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1.
Front Immunol ; 12: 767726, 2021.
Article in English | MEDLINE | ID: covidwho-1639598

ABSTRACT

Infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the rapid spread of coronavirus disease 2019 (COVID-19), has generated a public health crisis worldwide. The molecular mechanisms of SARS-CoV-2 infection and virus-host interactions are still unclear. In this study, we identified four unique microRNA-like small RNAs encoded by SARS-CoV-2. SCV2-miR-ORF1ab-1-3p and SCV2-miR-ORF1ab-2-5p play an important role in evasion of type I interferon response through targeting several genes in type I interferon signaling pathway. Particularly worth mentioning is that highly expressed SCV2-miR-ORF1ab-2-5p inhibits some key genes in the host innate immune response, such as IRF7, IRF9, STAT2, OAS1, and OAS2. SCV2-miR-ORF1ab-2-5p has also been found to mediate allelic differential expression of COVID-19-susceptible gene OAS1. In conclusion, these results suggest that SARS-CoV-2 uses its miRNAs to evade the type I interferon response and links the functional viral sequence to the susceptible genetic background of the host.


Subject(s)
Genetic Predisposition to Disease/genetics , Immune Evasion/genetics , Interferon Type I/genetics , SARS-CoV-2/genetics , 2',5'-Oligoadenylate Synthetase/genetics , COVID-19/pathology , Cell Line , HEK293 Cells , Host-Pathogen Interactions/genetics , Humans , Immunity, Innate/immunology , Interferon Regulatory Factor-7/genetics , Interferon-Stimulated Gene Factor 3, gamma Subunit/genetics , MicroRNAs/genetics , Polymorphism, Single Nucleotide/genetics , SARS-CoV-2/immunology , STAT2 Transcription Factor/genetics
2.
Front Immunol ; 12: 785355, 2021.
Article in English | MEDLINE | ID: covidwho-1594099

ABSTRACT

The lungs are constantly exposed to non-sterile air which carries harmful threats, such as particles and pathogens. Nonetheless, this organ is equipped with fast and efficient mechanisms to eliminate these threats from the airways as well as prevent pathogen invasion. The respiratory tract is densely innervated by sensory neurons, also known as nociceptors, which are responsible for the detection of external stimuli and initiation of physiological and immunological responses. Furthermore, expression of functional innate receptors by nociceptors have been reported; however, the influence of these receptors to the lung function and local immune response is poorly described. The COVID-19 pandemic has shown the importance of coordinated and competent pulmonary immunity for the prevention of pathogen spread as well as prevention of excessive tissue injury. New findings suggest that lung nociceptors can be a target of SARS-CoV-2 infection; what remains unclear is whether innate receptor trigger sensory neuron activation during SARS-CoV-2 infection and what is the relevance for the outcomes. Moreover, elderly individuals often present with respiratory, neurological and immunological dysfunction. Whether aging in the context of sensory nerve function and innate receptors contributes to the disorders of these systems is currently unknown. Here we discuss the expression of innate receptors by nociceptors, particularly in the lungs, and the possible impact of their activation on pulmonary immunity. We then demonstrate recent evidence that suggests lung sensory neurons as reservoirs for SARS-CoV-2 and possible viral recognition via innate receptors. Lastly, we explore the mechanisms by which lung nociceptors might contribute to disturbance in respiratory and immunological responses during the aging process.


Subject(s)
Aging/immunology , COVID-19/immunology , Immunity, Innate/immunology , Lung/immunology , Nociceptors/immunology , SARS-CoV-2/immunology , Transient Receptor Potential Channels/immunology , Aged , COVID-19/virology , Humans , Lung/innervation , Lung/virology , Nociceptors/metabolism , Nociceptors/virology , SARS-CoV-2/physiology , Sensory Receptor Cells/immunology , Sensory Receptor Cells/metabolism , Sensory Receptor Cells/virology , Transient Receptor Potential Channels/metabolism
3.
Int Immunol ; 33(10): 507-513, 2021 09 25.
Article in English | MEDLINE | ID: covidwho-1575069

ABSTRACT

Understanding the precise nature and durability of protective immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential in order to gain insight into the pathophysiology of coronavirus disease 2019 (COVID-19) and to develop novel treatment strategies to this disease. Here, I succinctly summarize what is currently known and unknown about the immune response during COVID-19 and discuss whether natural infections can lead to herd immunity.


