Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 21
Filter
1.
J Interferon Cytokine Res ; 41(11): 407-414, 2021 11.
Article in English | MEDLINE | ID: covidwho-1758604

ABSTRACT

Genetic polymorphisms at the IFNL4 loci are known to influence the clinical outcome of several different infectious diseases. Best described is the association between the IFNL4 genotype and hepatitis C virus clearance. However, an influence of the IFNL4 genotype on the adaptive immune system was suggested by several studies but never investigated in humans. In this cross-sectional study, we have genotyped 201 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive participants for 3 IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) and stratified them according to the IFNλ4 activity. Based on this stratification, we investigated the association between the IFNL4 genotype and the antibody as well as the CD8+ T cell response in the acute phase of the SARS-CoV-2 infection. We observed no differences in the genotype distribution compared with a Danish reference cohort or the 1,000 Genome Project, and we were not able to link the IFNL4 genotype to changes in either the antibody or CD8+ T cell responses of these patients.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , Interleukins/immunology , SARS-CoV-2/immunology , Adaptive Immunity/genetics , Adult , Aged , CD8-Positive T-Lymphocytes/immunology , Cohort Studies , Cross-Sectional Studies , Female , Genotype , Humans , Interleukins/genetics , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Polymorphism, Single Nucleotide/immunology , SARS-CoV-2/genetics , Young Adult
2.
Front Immunol ; 12: 769442, 2021.
Article in English | MEDLINE | ID: covidwho-1686473

ABSTRACT

The prevention of the COVID-19 pandemic is highly complicated by the prevalence of asymptomatic and recurrent infection. Many previous immunological studies have focused on symptomatic and convalescent patients, while the immune responses in asymptomatic patients and re-detectable positive cases remain unclear. Here we comprehensively analyzed the peripheral T-cell receptor (TCR) repertoire of 54 COVID-19 patients in different courses, including asymptomatic, symptomatic, convalescent, and re-detectable positive cases. We identified a set of V-J gene combinations characterizing the upward immune responses through asymptomatic and symptomatic courses. Furthermore, some of these V-J combinations could be awakened in the re-detectable positive cases, which may help predict the risk of recurrent infection. Therefore, TCR repertoire examination has the potential to strengthen the clinical surveillance and the immunotherapy development for COVID-19.


Subject(s)
COVID-19/pathology , Immunoglobulin J-Chains/genetics , Immunoglobulin Variable Region/genetics , Receptors, Antigen, T-Cell/genetics , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Adaptive Immunity/genetics , Adaptive Immunity/immunology , Adult , Aged , Asymptomatic Infections , COVID-19/immunology , Female , Gene Expression/genetics , Histocompatibility Antigens Class I/genetics , Humans , Male , Middle Aged , Receptors, Antigen, T-Cell/immunology , Severity of Illness Index , Young Adult
3.
Cell ; 185(5): 881-895.e20, 2022 03 03.
Article in English | MEDLINE | ID: covidwho-1649960

ABSTRACT

Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.


Subject(s)
COVID-19/complications , COVID-19/diagnosis , Convalescence , Adaptive Immunity/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Autoantibodies/blood , Biomarkers/metabolism , Blood Proteins/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Disease Progression , Female , Humans , Immunity, Innate/genetics , Longitudinal Studies , Male , Middle Aged , Risk Factors , SARS-CoV-2/isolation & purification , Transcriptome , Young Adult
4.
Nat Commun ; 13(1): 440, 2022 01 21.
Article in English | MEDLINE | ID: covidwho-1641960

