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1.
Viruses ; 12(6)2020 06 24.
Article in English | MEDLINE | ID: covidwho-620517

ABSTRACT

The respiratory Influenza A Viruses (IAVs) and emerging zoonotic viruses such as Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pose a significant threat to human health. To accelerate our understanding of the host-pathogen response to respiratory viruses, the use of more complex in vitro systems such as normal human bronchial epithelial (NHBE) cell culture models has gained prominence as an alternative to animal models. NHBE cells were differentiated under air-liquid interface (ALI) conditions to form an in vitro pseudostratified epithelium. The responses of well-differentiated (wd) NHBE cells were examined following infection with the 2009 pandemic Influenza A/H1N1pdm09 strain or following challenge with the dsRNA mimic, poly(I:C). At 30 h postinfection with H1N1pdm09, the integrity of the airway epithelium was severely impaired and apical junction complex damage was exhibited by the disassembly of zona occludens-1 (ZO-1) from the cell cytoskeleton. wdNHBE cells produced an innate immune response to IAV-infection with increased transcription of pro- and anti-inflammatory cytokines and chemokines and the antiviral viperin but reduced expression of the mucin-encoding MUC5B, which may impair mucociliary clearance. Poly(I:C) produced similar responses to IAV, with the exception of MUC5B expression which was more than 3-fold higher than for control cells. This study demonstrates that wdNHBE cells are an appropriate ex-vivo model system to investigate the pathogenesis of respiratory viruses.


Subject(s)
Influenza A Virus, H1N1 Subtype/physiology , Influenza, Human/virology , Respiratory Mucosa/cytology , Respiratory Mucosa/virology , Animals , Bronchi/cytology , Bronchi/virology , Cells, Cultured , Chemokines/metabolism , Cytokines/metabolism , Dogs , Host-Pathogen Interactions , Humans , Immunity, Innate , Influenza A Virus, H1N1 Subtype/immunology , Influenza, Human/epidemiology , Intercellular Junctions , Madin Darby Canine Kidney Cells , Models, Biological , Mucin 5AC/metabolism , Pandemics , Virus Cultivation
2.
Mol Diagn Ther ; 24(3): 251-262, 2020 06.
Article in English | MEDLINE | ID: covidwho-634822

ABSTRACT

This opinion article discusses the increasing attention paid to the role of activating damage-associated molecular patterns (DAMPs) in initiation of inflammatory diseases and suppressing/inhibiting DAMPs (SAMPs) in resolution of inflammatory diseases and, consequently, to the future roles of these novel biomarkers as therapeutic targets and therapeutics. Since controlled production of DAMPs and SAMPs is needed to achieve full homeostatic restoration and repair from tissue injury, only their pathological, not their homeostatic, concentrations should be therapeutically tackled. Therefore, distinct caveats are proposed regarding choosing DAMPs and SAMPs for therapeutic purposes. For example, we discuss the need to a priori identify and define a context-dependent "homeostatic DAMP:SAMP ratio" in each case and a "homeostatic window" of DAMP and SAMP concentrations to guarantee a safe treatment modality to patients. Finally, a few clinical examples of how DAMPs and SAMPs might be used as therapeutic targets or therapeutics in the future are discussed, including inhibition of DAMPs in hyperinflammatory processes (e.g., systemic inflammatory response syndrome, as currently observed in Covid-19), administration of SAMPs in chronic inflammatory diseases, inhibition of SAMPs in hyperresolving processes (e.g., compensatory anti-inflammatory response syndrome), and administration/induction of DAMPs in vaccination procedures and anti-cancer therapy.


Subject(s)
Inflammation/drug therapy , Inflammation/metabolism , Molecular Targeted Therapy/methods , Biomarkers/blood , Cell-Free Nucleic Acids/blood , Chronic Disease , Coronavirus Infections/drug therapy , HMGB1 Protein/blood , Homeostasis , Humans , Immunity, Innate/drug effects , Immunity, Innate/physiology , Pathogen-Associated Molecular Pattern Molecules/metabolism , S100 Proteins/blood , Vaccination
3.
ACS Nano ; 14(8): 9364-9388, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-646861

