Inflammation, Inflammatory Diseases, and Inflammasomes.

Inflammation represents the innate immune response of the body tissues against invading microbes and cellular danger signals, and, in this way, it is beneficial [...].

Innate and adaptive immunity to SARS-CoV-2 and predisposing factors.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has affected all countries worldwide. Although some symptoms are relatively mild, others are still associated with severe and even fatal clinical outcomes. Innate and adaptive immunity are important for the control of SARS-CoV-2 infections, whereas a comprehensive characterization of the innate and adaptive immune response to COVID-19 is still lacking and the mechanisms underlying immune pathogenesis and host predisposing factors are still a matter of scientific debate. Here, the specific functions and kinetics of innate and adaptive immunity involved in SARS-CoV-2 recognition and resultant pathogenesis are discussed, as well as their immune memory for vaccinations, viral-mediated immune evasion, and the current and future immunotherapeutic agents. We also highlight host factors that contribute to infection, which may deepen the understanding of viral pathogenesis and help identify targeted therapies that attenuate severe disease and infection.

Immune response induced by novel coronavirus infection.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has been prominent around the world since it was first discovered, affecting more than 100 million people. Although the symptoms of most infected patients are not serious, there is still a considerable proportion of patients who need hospitalization and even develop fatal symptoms such as cytokine storms, acute respiratory distress syndrome and so on. Cytokine storm is usually described as a collection of clinical manifestations caused by overactivation of the immune system, which plays an important role in tissue injury and multiorgan failure. The immune system of healthy individuals is composed of two interrelated parts, the innate immune system and the adaptive immune system. Innate immunity is the body's first line of defense against viruses; it can quickly perceive viruses through pattern recognition receptors and activate related inflammatory pathways to clear pathogens. The adaptive immune system is activated by specific antigens and is mainly composed of CD4+ T cells, CD8+ T cells and B cells, which play different roles in viral infection. Here, we discuss the immune response after SARS-CoV-2 infection. In-depth study of the recognition of and response of innate immunity and adaptive immunity to SARS-CoV-2 will help to prevent the development of critical cases and aid the exploration of more targeted treatments.

SARS-CoV-2 Evasion of the Interferon System: Can We Restore Its Effectiveness?

Type I and III Interferons (IFNs) are the first lines of defense in microbial infections. They critically block early animal virus infection, replication, spread, and tropism to promote the adaptive immune response. Type I IFNs induce a systemic response that impacts nearly every cell in the host, while type III IFNs' susceptibility is restricted to anatomic barriers and selected immune cells. Both IFN types are critical cytokines for the antiviral response against epithelium-tropic viruses being effectors of innate immunity and regulators of the development of the adaptive immune response. Indeed, the innate antiviral immune response is essential to limit virus replication at the early stages of infection, thus reducing viral spread and pathogenesis. However, many animal viruses have evolved strategies to evade the antiviral immune response. The Coronaviridae are viruses with the largest genome among the RNA viruses. Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) caused the coronavirus disease 2019 (COVID-19) pandemic. The virus has evolved numerous strategies to contrast the IFN system immunity. We intend to describe the virus-mediated evasion of the IFN responses by going through the main phases: First, the molecular mechanisms involved; second, the role of the genetic background of IFN production during SARS-CoV-2 infection; and third, the potential novel approaches to contrast viral pathogenesis by restoring endogenous type I and III IFNs production and sensitivity at the sites of infection.

Recent advances in ZBP1-derived PANoptosis against viral infections.

Innate immunity is an important first line of defense against pathogens, including viruses. These pathogen- and damage-associated molecular patterns (PAMPs and DAMPs, respectively), resulting in the induction of inflammatory cell death, are detected by specific innate immune sensors. Recently, Z-DNA binding protein 1 (ZBP1), also called the DNA-dependent activator of IFN regulatory factor (DAI) or DLM1, is reported to regulate inflammatory cell death as a central mediator during viral infection. ZBP1 is an interferon (IFN)-inducible gene that contains two Z-form nucleic acid-binding domains (Zα1 and Zα2) in the N-terminus and two receptor-interacting protein homotypic interaction motifs (RHIM1 and RHIM2) in the middle, which interact with other proteins with the RHIM domain. By sensing the entry of viral RNA, ZBP1 induces PANoptosis, which protects host cells against viral infections, such as influenza A virus (IAV) and herpes simplex virus (HSV1). However, some viruses, particularly coronaviruses (CoVs), induce PANoptosis to hyperactivate the immune system, leading to cytokine storm, organ failure, tissue damage, and even death. In this review, we discuss the molecular mechanism of ZBP1-derived PANoptosis and pro-inflammatory cytokines that influence the double-edged sword of results in the host cell. Understanding the ZBP1-derived PANoptosis mechanism may be critical for improving therapeutic strategies.

