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Rev Med Virol ; 31(6): e2234, 2021 11.
Article in English | MEDLINE | ID: covidwho-1574124


The coronavirus disease (Covid-19) pandemic is the most serious event of the year 2020, causing considerable global morbidity and mortality. The goal of this review is to provide a comprehensive summary of reported associations between inter-individual immunogenic variants and disease susceptibility or symptoms caused by the coronavirus strains severe acute respiratory syndrome-associated coronavirus, severe acute respiratory syndrome-associated coronavirus-2, and two of the main respiratory viruses, respiratory syncytial virus and influenza virus. The results suggest that the genetic background of the host could affect the levels of proinflammatory and anti-inflammatory cytokines and might modulate the progression of Covid-19 in affected patients. Notably, genetic variations in innate immune components such as toll-like receptors and mannose-binding lectin 2 play critical roles in the ability of the immune system to recognize coronavirus and initiate an early immune response to clear the virus and prevent the development of severe symptoms. This review provides promising clues related to the potential benefits of using immunotherapy and immune modulation for respiratory infectious disease treatment in a personalized manner.

COVID-19/immunology , Cytokine Release Syndrome/immunology , Genetic Predisposition to Disease , Influenza, Human/immunology , Respiratory Syncytial Virus Infections/immunology , Severe Acute Respiratory Syndrome/immunology , Antiviral Agents/therapeutic use , Biological Variation, Individual , COVID-19/drug therapy , COVID-19/genetics , COVID-19/virology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/virology , Gene Expression , Humans , Immunity, Innate , Immunologic Factors/therapeutic use , Influenza, Human/drug therapy , Influenza, Human/genetics , Influenza, Human/virology , Mannose-Binding Lectin/genetics , Mannose-Binding Lectin/immunology , Orthomyxoviridae/drug effects , Orthomyxoviridae/immunology , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/genetics , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Viruses/drug effects , Respiratory Syncytial Viruses/immunology , SARS Virus/drug effects , SARS Virus/immunology , SARS-CoV-2/classification , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/virology , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology
Am J Respir Cell Mol Biol ; 66(2): 206-222, 2022 02.
Article in English | MEDLINE | ID: covidwho-1501858


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 180 million people since the onset of the pandemic. Despite similar viral load and infectivity rates between children and adults, children rarely develop severe illness. Differences in the host response to the virus at the primary infection site are among the mechanisms proposed to account for this disparity. Our objective was to investigate the host response to SARS-CoV-2 in the nasal mucosa in children and adults and compare it with the host response to respiratory syncytial virus (RSV) and influenza virus. We analyzed clinical outcomes and gene expression in the nasal mucosa of 36 children with SARS-CoV-2, 24 children with RSV, 9 children with influenza virus, 16 adults with SARS-CoV-2, and 7 healthy pediatric and 13 healthy adult controls. In both children and adults, infection with SARS-CoV-2 led to an IFN response in the nasal mucosa. The magnitude of the IFN response correlated with the abundance of viral reads, not the severity of illness, and was comparable between children and adults infected with SARS-CoV-2 and children with severe RSV infection. Expression of ACE2 and TMPRSS2 did not correlate with age or presence of viral infection. SARS-CoV-2-infected adults had increased expression of genes involved in neutrophil activation and T-cell receptor signaling pathways compared with SARS-CoV-2-infected children, despite similar severity of illness and viral reads. Age-related differences in the immune response to SARS-CoV-2 may place adults at increased risk of developing severe illness.

Aging/immunology , COVID-19/immunology , Gene Expression Regulation/immunology , Immunity, Mucosal , Nasal Mucosa/immunology , SARS-CoV-2/immunology , Adolescent , Age Factors , Angiotensin-Converting Enzyme 2/immunology , Child , Child, Preschool , Female , Humans , Infant , Male , Nasal Mucosa/virology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Viruses/immunology , Serine Endopeptidases/immunology
Front Immunol ; 12: 650331, 2021.
Article in English | MEDLINE | ID: covidwho-1156125


Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection represents a global health crisis. Immune cell activation via pattern recognition receptors has been implicated as a driver of the hyperinflammatory response seen in COVID-19. However, our understanding of the specific immune responses to SARS-CoV-2 remains limited. Mast cells (MCs) and eosinophils are innate immune cells that play pathogenic roles in many inflammatory responses. Here we report MC-derived proteases and eosinophil-associated mediators are elevated in COVID-19 patient sera and lung tissues. Stimulation of viral-sensing toll-like receptors in vitro and administration of synthetic viral RNA in vivo induced features of hyperinflammation, including cytokine elevation, immune cell airway infiltration, and MC-protease production-effects suppressed by an anti-Siglec-8 monoclonal antibody which selectively inhibits MCs and depletes eosinophils. Similarly, anti-Siglec-8 treatment reduced disease severity and airway inflammation in a respiratory viral infection model. These results suggest that MC and eosinophil activation are associated with COVID-19 inflammation and anti-Siglec-8 antibodies are a potential therapeutic approach for attenuating excessive inflammation during viral infections.

Antigens, CD/immunology , Antigens, Differentiation, B-Lymphocyte/immunology , COVID-19/immunology , Eosinophils/immunology , Lectins/immunology , Mast Cells/immunology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Viruses/immunology , SARS-CoV-2/immunology , Toll-Like Receptors/immunology , Animals , Antibodies, Monoclonal/pharmacology , Antigens, CD/genetics , Antigens, CD/metabolism , Antigens, Differentiation, B-Lymphocyte/genetics , Antigens, Differentiation, B-Lymphocyte/metabolism , COVID-19/metabolism , COVID-19/prevention & control , COVID-19/virology , Case-Control Studies , Cytokines/metabolism , Disease Models, Animal , Eosinophils/drug effects , Eosinophils/metabolism , Eosinophils/virology , Host-Pathogen Interactions , Humans , Lectins/antagonists & inhibitors , Lectins/genetics , Lectins/metabolism , Mast Cells/drug effects , Mast Cells/metabolism , Mast Cells/virology , Mice, Transgenic , Peptide Hydrolases/metabolism , Respiratory Syncytial Virus Infections/metabolism , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus Infections/virology , Toll-Like Receptors/metabolism
Elife ; 92020 12 15.
Article in English | MEDLINE | ID: covidwho-977809


Vaccines are powerful tools to develop immune memory to infectious diseases and prevent excess mortality. In older adults, however vaccines are generally less efficacious and the molecular mechanisms that underpin this remain largely unknown. Autophagy, a process known to prevent aging, is critical for the maintenance of immune memory in mice. Here, we show that autophagy is specifically induced in vaccine-induced antigen-specific CD8+ T cells in healthy human volunteers. In addition, reduced IFNγ secretion by RSV-induced T cells in older vaccinees correlates with low autophagy levels. We demonstrate that levels of the endogenous autophagy-inducing metabolite spermidine fall in human T cells with age. Spermidine supplementation in T cells from old donors recovers their autophagy level and function, similar to young donors' cells, in which spermidine biosynthesis has been inhibited. Finally, our data show that endogenous spermidine maintains autophagy via the translation factor eIF5A and transcription factor TFEB. In summary, we have provided evidence for the importance of autophagy in vaccine immunogenicity in older humans and uncovered two novel drug targets that may increase vaccination efficiency in the aging context.

Aging/immunology , Autophagy/immunology , CD8-Positive T-Lymphocytes/immunology , Respiratory Syncytial Virus Vaccines/immunology , Spermidine/pharmacology , Adjuvants, Immunologic/pharmacology , Adult , Aged , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Cell Line, Tumor , Humans , Immunologic Memory/immunology , Interferon-gamma/blood , Jurkat Cells , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Peptide Initiation Factors/metabolism , RNA-Binding Proteins/metabolism , Respiratory Syncytial Viruses/immunology , Spermidine/blood , Vaccination , Young Adult
Mucosal Immunol ; 14(1): 14-25, 2021 01.
Article in English | MEDLINE | ID: covidwho-922255


Infection with respiratory viruses such as influenza, respiratory syncytial virus and coronavirus provides a difficult immunological challenge for the host, where a balance must be established between controlling viral replication and limiting damage to the delicate lung structure. Although the genetic architecture of host responses to respiratory viral infections is not yet understood, it is clear there is underlying heritability that influences pathogenesis. Immune control of virus replication is essential in respiratory infections, but overt activation can enhance inflammation and disease severity. Cytokines initiate antiviral immune responses but are implicated in viral pathogenesis. Here, we discuss how host genetic variation may influence cytokine responses to respiratory viral infections and, based on our current understanding of the role that cytokines play in viral pathogenesis, how this may influence disease severity. We also discuss how induced pluripotent stem cells may be utilised to probe the mechanistic implications of allelic variation in genes in virus-induced inflammatory responses. Ultimately, this could help to design better immune modulators, stratify high risk patients and tailor anti-inflammatory treatments, potentially expanding the ability to treat respiratory virus outbreaks in the future.

Cytokines/genetics , Inflammation/genetics , Influenza A virus/immunology , Respiratory Syncytial Viruses/immunology , SARS-CoV-2/immunology , COVID-19/immunology , COVID-19/pathology , Cytokines/blood , Genetic Variation/genetics , Genetic Variation/immunology , Humans , Induced Pluripotent Stem Cells , Inflammation/pathology , Influenza, Human/immunology , Lung/pathology , Lung/virology , Respiratory Syncytial Virus Infections/immunology
J Innate Immun ; 12(1): 4-20, 2020.
Article in English | MEDLINE | ID: covidwho-774824


The impact of respiratory virus infections on the health of children and adults can be very significant. Yet, in contrast to most other childhood infections as well as other viral and bacterial diseases, prophylactic vaccines or effective antiviral treatments against viral respiratory infections are either still not available, or provide only limited protection. Given the widespread prevalence, a general lack of natural sterilizing immunity, and/or high morbidity and lethality rates of diseases caused by influenza, respiratory syncytial virus, coronaviruses, and rhinoviruses, this difficult situation is a genuine societal challenge. A thorough understanding of the virus-host interactions during these respiratory infections will most probably be pivotal to ultimately meet these challenges. This review attempts to provide a comparative overview of the knowledge about an important part of the interaction between respiratory viruses and their host: the arms race between host innate immunity and viral innate immune evasion. Many, if not all, viruses, including the respiratory viruses listed above, suppress innate immune responses to gain a window of opportunity for efficient virus replication and setting-up of the infection. The consequences for the host's immune response are that it is often incomplete, delayed or diminished, or displays overly strong induction (after the delay) that may cause tissue damage. The affected innate immune response also impacts subsequent adaptive responses, and therefore viral innate immune evasion often undermines fully protective immunity. In this review, innate immune responses relevant for respiratory viruses with an RNA genome will briefly be summarized, and viral innate immune evasion based on shielding viral RNA species away from cellular innate immune sensors will be discussed from different angles. Subsequently, viral enzymatic activities that suppress innate immune responses will be discussed, including activities causing host shut-off and manipulation of stress granule formation. Furthermore, viral protease-mediated immune evasion and viral manipulation of the ubiquitin system will be addressed. Finally, perspectives for use of the reviewed knowledge for the development of novel antiviral strategies will be sketched.

Coronavirus Infections/virology , Coronavirus/pathogenicity , Immunity, Innate , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Viruses/pathogenicity , Animals , Coronavirus/genetics , Coronavirus/immunology , Coronavirus Infections/immunology , Host Microbial Interactions , Humans , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Viruses/genetics , Respiratory Syncytial Viruses/immunology , Signal Transduction , Virus Internalization , Virus Replication
Microbes Infect ; 22(9): 403-404, 2020 10.
Article in English | MEDLINE | ID: covidwho-618770

Betacoronavirus/pathogenicity , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Respiratory Syncytial Virus Infections/prevention & control , Severe Acute Respiratory Syndrome/prevention & control , Viral Vaccines/administration & dosage , Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , Betacoronavirus/immunology , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Eosinophils/drug effects , Eosinophils/immunology , Eosinophils/pathology , Eosinophils/virology , Humans , Lung/drug effects , Lung/immunology , Lung/pathology , Lung/virology , Middle East Respiratory Syndrome Coronavirus/immunology , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Monocytes/drug effects , Monocytes/immunology , Monocytes/pathology , Monocytes/virology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Respiratory Syncytial Virus Infections/epidemiology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Viruses/immunology , Respiratory Syncytial Viruses/pathogenicity , SARS Virus/immunology , SARS Virus/pathogenicity , SARS-CoV-2 , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology , Severity of Illness Index , Viral Vaccines/adverse effects