Subject(s)
COVID-19/immunology , Immunity, Herd/immunology , Immunity, Innate/immunology , Animals , Humans , SARS-CoV-2/immunology
4.
Int J Mol Sci ; 22(24)2021 Dec 15.
Article in English | MEDLINE | ID: covidwho-1572496

ABSTRACT

In humans, over-activation of innate immunity in response to viral or bacterial infections often causes severe illness and death. Furthermore, similar mechanisms related to innate immunity can cause pathogenesis and death in sepsis, massive trauma (including surgery and burns), ischemia/reperfusion, some toxic lesions, and viral infections including COVID-19. Based on the reviewed observations, we suggest that such severe outcomes may be manifestations of a controlled suicidal strategy protecting the entire population from the spread of pathogens and from dangerous pathologies rather than an aberrant hyperstimulation of defense responses. We argue that innate immunity may be involved in the implementation of an altruistic programmed death of an organism aimed at increasing the well-being of the whole community. We discuss possible ways to suppress this atavistic program by interfering with innate immunity and suggest that combating this program should be a major goal of future medicine.


Subject(s)
Altruism , Apoptosis/immunology , Immunity, Innate/immunology , Animals , COVID-19/immunology , Cell Death/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/mortality , Humans , Inflammasomes/immunology , Inflammation/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Signal Transduction/immunology
5.
Chem Biol Interact ; 352: 109776, 2022 Jan 25.
Article in English | MEDLINE | ID: covidwho-1568541

ABSTRACT

Boosting or suppressing our immune system represents an attractive adjunct in the treatment of infections including SARS-CoV-2, cancer, AIDS, malnutrition, age related problems and some inflammatory disorders. Thus, there has been a growing interest in exploring and developing novel drugs, natural or synthetic, that can manipulate our defence mechanism. Many of such studies, reported till date, have been designed to explore effect of the therapeutic on function of macrophages, being a key component in innate immune system. Indeed, RAW264.7, J774A.1, THP-1 and U937 cell lines act as ideal model systems for preliminary investigation and selection of dose for in vivo studies. Several bioassays have been standardized so far where many techniques require high throughput instruments, cost effective reagents and technical assistance that may hinder many scholars to perform a method demanding compilation of available protocols. In this review, we have taken an attempt for the first time to congregate commonly used in vitro immune-modulating techniques explaining their principles. The study detected that among about 40 different assays and more than 150 sets of primers, the methods of cell proliferation by MTT, phagocytosis by neutral red, NO detection by Griess reaction and estimation of expression of TLRs, COX-2, iNOS, TNF-α, IL-6 and IL-1ß by PCR have been the most widely used to screen the therapeutics under investigation.


Subject(s)
Immunity, Innate/immunology , Immunomodulation/immunology , Animals , Cell Line , Cell Line, Tumor , Cell Proliferation/physiology , Humans , Inflammation/immunology , Phagocytosis/immunology
6.
Chem Biol Interact ; 352: 109777, 2022 Jan 25.
Article in English | MEDLINE | ID: covidwho-1559106

ABSTRACT

OBJECTIVE: To determine the differences in the immune response against SARS-CoV-2 infection of patients based on sex and disease severity. METHODS: We used an analytical framework of 382 transcriptional modules and multi-omics analyses to discriminate COVID-19 patients based on sex and disease severity. RESULTS: Male and female patients overexpressed modules related to the innate immune response. The expression of modules related to the adaptive immune response showed lower enrichment levels in males than females. Inflammation modules showed ascending overexpression in male and female patients, while a higher level was observed in severe female patients. Moderate female patients demonstrated significant overexpression to interferon, cytolytic lymphocyte, T & B cells, and erythrocytes modules. Moderate female patients showed a higher adaptive immune response than males matched group. Pathways involved in metabolism dysregulation and Hippo signaling were upregulated in females than in male patients. Females and moderate cases showed higher levels of metabolic dysregulation. CONCLUSIONS: The immune landscape in COVID-19 patients was noticeably different between the sexes, and these differences may highlight disease vulnerability in males. This study suggested that certain treatments that increase or decrease the immune responses to SARS-CoV-2 might be necessary for male and female patients at certain disease stages.