Modulation of innate immunity in airway epithelium for host-directed therapy.

Innate immunity of the mucosal surfaces provides the first-line defense from invading pathogens and pollutants conferring protection from the external environment. Innate immune system of the airway epithelium consists of several components including the mucus layer, mucociliary clearance of beating cilia, production of host defense peptides, epithelial barrier integrity provided by tight and adherens junctions, pathogen recognition receptors, receptors for chemokines and cytokines, production of reactive oxygen species, and autophagy. Therefore, multiple components interplay with each other for efficient protection from pathogens that still can subvert host innate immune defenses. Hence, the modulation of innate immune responses with different inducers to boost host endogenous front-line defenses in the lung epithelium to fend off pathogens and to enhance epithelial innate immune responses in the immunocompromised individuals is of interest for host-directed therapy. Herein, we reviewed possibilities of modulation innate immune responses in the airway epithelium for host-directed therapy presenting an alternative approach to standard antibiotics.

STING is redundant for host defense and pathology of COVID-19-like disease in mice.

Critical COVID-19 is characterized by lack of early type I interferon-mediated host defense and subsequent hyper-inflammation in the lungs. Aberrant activation of macrophages and neutrophils has been reported to lead to excessive activation of innate immunological pathways. It has recently been suggested that the DNA-sensing cGAS-STING pathway drives pathology in the SARS-CoV-2-infected lungs, but mechanistic understanding from in vivo models is needed. Here, we tested whether STING is involved in COVID-19-like disease using the K18-hACE2 mouse model. We report that disease development after SARS-CoV-2 infection is unaltered in STING-deficient K18-hACE2 mice. In agreement with this, STING deficiency did not affect control of viral replication or production of interferons and inflammatory cytokines. This was accompanied by comparable profiles of infiltrating immune cells into the lungs of infected mice. These data do not support a role for STING in COVID-19 pathology and calls for further investigation into the pathogenesis of critical COVID-19.

Current hotspot and study trend of innate immunity in COVID-19: a bibliometric analysis from 2020 to 2022.

Background: Since the coronavirus disease 2019 (COVID-19) has spread throughout the world, many studies on innate immunity in COVID-19 have been published, and great progress has been achieved, while bibliometric analysis on hotspots and research trends in this field remains lacking. Methods: On 17 November 2022, articles and reviews on innate immunity in COVID-19 were recruited from the Web of Science Core Collection (WoSCC) database after papers irrelevant to COVID-19 were further excluded. The number of annual publications and the average citations per paper were analyzed by Microsoft Excel. Bibliometric analysis and visualization of the most prolific contributors and hotspots in the field were performed by VOSviewer and CiteSpace software. Results: There were 1,280 publications that met the search strategy on innate immunity in COVID-19 and were published from 1 January 2020 to 31 October 2022. Nine hundred thirteen articles and reviews were included in the final analysis. The USA had the highest number of publications (Np) at 276 and number of citations without self-citations (Nc) at 7,085, as well as an H-index of 42, which contributed 30.23% of the total publications, followed by China (Np: 135, Nc: 4,798, and H-index: 23) with 14.79% contribution. Regarding Np for authors, Netea, Mihai G. (Np: 7) from the Netherlands was the most productive author, followed by Joosten, Leo A. B. (Np: 6) and Lu, Kuo-Cheng (Np: 6). The Udice French Research Universities had the most publications (Np: 31, Nc: 2,071, H-index: 13), with an average citation number (ACN) at 67. The journal Frontiers in Immunology possessed the most publications (Np: 89, Nc: 1,097, ACN: 12.52). "Evasion" (strength 1.76, 2021-2022), "neutralizing antibody" (strength 1.76, 2021-2022), "messenger RNA" (strength 1.76, 2021-2022), "mitochondrial DNA" (strength 1.51, 2021-2022), "respiratory infection" (strength 1.51, 2021-2022), and "toll-like receptors" (strength 1.51, 2021-2022) were the emerging keywords in this field. Conclusion: The study on innate immunity in COVID-19 is a hot topic. The USA was the most productive and influential country in this field, followed by China. The journal with the most publications was Frontiers in Immunology. "Messenger RNA," "mitochondrial DNA," and "toll-like receptors" are the current hotspots and potential targets in future research.

Mapping interindividual dynamics of innate immune response at single-cell resolution.