ABSTRACT

The SARS-Cov-2 pandemic has spread worldwide during 2020, setting up an uncertain start of this decade. The measures to contain infection taken by many governments have been extremely severe by imposing home lockdown and industrial production shutdown, making this the biggest crisis since the second world war. Additionally, the continuous colonization of wild natural lands may touch unknown virus reservoirs, causing the spread of epidemics. Apart from SARS-Cov-2, the recent history has seen the spread of several viral pandemics such as H2N2 and H3N3 flu, HIV, and SARS, while MERS and Ebola viruses are considered still in a prepandemic phase. Hard nanomaterials (HNMs) have been recently used as antimicrobial agents, potentially being next-generation drugs to fight viral infections. HNMs can block infection at early (disinfection, entrance inhibition) and middle (inside the host cells) stages and are also able to mitigate the immune response. This review is focused on the application of HNMs as antiviral agents. In particular, mechanisms of actions, biological outputs, and limitations for each HNM will be systematically presented and analyzed from a material chemistry point-of-view. The antiviral activity will be discussed in the context of the different pandemic viruses. We acknowledge that HNM antiviral research is still at its early stage, however, we believe that this field will rapidly blossom in the next period.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/therapy , Nanostructures/therapeutic use , Pandemics , Pneumonia, Viral/therapy , Adaptive Immunity , Betacoronavirus/drug effects , Betacoronavirus/physiology , Betacoronavirus/ultrastructure , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Drug Delivery Systems , Fullerenes/therapeutic use , Host Microbial Interactions/drug effects , Humans , Immunity, Innate , Metal Nanoparticles/therapeutic use , Models, Biological , Nanotechnology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Reactive Oxygen Species/therapeutic use , Virus Internalization/drug effects
4.
Int J Immunogenet ; 47(4): 319-323, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-640248

ABSTRACT

Susceptibility to viral infection, development of immunity, response to treatment and patient clinical outcomes are all under the control of heritable factors in the host. In the context of the current SARS-Cov-2 pandemic, this review considers existing immunogenetic knowledge of virus-immune system interactions. A major focus is to highlight areas in which work is required in order to improve understanding of antiviral immune responses and to move towards improved patient management.


Subject(s)
Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokine Release Syndrome/immunology , Immunity, Innate/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Betacoronavirus/immunology , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/pathology , Disease Susceptibility/immunology , Humans , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Pandemics , Pneumonia, Viral/drug therapy , Tumor Necrosis Factor-alpha/metabolism
5.
Oral Oncol ; 108: 104821, 2020 09.
Article in English | MEDLINE | ID: covidwho-753019

ABSTRACT

Outbreak pneumonia announced in Wuhan, China, in December 2019, had its causative factor classified as a new coronavirus (SARS-CoV-2). Since saliva can host several viruses including SARS-CoV-2, the transmission chance of viruses through saliva, particularly those causing respiratory infections, is unavoidable. COVID-19 can be detected through salivary diagnostic testing which has lots of advantages for medical care professionals and patients. It should be noted that not only does saliva offer an ecological niche for the colonization and development of oral microorganisms, but it also prevents the overgrowth of particular pathogens such as viral factors. The aim of this study is to gather all the information about saliva and its association with COVID-19 for the whole health care professionals across the world.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , Saliva/immunology , Saliva/virology , Sialadenitis/diagnosis , Aged , Betacoronavirus/genetics , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Dental Care , Dentists/psychology , Diagnostic Tests, Routine/methods , Female , Humans , Immunity, Innate , Infection Control/methods , Male , Middle Aged , Pandemics , Patient Safety , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Practice Patterns, Dentists' , Reverse Transcriptase Polymerase Chain Reaction , Salivary Gland Neoplasms/diagnosis , Salivary Glands/metabolism , Salivary Glands/virology , Salivary Proteins and Peptides/immunology , Sialadenitis/virology , Telemedicine/methods , Xerostomia
6.
Int J Mol Sci ; 21(17)2020 Sep 01.
Article in English | MEDLINE | ID: covidwho-742800