ABSTRACT

Dysregulated immune responses against the SARS-CoV-2 virus are instrumental in severe COVID-19. However, the immune signatures associated with immunopathology are poorly understood. Here we use multi-omics single-cell analysis to probe the dynamic immune responses in hospitalized patients with stable or progressive course of COVID-19, explore V(D)J repertoires, and assess the cellular effects of tocilizumab. Coordinated profiling of gene expression and cell lineage protein markers shows that S100Ahi/HLA-DRlo classical monocytes and activated LAG-3hi T cells are hallmarks of progressive disease and highlights the abnormal MHC-II/LAG-3 interaction on myeloid and T cells, respectively. We also find skewed T cell receptor repertories in expanded effector CD8+ clones, unmutated IGHG+ B cell clones, and mutated B cell clones with stable somatic hypermutation frequency over time. In conclusion, our in-depth immune profiling reveals dyssynchrony of the innate and adaptive immune interaction in progressive COVID-19.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , Gene Expression Profiling/methods , Immunity, Innate/immunology , SARS-CoV-2/immunology , Single-Cell Analysis/methods , Adaptive Immunity/drug effects , Adaptive Immunity/genetics , Aged , Antibodies, Monoclonal, Humanized/therapeutic use , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , COVID-19/drug therapy , COVID-19/genetics , Cells, Cultured , Female , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Humans , Immunity, Innate/drug effects , Immunity, Innate/genetics , Male , RNA-Seq/methods , Receptors, Antigen, B-Cell/genetics , Receptors, Antigen, B-Cell/immunology , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology
5.
Int J Mol Sci ; 23(2)2022 Jan 14.
Article in English | MEDLINE | ID: covidwho-1633064

ABSTRACT

Peripheral blood mononuclear cells (PBMCs) belong to the innate and adaptive immune system and are highly sensitive and responsive to changes in their systemic environment. In this study, we focused on the time course of transcriptional changes in freshly isolated human PBMCs 4, 8, 24 and 48 h after onset of stimulation with the active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). Taking all four time points together, 662 target genes were identified and segregated either by time of differential gene expression into 179 primary and 483 secondary targets or by driver of expression change into 293 direct and 369 indirect targets. The latter classification revealed that more than 50% of target genes were primarily driven by the cells' response to ex vivo exposure than by the nuclear hormone and largely explained its down-regulatory effect. Functional analysis indicated vitamin D's role in the suppression of the inflammatory and adaptive immune response by down-regulating ten major histocompatibility complex class II genes, five alarmins of the S100 calcium binding protein A family and by affecting six chemokines of the C-X-C motif ligand family. Taken together, studying time-resolved responses allows to better contextualize the effects of vitamin D on the immune system.


Subject(s)
Adaptive Immunity/genetics , Gene Expression Profiling , Gene Expression Regulation , Inflammation Mediators/metabolism , Transcriptome , Vitamin D/metabolism , Computational Biology/methods , Gene Expression Profiling/methods , Gene Expression Regulation/drug effects , Humans , Inflammation/etiology , Inflammation/metabolism , Inflammation/pathology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Molecular Sequence Annotation , Vitamin D/analogs & derivatives , Vitamin D/pharmacology
6.
JCI Insight ; 6(24)2021 12 22.
Article in English | MEDLINE | ID: covidwho-1598468

ABSTRACT

mRNA vaccines for SARS-CoV-2 have shown exceptional clinical efficacy, providing robust protection against severe disease. However, our understanding of transcriptional and repertoire changes following full vaccination remains incomplete. We used scRNA-Seq and functional assays to compare humoral and cellular responses to 2 doses of mRNA vaccine with responses observed in convalescent individuals with asymptomatic disease. Our analyses revealed enrichment of spike-specific B cells, activated CD4+ T cells, and robust antigen-specific polyfunctional CD4+ T cell responses following vaccination. On the other hand, although clonally expanded CD8+ T cells were observed following both vaccination and natural infection, CD8+ T cell responses were relatively weak and variable. In addition, TCR gene usage was variable, reflecting the diversity of repertoires and MHC polymorphism in the human population. Natural infection induced expansion of CD8+ T cell clones that occupy distinct clusters compared to those induced by vaccination and likely recognize a broader set of viral antigens of viral epitopes presented by the virus not seen in the mRNA vaccine. Our study highlights a coordinated adaptive immune response in which early CD4+ T cell responses facilitate the development of the B cell response and substantial expansion of effector CD8+ T cells, together capable of contributing to future recall responses.


Subject(s)
/immunology , COVID-19/immunology , Immunity, Cellular/immunology , Immunity, Humoral/immunology , /therapeutic use , Adaptive Immunity/genetics , Adaptive Immunity/immunology , Adult , Aged , Antigens, Viral , B-Lymphocytes , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , COVID-19/prevention & control , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Carrier State , Convalescence , Epitopes , