral effect of IFNα and IFNγ against MDV infections in vitro. Moreover, we demonstrate that both cytokines can delay Marek’s disease onset and progression in vivo. Additionally, blocking of endogenous IFNα using a specific monoclonal antibody, in turn, accelerated disease. In summary, our data reveal the effects of IFNα and IFNγ on MDV infection and improve our understanding of innate immune responses against this oncogenic virus.

scholarly journals Induction of Innate Immune Responses by SIV In Vivo and In Vitro: Differential Expression and Function of RIG-I and MDA5

2011 ◽  
Vol 204 (7) ◽  
pp. 1104-1114 ◽  
Author(s):  
Juliene G. Co ◽  
Kenneth W. Witwer ◽  
Lucio Gama ◽  
M. Christine Zink ◽  
Janice E. Clements
Keyword(s):  
Immune Responses ◽  
Differential Expression ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
And Function

scholarly journals Meta-analysis of immune induced gene expression changes in diverse Drosophila melanogaster innate immune responses

2021 ◽  
Author(s):  
Ashley L Waring ◽  
Joshua Hill ◽  
Brooke M Allen ◽  
Nicholas M Bretz ◽  
Nguyen Le ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drosophila Melanogaster ◽  
Immune Responses ◽  
Meta Analysis ◽  
Nuclear Factor Κb ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Response Factors ◽  
Induced Genes ◽  
Conserved Gene

Background: Organisms are commonly infected by a diverse array of pathogen types including bacteria, fungi, viruses, and parasites, and mount functionally distinct responses to each of these varied immune challenges. Host immune responses are characterized by the induction of gene expression in response to infection. However, the extent to which expression changes are shared among responses to distinct pathogens is largely unknown. Results: We performed meta-analysis of gene expression data collected from Drosophila melanogaster following infection with a wide array of pathogens. We identified 62 genes that are significantly induced by infection. While many of these infection-induced genes encode known immune response factors, we also identified 21 genes that have not been previously associated with host immunity. Examination of the upstream flanking sequences of the infection-induced genes lead to the identification of two conserved enhancer sites. These sites correspond to conserved binding sites for GATA and nuclear factor κB (NFκB) family transcription factors and are associated with higher levels of transcript induction. We further identified 31 genes with predicted functions in metabolism and organismal development that are significantly downregulated following infection by diverse pathogens. Conclusions: Our study identifies conserved gene expression changes in Drosophila melanogaster following infection with varied pathogens, and transcription factor families that may regulate this immune induction. These findings provide new insight into transcriptional changes that accompany Drosophila immunity. They may suggest possible roles for the differentially regulated genes in innate immune responses to diverse classes of pathogens, and serve to identify candidate genes for further empirical study of these processes.

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

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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