ABSTRACT

When facing an acute viral infection, our immune systems need to function with finite precision to enable the elimination of the pathogen, whilst protecting our bodies from immune-related damage. In many instances however this "perfect balance" is not achieved, factors such as ageing, cancer, autoimmunity and cardiovascular disease all skew the immune response which is then further distorted by viral infection. In SARS-CoV-2, although the vast majority of COVID-19 cases are mild, as of 24 August 2020, over 800,000 people have died, many from the severe inflammatory cytokine release resulting in extreme clinical manifestations such as acute respiratory distress syndrome (ARDS) and hemophagocytic lymphohistiocytosis (HLH). Severe complications are more common in elderly patients and patients with cardiovascular diseases. Natural killer (NK) cells play a critical role in modulating the immune response and in both of these patient groups, NK cell effector functions are blunted. Preliminary studies in COVID-19 patients with severe disease suggests a reduction in NK cell number and function, resulting in decreased clearance of infected and activated cells, and unchecked elevation of tissue-damaging inflammation markers. SARS-CoV-2 infection skews the immune response towards an overwhelmingly inflammatory phenotype. Restoration of NK cell effector functions has the potential to correct the delicate immune balance required to effectively overcome SARS-CoV-2 infection.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Susceptibility/immunology , Host-Pathogen Interactions/immunology , Immunity, Innate , Killer Cells, Natural/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Autoimmunity , Coronavirus Infections/metabolism , Humans , Immunomodulation , Killer Cells, Natural/metabolism , Pandemics , Pneumonia, Viral/metabolism
7.
J Virol ; 94(13)2020 06 16.
Article in English | MEDLINE | ID: covidwho-736047

ABSTRACT

Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We performed a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA-A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explored the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome was successfully sampled and was represented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting that individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (M. Lin, H.-T. Tseng, J. A. Trejaut, H.-L. Lee, et al., BMC Med Genet 4:9, 2003, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-4-9). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting that it could enable cross-protective T-cell-based immunity. Finally, we reported global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.IMPORTANCE Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of severity of viral disease in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/virology , Histocompatibility Testing/methods , Pneumonia, Viral/virology , Amino Acid Sequence , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Epitopes, T-Lymphocyte/immunology , Genetic Variation , Genotype , Haplotypes , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Humans , Immunity, Innate/immunology , Pandemics , Pneumonia, Viral/immunology , T-Lymphocytes/immunology
8.
Int J Biol Sci ; 16(14): 2479-2489, 2020.
Article in English | MEDLINE | ID: covidwho-721623

ABSTRACT

The emergence of SARS-CoV-2 virus and its associated disease COVID-19 have triggered significant threats to public health, in addition to political and social changes. An important number of studies have reported the onset of symptoms compatible with pneumonia accompanied by coagulopathy and lymphocytopenia during COVID-19. Increased cytokine levels, the emergence of acute phase reactants, platelet activation and immune checkpoint expression are some of the biomarkers postulated in this context. As previously observed in prolonged sepsis, T-cell exhaustion due to SARS-CoV-2 and even their reduction in numbers due to apoptosis hinder the response to the infection. In this review, we synthesized the immune changes observed during COVID-19, the role of immune molecules as severity markers for patient stratification and their associated therapeutic options.


Subject(s)
Coronavirus Infections/immunology , Coronavirus Infections/physiopathology , Pneumonia, Viral/immunology , Pneumonia, Viral/physiopathology , Sepsis/physiopathology , Adrenal Cortex Hormones/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus , Biomarkers , Blood Coagulation Disorders/immunology , Cytokines/metabolism , Humans , Immune System , Immunity, Innate , Interferons/metabolism , Lymphopenia/immunology , Pandemics , Phenotype , Platelet Activation
9.
J Immunol Res ; 2020: 8624963, 2020.
Article in English | MEDLINE | ID: covidwho-721226

ABSTRACT

Single-cell RNA sequencing allows highly detailed profiling of cellular immune responses from limited-volume samples, advancing prospects of a new era of systems immunology. The power of single-cell RNA sequencing offers various opportunities to decipher the immune response to infectious diseases and vaccines. Here, we describe the potential uses of single-cell RNA sequencing methods in prophylactic vaccine development, concentrating on infectious diseases including COVID-19. Using examples from several diseases, we review how single-cell RNA sequencing has been used to evaluate the immunological response to different vaccine platforms and regimens. By highlighting published and unpublished single-cell RNA sequencing studies relevant to vaccinology, we discuss some general considerations how the field could be enriched with the widespread adoption of this technology.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , RNA-Seq/methods , Single-Cell Analysis , Vaccinology/methods , Viral Vaccines/administration & dosage , Animals , Cell Line , Clinical Trials as Topic , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Models, Animal , Drug Evaluation, Preclinical , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunity, Cellular/genetics , Immunity, Innate/genetics , Immunogenicity, Vaccine , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , RNA, Viral/isolation & purification , Viral Vaccines/immunology
10.
PLoS Pathog ; 16(8): e1008718, 2020 08.
Article in English | MEDLINE | ID: covidwho-717612