Common genetic variants across individuals modulate the cellular response to pathogens and are implicated in diverse immune pathologies, yet how they dynamically alter the response upon infection is not well understood. Here, we triggered antiviral responses in human fibroblasts from 68 healthy donors, and profiled tens of thousands of cells using single-cell RNA-sequencing. We developed GASPACHO (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity), a statistical approach designed to identify nonlinear dynamic genetic effects across transcriptional trajectories of cells. This approach identified 1,275 expression quantitative trait loci (local false discovery rate 10%) that manifested during the responses, many of which were colocalized with susceptibility loci identified by genome-wide association studies of infectious and autoimmune diseases, including the OAS1 splicing quantitative trait locus in a COVID-19 susceptibility locus. In summary, our analytical approach provides a unique framework for delineation of the genetic variants that shape a wide spectrum of transcriptional responses at single-cell resolution.

Cytoplasmic DNAs: Sources, sensing, and roles in the development of lung inflammatory diseases and cancer.

Cytoplasmic DNA is emerging as a pivotal contributor to the pathogenesis of inflammatory diseases and cancer, such as COVID-19 and lung carcinoma. However, the complexity of various cytoplasmic DNA-related pathways and their crosstalk remains challenging to distinguish their specific roles in many distinct inflammatory diseases, especially for the underlying mechanisms. Here, we reviewed the latest findings on cytoplasmic DNA and its signaling pathways in inflammatory lung conditions and lung cancer progression. We found that sustained activation of cytoplasmic DNA sensing pathways contributes to the development of common lung diseases, which may result from external factors or mutations of key genes in the organism. We further discussed the interplays between cytoplasmic DNA and anti-inflammatory or anti-tumor effects for potential immunotherapy. In sum, this review aids in understanding the roles of cytoplasmic DNAs and exploring more therapeutic strategies.

Interferon production by Viral, Bacterial & Yeast system: A comparative overview in 2023.

Interferons play a critical role in the innate immune response against several infections and play a key role in the control of a variety of viral and bacterial infectious diseases such as hepatitis, covid-19, cancer, and multiple sclerosis. Therefore, natural or synthetic IFN production is important and had three common methods, including bacterial fermentation, animal cell culture, and recombinant nucleic acid technology. However, the safety, purity, and accuracy of the most preferred INF production systems have not been extensively studied. This study provides a comprehensive comparative overview of interferon production in various systems that include viral, bacterial, yeast, and mammalian. We aim to determine the most efficient, safe, and accurate interferon production system available in the year 2023. The mechanisms of artificial interferon production were reviewed in various organisms, and the types and subtypes of interferons produced by each system were compared. Our analysis provides a comprehensive overview of the similarities and differences in interferon production and highlights the potential for developing new therapeutic strategies to combat infectious diseases. This review article offers the diverse strategies used by different organisms in producing and utilizing interferons, providing a framework for future research into the evolution and function of this critical immune response pathway.

Systems analysis of human innate immunity in COVID-19.

Recent developments in sequencing technologies, the computer and data sciences, as well as increasingly high-throughput immunological measurements have made it possible to derive holistic views on pathophysiological processes of disease and treatment effects directly in humans. We and others have illustrated that incredibly predictive data for immune cell function can be generated by single cell multi-omics (SCMO) technologies and that these technologies are perfectly suited to dissect pathophysiological processes in a new disease such as COVID-19, triggered by SARS-CoV-2 infection. Systems level interrogation not only revealed the different disease endotypes, highlighted the differential dynamics in context of disease severity, and pointed towards global immune deviation across the different arms of the immune system, but was already instrumental to better define long COVID phenotypes, suggest promising biomarkers for disease and therapy outcome predictions and explains treatment responses for the widely used corticosteroids. As we identified SCMO to be the most informative technologies in the vest to better understand COVID-19, we propose to routinely include such single cell level analysis in all future clinical trials and cohorts addressing diseases with an immunological component.

Die Kämpfe únd schláchten-the struggles and battles of innate-like effector T lymphocytes with microbes.

The large majority of lymphocytes belong to the adaptive immune system, which are made up of B2 B cells and the αß T cells; these are the effectors in an adaptive immune response. A multitudinous group of lymphoid lineage cells does not fit the conventional lymphocyte paradigm; it is the unconventional lymphocytes. Unconventional lymphocytes-here called innate/innate-like lymphocytes, include those that express rearranged antigen receptor genes and those that do not. Even though the innate/innate-like lymphocytes express rearranged, adaptive antigen-specific receptors, they behave like innate immune cells, which allows them to integrate sensory signals from the innate immune system and relay that umwelt to downstream innate and adaptive effector responses. Here, we review natural killer T cells and mucosal-associated invariant T cells-two prototypic innate-like T lymphocytes, which sense their local environment and relay that umwelt to downstream innate and adaptive effector cells to actuate an appropriate host response that confers immunity to infectious agents.