Subject(s)
COVID-19/immunology , COVID-19/metabolism , Adaptive Immunity/immunology , Adult , Aged , COVID-19/pathology , Female , Humans , Immunity, Innate/immunology , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Lymphocytes/immunology , Lymphocytes/metabolism , Lymphocytes/pathology , Male , Middle Aged , SARS-CoV-2/immunology , Severity of Illness Index , Sex Characteristics
7.
J Med Virol ; 94(1): 63-81, 2022 01.
Article in English | MEDLINE | ID: covidwho-1544343

ABSTRACT

Although significant research has been done to find effective drugs against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), no definite effective drug exists. Thus, research has now shifted towards immunomodulatory agents other than antivirals. In this review, we aim to describe the latest findings on the role of type I interferon (IFN)-mediated innate antiviral response against SARS-CoV-2 and discuss the use of IFNs as a medication for COVID-19. A growing body of evidence has indicated a promoting active but delayed IFNs response to SARS-CoV-2 and Middle East respiratory syndrome coronavirus in infected bronchial epithelial cells. Studies have demonstrated that IFNs' administration before the viral peak and the inflammatory phase of disease could offer a highly protective effect. However, IFNs' treatment during the inflammatory and severe stages of the disease causes immunopathology and long-lasting harm for patients. Therefore, it is critical to note the best time window for IFNs' administration. Further investigation of the clinical effectiveness of interferon for patients with mild to severe COVID-19 and its optimal timing and route of administration can be beneficial in finding a safe and effective antiviral therapy for the COVID-19 disease.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Interferon Type I/therapeutic use , SARS-CoV-2/drug effects , Humans , Immunity, Innate/immunology , Immunologic Factors/therapeutic use , Immunomodulation/drug effects
8.
Front Immunol ; 12: 689866, 2021.
Article in English | MEDLINE | ID: covidwho-1503883

ABSTRACT

Rapid recruitment of neutrophils to an inflamed site is one of the hallmarks of an effective host defense mechanism. The main pathway through which this happens is by the innate immune response. Neutrophils, which play an important part in innate immune defense, migrate into lungs through the modulation actions of chemokines to execute a variety of pro-inflammatory functions. Despite the importance of chemokines in host immunity, little has been discussed on their roles in host immunity. A holistic understanding of neutrophil recruitment, pattern recognition pathways, the roles of chemokines and the pathophysiological roles of neutrophils in host immunity may allow for new approaches in the treatment of infectious and inflammatory disease of the lung. Herein, this review aims at highlighting some of the developments in lung neutrophil-immunity by focusing on the functions and roles of CXC/CC chemokines and pattern recognition receptors in neutrophil immunity during pulmonary inflammations. The pathophysiological roles of neutrophils in COVID-19 and thromboembolism have also been summarized. We finally summarized various neutrophil biomarkers that can be utilized as prognostic molecules in pulmonary inflammations and discussed various neutrophil-targeted therapies for neutrophil-driven pulmonary inflammatory diseases.


Subject(s)
Immunity, Innate/immunology , Neutrophils/immunology , Pneumonia/immunology , Biomarkers/blood , COVID-19/immunology , Cell Degranulation/immunology , Chemokines/immunology , Clinical Trials as Topic , Extracellular Traps/immunology , Humans , Integrins/immunology , Lung/immunology , Lung/pathology , Neutrophils/drug effects , Pneumonia/diagnosis , Pneumonia/drug therapy , Receptors, Pattern Recognition/immunology , Respiratory Burst/immunology , SARS-CoV-2 , Thromboembolism/immunology
9.
Clin Microbiol Rev ; 34(3)2021 06 16.
Article in English | MEDLINE | ID: covidwho-1501524

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a rapidly evolving pandemic worldwide with at least 68 million COVID-19-positive cases and a mortality rate of about 2.2%, as of 10 December 2020. About 20% of COVID-19 patients exhibit moderate to severe symptoms. Severe COVID-19 manifests as acute respiratory distress syndrome (ARDS) with elevated plasma proinflammatory cytokines, including interleukin 1ß (IL-1ß), IL-6, tumor necrosis factor α (TNF-α), C-X-C motif chemokine ligand 10 (CXCL10/IP10), macrophage inflammatory protein 1 alpha (MIP-1α), and chemokine (C-C motif) ligand 2 (CCL2), with low levels of interferon type I (IFN-I) in the early stage and elevated levels of IFN-I during the advanced stage of COVID-19. Most of the severe and critically ill COVID-19 patients have had preexisting comorbidities, including hypertension, diabetes, cardiovascular diseases, and respiratory diseases. These conditions are known to perturb the levels of cytokines, chemokines, and angiotensin-converting enzyme 2 (ACE2), an essential receptor involved in SARS-CoV-2 entry into the host cells. ACE2 downregulation during SARS-CoV-2 infection activates the angiotensin II/angiotensin receptor (AT1R)-mediated hypercytokinemia and hyperinflammatory syndrome. However, several SARS-CoV-2 proteins, including open reading frame 3b (ORF3b), ORF6, ORF7, ORF8, and the nucleocapsid (N) protein, can inhibit IFN type I and II (IFN-I and -II) production. Thus, hyperinflammation, in combination with the lack of IFN responses against SARS-CoV-2 early on during infection, makes the patients succumb rapidly to COVID-19. Therefore, therapeutic approaches involving anti-cytokine/anti-cytokine-signaling and IFN therapy would favor the disease prognosis in COVID-19. This review describes critical host and viral factors underpinning the inflammatory "cytokine storm" induction and IFN antagonism during COVID-19 pathogenesis. Therapeutic approaches to reduce hyperinflammation and their limitations are also discussed.


Subject(s)
COVID-19/pathology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/pathology , Interferon Type I/blood , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/blood , COVID-19/therapy , Comorbidity , Humans , Immunity, Innate/immunology , Immunization, Passive/methods , Interleukin-6/antagonists & inhibitors , Interleukin-6/blood , Spike Glycoprotein, Coronavirus/metabolism
10.
Acc Chem Res ; 54(21): 4012-4023, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1483069

ABSTRACT

In vitro-transcribed RNAs are emerging as new biologics for therapeutic innovation, as exemplified by their application recently in SARS-CoV-2 vaccinations. RNAs prepared by in vitro transcription (IVT) allow transient expression of proteins of interest, conferring safety over DNA- or virus-mediated gene delivery systems. However, in vitro-transcribed RNAs should be used with caution because of their immunogenicity, which is in part triggered by double-stranded RNA (dsRNA) byproducts during IVT. Cellular innate immune response to dsRNA byproducts can lead to undesirable consequences, including suppression of protein synthesis and cell death, which in turn can detrimentally impact the efficacy of mRNA therapy. Thus, it is critical to understand the nature of IVT byproducts and the mechanisms by which they trigger innate immune responses.Our lab has been investigating the mechanisms by which the innate immune system discriminates between "self" and "nonself" RNA, with the focus on the cytoplasmic dsRNA receptors retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated 5 (MDA5). We have biochemically and structurally characterized critical events involving RNA discrimination and signal transduction by RIG-I or MDA5. We have used in vitro-transcribed RNAs as tools to investigate RNA specificity of RIG-I and MDA5, which required optimization of the IVT reaction and purification processes to eliminate the effect of IVT byproducts. In this Account, we summarize our current understanding of RIG-I and MDA5 and IVT reactions and propose future directions for improving IVT as a method to generate both research tools and therapeutics. Other critical proteins in cellular innate immune response to dsRNAs are also discussed. We arrange the contents in the following order: (i) innate immunity sensors for nonself RNA, including the RIG-I-like receptors (RLRs) in the cytosol and the toll-like receptors (TLRs) in the endosome, as well as cytoplasmic dsRNA-responding proteins, including protein kinase R (PKR) and 2',5'-oligoadenylate synthetases (OASes), illustrating the feature of protein-RNA binding and its consequences; (ii) the immunogenicity of IVT byproducts, specifically the generation of dsRNA molecules during IVT; and (iii) methods to reduce IVT RNA immunogenicity, including optimizations of RNA polymerases, reagents, and experimental conditions during IVT and subsequent purification.


Subject(s)
RNA, Viral/immunology , SARS-CoV-2/genetics , DEAD Box Protein 58/genetics , DEAD Box Protein 58/immunology , Humans , Immunity, Innate/genetics , Immunity, Innate/immunology , Interferon-Induced Helicase, IFIH1/genetics , Interferon-Induced Helicase, IFIH1/immunology , RNA, Viral/genetics , Receptors, Immunologic/genetics , Receptors, Immunologic/immunology , SARS-CoV-2/immunology
12.
Front Immunol ; 12: 746203, 2021.
Article in English | MEDLINE | ID: covidwho-1477828

ABSTRACT

The reasons behind the clinical variability of SARS-CoV-2 infection, ranging from asymptomatic infection to lethal disease, are still unclear. We performed genome-wide transcriptional whole-blood RNA sequencing, bioinformatics analysis and PCR validation to test the hypothesis that immune response-related gene signatures reflecting baseline may differ between healthy individuals, with an equally robust antibody response, who experienced an entirely asymptomatic (n=17) versus clinical SARS-CoV-2 infection (n=15) in the past months (mean of 14 weeks). Among 12.789 protein-coding genes analysed, we identified six and nine genes with significantly decreased or increased expression, respectively, in those with prior asymptomatic infection relatively to those with clinical infection. All six genes with decreased expression (IFIT3, IFI44L, RSAD2, FOLR3, PI3, ALOX15), are involved in innate immune response while the first two are interferon-induced proteins. Among genes with increased expression six are involved in immune response (GZMH, CLEC1B, CLEC12A), viral mRNA translation (GCAT), energy metabolism (CACNA2D2) and oxidative stress response (ENC1). Notably, 8/15 differentially expressed genes are regulated by interferons. Our results suggest that subtle differences at baseline expression of innate immunity-related genes may be associated with an asymptomatic disease course in SARS-CoV-2 infection. Whether a certain gene signature predicts, or not, those who will develop a more efficient immune response upon exposure to SARS-CoV-2, with implications for prioritization for vaccination, warrant further study.


Subject(s)
Antibodies, Viral/blood , Asymptomatic Infections , Immunity, Innate/genetics , SARS-CoV-2/immunology , Transcriptome/genetics , Adult , COVID-19/pathology , Female , Gene Expression Profiling , Humans , Immunity, Innate/immunology , Male , RNA, Messenger/genetics , Sequence Analysis, RNA , Severity of Illness Index
13.
Front Immunol ; 12: 742941, 2021.
Article in English | MEDLINE | ID: covidwho-1477827

ABSTRACT

The coronavirus disease-19 (COVID-19) elicited by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused devastating health, economic and social impact worldwide. Its clinical spectrum ranges from asymptomatic to respiratory failure and multi-organ failure or death. The pathogenesis of SARS-CoV-2 infection is attributed to a complex interplay between virus and host immune response. It involves activation of multiple inflammatory pathways leading to hyperinflammation and cytokine storm, resulting in tissue damage, acute respiratory distress syndrome (ARDS) and multi-organ failure. Accumulating evidence has raised concern over the long-term health effects of COVID-19. Importantly, the neuroinvasive potential of SARS-CoV-2 may have devastating consequences in the brain. This review provides a conceptual framework on how the virus tricks the host immune system to induce infection and cause severe disease. We also explore the key differences between mild and severe COVID-19 and its short- and long-term effects, particularly on the human brain.


Subject(s)
Adaptive Immunity/immunology , COVID-19/pathology , Cytokine Release Syndrome/pathology , Immunity, Innate/immunology , SARS-CoV-2/immunology , COVID-19/complications , COVID-19/immunology , Cytokine Release Syndrome/immunology , Cytokines/blood , Humans , Multiple Organ Failure/pathology , Respiratory Distress Syndrome/pathology , Sex Factors
14.
Eur J Immunol ; 51(7): 1641-1651, 2021 07.
Article in English | MEDLINE | ID: covidwho-1473829

ABSTRACT

Emerging life-threatening viruses have posed great challenges to public health. It is now increasingly clear that epigenetics plays a role in shaping host-virus interactions and there is a great need for a more thorough understanding of these intricate interactions through the epigenetic lens, which may represent potential therapeutic opportunities in the clinic. In this review, we highlight the current understanding of the roles of key epigenetic regulators - chromatin remodeling and histone modification - in modulating chromatin openness during host defense against virus. We also discuss how the RNA modification m6A (N6-methyladenosine) affects fundamental aspects of host-virus interactions. We conclude with future directions for uncovering more detailed functions that epigenetic regulation exerts on both host cells and viruses during infection.


Subject(s)
Antiviral Agents/immunology , Epigenesis, Genetic/genetics , Epigenesis, Genetic/immunology , Immunity, Innate/genetics , Immunity, Innate/immunology , Animals , Chromatin/genetics , Chromatin/immunology , Histones/genetics , Histones/immunology , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , RNA Processing, Post-Transcriptional/genetics , RNA Processing, Post-Transcriptional/immunology
15.
Viruses ; 13(10)2021 10 15.
Article in English | MEDLINE | ID: covidwho-1470996

ABSTRACT

Infections with viral pathogens are widespread and can cause a variety of different diseases. In-depth knowledge about viral triggers initiating an immune response is necessary to decipher viral pathogenesis. Inflammasomes, as part of the innate immune system, can be activated by viral pathogens. However, viral structural components responsible for inflammasome activation remain largely unknown. Here we analyzed glycoproteins derived from SARS-CoV-1/2, HCMV and HCV, required for viral entry and fusion, as potential triggers of NLRP3 inflammasome activation and pyroptosis in THP-1 macrophages. All tested glycoproteins were able to potently induce NLRP3 inflammasome activation, indicated by ASC-SPECK formation and secretion of cleaved IL-1ß. Lytic cell death via gasdermin D (GSDMD), pore formation, and pyroptosis are required for IL-1ß release. As a hallmark of pyroptosis, we were able to detect cleavage of GSDMD and, correspondingly, cell death in THP-1 macrophages. CRISPR-Cas9 knockout of NLRP3 and GSDMD in THP-1 macrophages confirmed and strongly support the evidence that viral glycoproteins can act as innate immunity triggers. With our study, we decipher key mechanisms of viral pathogenesis by showing that viral glycoproteins potently induce innate immune responses. These insights could be beneficial in vaccine development and provide new impulses for the investigation of vaccine-induced innate immunity.


Subject(s)
Immunity, Innate/immunology , Inflammasomes/immunology , Macrophages/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Viral Envelope Proteins/immunology , Viral Fusion Proteins/immunology , Cell Line, Tumor , Cytomegalovirus/immunology , Hepacivirus/immunology , Humans , Interleukin-1beta/biosynthesis , Interleukin-1beta/immunology , Pyroptosis/immunology , SARS Virus/immunology , SARS-CoV-2/immunology , THP-1 Cells
16.
Viruses ; 13(10)2021 10 14.
Article in English | MEDLINE | ID: covidwho-1470993

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the Coronaviridae family, which is responsible for the COVID-19 pandemic followed by unprecedented global societal and economic disruptive impact. The innate immune system is the body's first line of defense against invading pathogens and is induced by a variety of cellular receptors that sense viral components. However, various strategies are exploited by SARS-CoV-2 to disrupt the antiviral innate immune responses. Innate immune dysfunction is characterized by the weak generation of type I interferons (IFNs) and the hypersecretion of pro-inflammatory cytokines, leading to mortality and organ injury in patients with COVID-19. This review summarizes the existing understanding of the mutual effects between SARS-CoV-2 and the type I IFN (IFN-α/ß) responses, emphasizing the relationship between host innate immune signaling and viral proteases with an insight on tackling potential therapeutic targets.


Subject(s)
COVID-19/immunology , Immune Evasion/immunology , Immunity, Innate/immunology , Interferon Type I/immunology , SARS-CoV-2/immunology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , Cytokines/metabolism , Drug Combinations , Humans , Interferon Type I/biosynthesis , Lopinavir/therapeutic use , Ribavirin/therapeutic use , Ritonavir/therapeutic use , Signal Transduction/immunology
17.
Cells ; 10(9)2021 09 13.
Article in English | MEDLINE | ID: covidwho-1468387

ABSTRACT

Neutrophils are key cells of the innate immune system. It is now understood that this leukocyte population is diverse in both the basal composition and functional plasticity. Underlying this plasticity is a post-translational framework for rapidly achieving early activation states, but also a transcriptional capacity that is becoming increasingly recognized by immunologists. Growing interest in the contribution of neutrophils to health and disease has resulted in more efforts to describe their transcriptional activity. Whilst initial efforts focused predominantly on understanding the existing biology, investigations with advanced methods such as single cell RNA sequencing to understand interactions of the entire immune system are revealing higher flexibility in neutrophil transcription than previously thought possible and multiple transition states. It is now apparent that neutrophils utilise many forms of RNA in the regulation of their function. This review collates current knowledge on the nuclei structure and gene expression activity of human neutrophils across homeostasis and disease, before highlighting knowledge gaps that are research priority areas.


Subject(s)
Disease/etiology , Gene Expression Regulation , Immunity, Innate/immunology , Neutrophils/immunology , Neutrophils/pathology , Transcriptome , Animals , Homeostasis , Humans , Neutrophils/metabolism , Signal Transduction
18.
mBio ; 12(4): e0178121, 2021 08 31.
Article in English | MEDLINE | ID: covidwho-1349195

ABSTRACT

The 2',5'-oligoadenylate (2-5A)-dependent endoribonuclease, RNase L, is a principal mediator of the interferon (IFN) antiviral response. Therefore, the regulation of cellular levels of 2-5A is a key point of control in antiviral innate immunity. Cellular 2-5A levels are determined by IFN-inducible 2',5'-oligoadenylate synthetases (OASs) and by enzymes that degrade 2-5A. Importantly, many coronaviruses (CoVs) and rotaviruses encode 2-5A-degrading enzymes, thereby antagonizing RNase L and its antiviral effects. A-kinase-anchoring protein 7 (AKAP7), a mammalian counterpart, could possibly limit tissue damage from excessive or prolonged RNase L activation during viral infections or from self-double-stranded RNAs that activate OAS. We show that these enzymes, members of the two-histidine phosphoesterase (2H-PE) superfamily, constitute a subfamily referred here as 2',5'-PEs. 2',5'-PEs from the mouse CoV mouse hepatitis virus (MHV) (NS2), Middle East respiratory syndrome coronavirus (MERS-CoV) (NS4b), group A rotavirus (VP3), and mouse (AKAP7) were investigated for their evolutionary relationships and activities. While there was no activity against 3',5'-oligoribonucleotides, they all cleaved 2',5'-oligoadenylates efficiently but with variable activity against other 2',5'-oligonucleotides. The 2',5'-PEs are shown to be metal ion-independent enzymes that cleave trimer 2-5A (2',5'-p3A3) producing mono- or diadenylates with 2',3'-cyclic phosphate termini. Our results suggest that the elimination of 2-5A might be the sole function of viral 2',5'-PEs, thereby promoting viral escape from innate immunity by preventing or limiting the activation of RNase L. IMPORTANCE Viruses often encode accessory proteins that antagonize the host antiviral immune response. Here, we probed the evolutionary relationships and biochemical activities of two-histidine phosphoesterases (2H-PEs) that allow some coronaviruses and rotaviruses to counteract antiviral innate immunity. In addition, we investigated the mammalian enzyme AKAP7, which has homology and shared activities with the viral enzymes and might reduce self-injury. These viral and host enzymes, which we refer to as 2',5'-PEs, specifically degrade 2',5'-oligoadenylate activators of the antiviral enzyme RNase L. We show that the host and viral enzymes are metal ion independent and exclusively cleave 2',5'- and not 3',5'-phosphodiester bonds, producing cleavage products with cyclic 2',3'-phosphate termini. Our study defines 2',5'-PEs as enzymes that share characteristic conserved features with the 2H-PE superfamily but have specific and distinct biochemical cleavage activities. These findings may eventually lead to pharmacological strategies for developing antiviral drugs against coronaviruses, rotaviruses, and other viruses.


Subject(s)
A Kinase Anchor Proteins/metabolism , Adenine Nucleotides/metabolism , Endoribonucleases/metabolism , Middle East Respiratory Syndrome Coronavirus/enzymology , Murine hepatitis virus/enzymology , Oligoribonucleotides/metabolism , Rotavirus/enzymology , Animals , Humans , Immunity, Innate/immunology , Interferons/immunology , Mice
19.
Eur J Pharmacol ; 912: 174548, 2021 Dec 05.
Article in English | MEDLINE | ID: covidwho-1446596

ABSTRACT

The importance of sex differences is increasingly acknowledged in the incidence and treatment of disease. Accumulating clinical evidence demonstrates that sex differences are noticeable in COVID-19, and the prevalence, severity, and mortality rate of COVID-19 are higher among males than females. Sex-related genetic and hormonal factors and immunological responses may underlie the sex bias in COVID-19 patients. Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2) are essential proteins involved in the cell entry of SARS-CoV-2. Since ACE2 is encoded on the X-chromosome, a double copy of ACE2 in females may compensate for virus-mediated downregulation of ACE2, and thus ACE2-mediated cellular protection is greater in females. The X chromosome also contains the largest immune-related genes leading females to develop more robust immune responses than males. Toll-like receptor-7 (TLR-7), one of the key players in innate immunity, is linked to sex differences in autoimmunity and vaccine efficacy, and its expression is greater in females. Sex steroids also affect immune cell function. Estrogen contributes to higher CD4+ and CD8+ T cell activation levels, and females have more B cells than males. Sex differences not only affect the severity and progression of the disease, but also alter the efficacy of pharmacological treatment and adverse events related to the drugs/vaccines used against COVID-19. Administration of different drugs/vaccines in different doses or intervals may be useful to eliminate sex differences in efficacy and side/adverse effects. It should be noted that studies should include sex-specific analyses to develop further sex-specific treatments for COVID-19.


Subject(s)
COVID-19/etiology , COVID-19/genetics , Genetic Predisposition to Disease/genetics , Adult , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Estrogens/genetics , Estrogens/immunology , Female , Humans , Immunity, Innate/genetics , Immunity, Innate/immunology , Male , Middle Aged , SARS-CoV-2/immunology , Serine Endopeptidases/genetics , Serine Endopeptidases/immunology , Sex Characteristics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
20.
PLoS One ; 16(9): e0257965, 2021.
Article in English | MEDLINE | ID: covidwho-1443851

ABSTRACT

Many important questions remain regarding severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the viral pathogen responsible for COVID-19. These questions include the mechanisms explaining the high percentage of asymptomatic but highly infectious individuals, the wide variability in disease susceptibility, and the mechanisms of long-lasting debilitating effects. Bioinformatic analysis of four coronavirus datasets representing previous outbreaks (SARS-CoV-1 and MERS-CoV), as well as SARS-CoV-2, revealed evidence of diverse host factors that appear to be coopted to facilitate virus-induced suppression of interferon-induced innate immunity, promotion of viral replication and subversion and/or evasion of antiviral immune surveillance. These host factors merit further study given their postulated roles in COVID-19-induced loss of smell and brain, heart, vascular, lung, liver, and gut dysfunction.


Subject(s)
COVID-19/drug therapy , COVID-19/epidemiology , SARS-CoV-2/drug effects , Antiviral Agents/therapeutic use , COVID-19/metabolism , Coronavirus Infections/epidemiology , Databases, Factual , Host-Pathogen Interactions , Humans , Immune Evasion/immunology , Immunity, Innate/immunology , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/pathogenicity , SARS Virus/drug effects , SARS Virus/pathogenicity , SARS-CoV-2/pathogenicity , Severe Acute Respiratory Syndrome/epidemiology , Virus Replication/drug effects
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