ABSTRACT

APOBEC3 enzymes are innate immune effectors that introduce mutations into viral genomes. These enzymes are cytidine deaminases which transform cytosine into uracil. They preferentially mutate cytidine preceded by thymidine making the 5'TC motif their favored target. Viruses have evolved different strategies to evade APOBEC3 restriction. Certain viruses actively encode viral proteins antagonizing the APOBEC3s, others passively face the APOBEC3 selection pressure thanks to a depleted genome for APOBEC3-targeted motifs. Hence, the APOBEC3s left on the genome of certain viruses an evolutionary footprint. The aim of our study is the identification of these viruses having a genome shaped by the APOBEC3s. We analyzed the genome of 33,400 human viruses for the depletion of APOBEC3-favored motifs. We demonstrate that the APOBEC3 selection pressure impacts at least 22% of all currently annotated human viral species. The papillomaviridae and polyomaviridae are the most intensively footprinted families; evidencing a selection pressure acting genome-wide and on both strands. Members of the parvoviridae family are differentially targeted in term of both magnitude and localization of the footprint. Interestingly, a massive APOBEC3 footprint is present on both strands of the B19 erythroparvovirus; making this viral genome one of the most cleaned sequences for APOBEC3-favored motifs. We also identified the endemic coronaviridae as significantly footprinted. Interestingly, no such footprint has been detected on the zoonotic MERS-CoV, SARS-CoV-1 and SARS-CoV-2 coronaviruses. In addition to viruses that are footprinted genome-wide, certain viruses are footprinted only on very short sections of their genome. That is the case for the gamma-herpesviridae and adenoviridae where the footprint is localized on the lytic origins of replication. A mild footprint can also be detected on the negative strand of the reverse transcribing HIV-1, HIV-2, HTLV-1 and HBV viruses. Together, our data illustrate the extent of the APOBEC3 selection pressure on the human viruses and identify new putatively APOBEC3-targeted viruses.


Subject(s)
Cytidine Deaminase/metabolism , Genome, Viral/genetics , Host-Pathogen Interactions/genetics , Selection, Genetic/genetics , Virus Replication/genetics , Coronaviridae/genetics , Humans , Immunity, Innate/immunology , Papillomaviridae/genetics , Parvoviridae/genetics , Polyomaviridae/genetics , Viral Proteins/genetics
11.
Clin Immunol ; 219: 108572, 2020 10.
Article in English | MEDLINE | ID: covidwho-713545

ABSTRACT

Human Leukocyte Antigen (HLA) includes a large set of genes with important actions in immune response against viral infection. Numerous studies have revealed the existence of significant associations between certain HLA alleles and the susceptibility and prognosis of different infectious diseases. In this pilot study we analyse the binding affinity between 66 class I HLA alleles and SARS-CoV-2 viral peptides, and its association with the severity of the disease. A total of 45 Spanish patients with mild, moderate and severe SARS-CoV-2 infection were typed for HLA class I; after that, we analysed if an in silico model of HLA I-viral peptide binding affinity and classical HLA supertypes could be correlated to the severity of the disease. Our results suggest that patients with mild disease present Class I HLA molecules with a higher theoretical capacity for binding SARS-Cov-2 peptides and showed greater heterozygosity when comparing them with moderate and severe groups. In this regard, identifying HLA-SARS-CoV-2 peptides binding differences between individuals would help to clarify the heterogeneity of clinical responses to the disease and will also be useful to guide a personalized treatment according to its particular risk.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/genetics , Histocompatibility Antigens Class I/genetics , Host-Pathogen Interactions/immunology , Pneumonia, Viral/genetics , Viral Proteins/genetics , Adult , Aged , Alleles , Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Disease Progression , Female , Gene Expression , Gene Frequency , Histocompatibility Antigens Class I/classification , Histocompatibility Antigens Class I/immunology , Humans , Immunity, Innate , Male , Middle Aged , Pandemics , Peptides/genetics , Peptides/immunology , Pilot Projects , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Protein Binding , Severity of Illness Index , Spain , Viral Proteins/immunology
12.
Appl Microbiol Biotechnol ; 104(18): 7777-7785, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-709732