Mechanisms of impairment of interferon production by SARS-CoV-2.

Interferons (IFNs) are crucial components of the cellular innate immune response to viral infections. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown a remarkable capacity to suppress the host IFN production to benefit viral replication and spread. Thus far, of the 28 known virus-encoded proteins, 16 have been found to impair the host's innate immune system at various levels ranging from detection and signaling to transcriptional and post-transcriptional regulation of expression of the components of the cellular antiviral response. Additionally, there is evidence that the viral genome encodes non-protein-coding microRNA-like elements that could also target IFN-stimulated genes. In this brief review, we summarise the current state of knowledge regarding the factors and mechanisms by which SARS-CoV-2 impairs the production of IFNs and thereby dampens the host's innate antiviral immune response.

Circulating extracellular particles from severe COVID-19 patients show altered profiling and innate lymphoid cell-modulating ability.

Introduction: Extracellular vesicles (EVs) and particles (EPs) represent reliable biomarkers for disease detection. Their role in the inflammatory microenvironment of severe COVID-19 patients is not well determined. Here, we characterized the immunophenotype, the lipidomic cargo and the functional activity of circulating EPs from severe COVID-19 patients (Co-19-EPs) and healthy controls (HC-EPs) correlating the data with the clinical parameters including the partial pressure of oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) and the sequential organ failure assessment (SOFA) score. Methods: Peripheral blood (PB) was collected from COVID-19 patients (n=10) and HC (n=10). EPs were purified from platelet-poor plasma by size exclusion chromatography (SEC) and ultrafiltration. Plasma cytokines and EPs were characterized by multiplex bead-based assay. Quantitative lipidomic profiling of EPs was performed by liquid chromatography/mass spectrometry combined with quadrupole time-of-flight (LC/MS Q-TOF). Innate lymphoid cells (ILC) were characterized by flow cytometry after co-cultures with HC-EPs or Co-19-EPs. Results: We observed that EPs from severe COVID-19 patients: 1) display an altered surface signature as assessed by multiplex protein analysis; 2) are characterized by distinct lipidomic profiling; 3) show correlations between lipidomic profiling and disease aggressiveness scores; 4) fail to dampen type 2 innate lymphoid cells (ILC2) cytokine secretion. As a consequence, ILC2 from severe COVID-19 patients show a more activated phenotype due to the presence of Co-19-EPs. Discussion: In summary, these data highlight that abnormal circulating EPs promote ILC2-driven inflammatory signals in severe COVID-19 patients and support further exploration to unravel the role of EPs (and EVs) in COVID-19 pathogenesis.

The substrate selectivity of papain-like proteases from human-infecting coronaviruses correlates with innate immune suppression.

Coronaviruses that can infect humans can cause either common colds (HCoV-NL63, HCoV-229E, HCoV-HKU1, and HCoV-OC43) or severe respiratory symptoms (SARS-CoV-2, SARS-CoV, and MERS-CoV). The papain-like proteases (PLPs) of SARS-CoV, SARS-CoV-2, MERS-CoV, and HCoV-NL63 function in viral innate immune evasion and have deubiquitinating (DUB) and deISGylating activities. We identified the PLPs of HCoV-229E, HCoV-HKU1, and HCoV-OC43 and found that their enzymatic properties correlated with their ability to suppress innate immune responses. A conserved noncatalytic aspartic acid residue was critical for both DUB and deISGylating activities, but the PLPs had differing ubiquitin (Ub) chain cleavage selectivities and binding affinities for Ub, K48-linked diUb, and interferon-stimulated gene 15 (ISG15) substrates. The crystal structure of HKU1-PLP2 in complex with Ub revealed binding interfaces that accounted for the unusually high binding affinity between this PLP and Ub. In cellular assays, the PLPs from the severe disease-causing coronaviruses strongly suppressed innate immune IFN-I and NF-κB signaling and stimulated autophagy, whereas the PLPs from the mild disease-causing coronaviruses generally showed weaker effects on immune suppression and autophagy induction. In addition, a PLP from a SARS-CoV-2 variant of concern showed increased suppression of innate immune signaling pathways. Overall, these results demonstrated that the DUB and deISGylating activities and substrate selectivities of these PLPs differentially contribute to viral innate immune evasion and may affect viral pathogenicity.