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel ß-coronavirus, is the main pathogenic agent of the rapidly spreading pneumonia called coronavirus disease 2019 (COVID-19). SARS-CoV-2 infects much more people, especially the elder population, around the world than other coronavirus, such as SARS-CoV and MERS-CoV, which is challenging current global public health system. Beyond the pathogenesis of SARS-CoV-2, microbial coinfection plays an important role in the occurrence and development of SARS-CoV-2 infection by raising the difficulties of diagnosis, treatment, prognosis of COVID-19, and even increasing the disease symptom and mortality. We summarize the coinfection of virus, bacteria and fungi with SARS-CoV-2, their effects on COVID-19, the reasons of coinfection, and the diagnosis to emphasize the importance of microbial coinfection in COVID-19. KEY POINTS: • Microbial coinfection is a nonnegligible factor in COVID-19. • Microbial coinfection exacerbates the processes of the occurrence, development and prognosis of COVID-19, and the difficulties of clinical diagnosis and treatment. • Different virus, bacteria, and fungi contributed to the coinfection with SARS-CoV-2.


Subject(s)
Bacterial Infections/epidemiology , Coronavirus Infections/epidemiology , Cytokine Release Syndrome/epidemiology , Lymphopenia/epidemiology , Mycoses/epidemiology , Pandemics , Pneumonia, Viral/epidemiology , Virus Diseases/epidemiology , Anti-Bacterial Agents/therapeutic use , Antiviral Agents/therapeutic use , Bacterial Infections/drug therapy , Bacterial Infections/microbiology , Bacterial Infections/virology , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , Coinfection , Coronavirus Infections/drug therapy , Coronavirus Infections/microbiology , Coronavirus Infections/virology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/microbiology , Cytokine Release Syndrome/virology , Cytokines/biosynthesis , Disease Progression , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate/drug effects , Lymphocytes/microbiology , Lymphocytes/virology , Lymphopenia/drug therapy , Lymphopenia/microbiology , Lymphopenia/virology , Mycoses/drug therapy , Mycoses/microbiology , Mycoses/virology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/microbiology , Pneumonia, Viral/virology , Virus Diseases/drug therapy , Virus Diseases/microbiology , Virus Diseases/virology
14.
Front Immunol ; 11: 1782, 2020.
Article in English | MEDLINE | ID: covidwho-697900

ABSTRACT

As the SARS-CoV-2 virus wreaks havoc on the populations, health care infrastructures and economies of nations around the world, finding ways to protect health care workers and bolster immune responses in the general population while we await an effective vaccine will be the difference between life and death for many people. Recent studies show that innate immune populations may possess a form of memory, termed Trained Immunity (TRIM), where innate immune cells undergo metabolic, mitochondrial, and epigenetic reprogramming following exposure to an initial stimulus that results in a memory phenotype of enhanced immune responses when exposed to a secondary, heterologous, stimulus. Throughout the literature, it has been shown that the induction of TRIM using such inducers as the BCG vaccine and ß-glucan can provide protection through altered immune responses against a range of viral infections. Here we hypothesize a potential role for ß-glucan in decreasing worldwide morbidity and mortality due to COVID-19, and posit several ideas as to how TRIM may actually shape the observed epidemiological phenomena related to COVID-19. We also evaluate the potential effects of ß-glucan in relation to the immune dysregulation and cytokine storm observed in COVID-19. Ultimately, we hypothesize that the use of oral ß-glucan in a prophylactic setting could be an effective way to boost immune responses and abrogate symptoms in COVID-19, though clinical trials are necessary to confirm the efficacy of this treatment and to further examine differential effects of ß-glucan's from various sources.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/diet therapy , Coronavirus Infections/immunology , Dietary Fiber/therapeutic use , Immunologic Memory/drug effects , Pneumonia, Viral/diet therapy , Pneumonia, Viral/immunology , beta-Glucans/therapeutic use , Administration, Oral , Adult , Age Factors , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/immunology , Antiviral Agents/pharmacology , BCG Vaccine/immunology , Child , Coronavirus Infections/blood , Coronavirus Infections/virology , Cytokines/blood , Dietary Fiber/administration & dosage , Epigenesis, Genetic/immunology , Humans , Immunity, Innate/drug effects , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/virology , Pre-Exposure Prophylaxis , beta-Glucans/administration & dosage , beta-Glucans/immunology , beta-Glucans/pharmacology
15.
PLoS Pathog ; 16(7): e1008737, 2020 07.
Article in English | MEDLINE | ID: covidwho-691046

ABSTRACT

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic. An unbalanced immune response, characterized by a weak production of type I interferons (IFN-Is) and an exacerbated release of proinflammatory cytokines, contributes to the severe forms of the disease. SARS-CoV-2 is genetically related to SARS-CoV and Middle East respiratory syndrome-related coronavirus (MERS-CoV), which caused outbreaks in 2003 and 2013, respectively. Although IFN treatment gave some encouraging results against SARS-CoV and MERS-CoV in animal models, its potential as a therapeutic against COVID-19 awaits validation. Here, we describe our current knowledge of the complex interplay between SARS-CoV-2 infection and the IFN system, highlighting some of the gaps that need to be filled for a better understanding of the underlying molecular mechanisms. In addition to the conserved IFN evasion strategies that are likely shared with SARS-CoV and MERS-CoV, novel counteraction mechanisms are being discovered in SARS-CoV-2-infected cells. Since the last coronavirus epidemic, we have made considerable progress in understanding the IFN-I response, including its spatiotemporal regulation and the prominent role of plasmacytoid dendritic cells (pDCs), which are the main IFN-I-producing cells. While awaiting the results of the many clinical trials that are evaluating the efficacy of IFN-I alone or in combination with antiviral molecules, we discuss the potential benefits of a well-timed IFN-I treatment and propose strategies to boost pDC-mediated IFN responses during the early stages of viral infection.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/immunology , Coronavirus Infections/drug therapy , Dendritic Cells/immunology , Immunity, Innate/immunology , Interferon Type I/therapeutic use , Pneumonia, Viral/drug therapy , Betacoronavirus/isolation & purification , Coronavirus Infections/immunology , Coronavirus Infections/virology , Dendritic Cells/drug effects , Humans , Immunity, Innate/drug effects , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Prognosis
16.
Endocrinology ; 161(9)2020 09 01.
Article in English | MEDLINE | ID: covidwho-690822

ABSTRACT

Severe outcomes and death from the novel coronavirus disease 2019 (COVID-19) appear to be characterized by an exaggerated immune response with hypercytokinemia leading to inflammatory infiltration of the lungs and acute respiratory distress syndrome. Risk of severe COVID-19 outcomes is consistently lower in women than men worldwide, suggesting that female biological sex is instrumental in protection. This mini-review discusses the immunomodulatory and anti-inflammatory actions of high physiological concentrations of the steroids 17ß-estradiol (E2) and progesterone (P4). We review how E2 and P4 favor a state of decreased innate immune inflammatory response while enhancing immune tolerance and antibody production. We discuss how the combination of E2 and P4 may improve the immune dysregulation that leads to the COVID-19 cytokine storm. It is intended to stimulate novel consideration of the biological forces that are protective in women compared to men, and to therapeutically harness these factors to mitigate COVID-19 morbidity and mortality.


Subject(s)
Coronavirus Infections/immunology , Estradiol/immunology , Immunomodulation/immunology , Pneumonia, Viral/immunology , Progesterone/immunology , Antibody Formation/immunology , Betacoronavirus , Contraceptives, Oral, Hormonal/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/mortality , Coronavirus Infections/physiopathology , Cytokine Release Syndrome/immunology , Drug Repositioning , Estradiol/therapeutic use , Estrogen Replacement Therapy , Estrogens/therapeutic use , Female , Humans , Immune Tolerance/immunology , Immunity, Innate/immunology , Male , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/mortality , Pneumonia, Viral/physiopathology , Pregnancy , Pregnancy Complications, Infectious/immunology , Progesterone/therapeutic use , Progestins/therapeutic use , Selective Estrogen Receptor Modulators/therapeutic use , Severity of Illness Index , Sex Factors
17.
Nat Commun ; 11(1): 3810, 2020 07 30.
Article in English | MEDLINE | ID: covidwho-690732

ABSTRACT

The pandemic of COVID-19 has posed an unprecedented threat to global public health. However, the interplay between the viral pathogen of COVID-19, SARS-CoV-2, and host innate immunity is poorly understood. Here we show that SARS-CoV-2 induces overt but delayed type-I interferon (IFN) responses. By screening 23 viral proteins, we find that SARS-CoV-2 NSP1, NSP3, NSP12, NSP13, NSP14, ORF3, ORF6 and M protein inhibit Sendai virus-induced IFN-ß promoter activation, whereas NSP2 and S protein exert opposite effects. Further analyses suggest that ORF6 inhibits both type I IFN production and downstream signaling, and that the C-terminus region of ORF6 is critical for its antagonistic effect. Finally, we find that IFN-ß treatment effectively blocks SARS-CoV-2 replication. In summary, our study shows that SARS-CoV-2 perturbs host innate immune response via both its structural and nonstructural proteins, and thus provides insights into the pathogenesis of SARS-CoV-2.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/virology , Immune Evasion , Interferon Type I/metabolism , Pneumonia, Viral/virology , Signal Transduction , Betacoronavirus/genetics , Betacoronavirus/immunology , Betacoronavirus/metabolism , Cell Line , Coronavirus Infections/immunology , Humans , Immunity, Innate , Interferon-beta/genetics , Interferon-beta/metabolism , Interferon-beta/pharmacology , Mutation , Open Reading Frames , Pandemics , Pneumonia, Viral/immunology , Promoter Regions, Genetic , Signal Transduction/drug effects , Viral Proteins/genetics , Viral Proteins/metabolism , Virus Replication/drug effects
18.
Nat Rev Immunol ; 20(9): 515-516, 2020 09.
Article in English | MEDLINE | ID: covidwho-690707
19.
Clin Appl Thromb Hemost ; 26: 1076029620943293, 2020.
Article in English | MEDLINE | ID: covidwho-690632

ABSTRACT

Since the onset of the global pandemic in early 2020, coronavirus disease 2019 (COVID-19) has posed a multitude of challenges to health care systems worldwide. In order to combat these challenges and devise appropriate therapeutic strategies, it becomes of paramount importance to elucidate the pathophysiology of this illness. Coronavirus disease 2019, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), is characterized by a dysregulated immune system and hypercoagulability. COVID-associated coagulopathy (CAC) was recognized based on profound d-dimer elevations and evidence of microthrombi and macrothrombi, both in venous and arterial systems. The underlying mechanisms associated with CAC have been suggested, but not clearly defined. The model of immunothrombosis illustrates the elaborate crosstalk between the innate immune system and coagulation. The rendering of a procoagulant state in COVID-19 involves the interplay of many innate immune pathways. The SARS-CoV2 virus can directly infect immune and endothelial cells, leading to endothelial injury and dysregulation of the immune system. Activated leukocytes potentiate a procoagulant state via release of intravascular tissue factor, platelet activation, NETosis, and inhibition of anticoagulant mechanisms. Additional pathways of specific relevance in CAC include cytokine release and complement activation. All these mechanisms have recently been reported in COVID-19. Immunothrombosis provides a comprehensive perspective of the several synergistic pathways pertinent to the pathogenesis of CAC.


Subject(s)
Betacoronavirus , Blood Coagulation Disorders/virology , Coronavirus Infections/complications , Pneumonia, Viral/complications , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/pathology , Coronavirus Infections/physiopathology , Coronavirus Infections/virology , Endothelial Cells/pathology , Endothelial Cells/virology , Humans , Immunity, Innate , Leukocytes/metabolism , Leukocytes/pathology , Pandemics , Pneumonia, Viral/physiopathology , Pneumonia, Viral/virology , Thrombophilia/immunology , Thrombophilia/virology , Thrombosis/etiology , Thrombosis/immunology , Thrombosis/virology
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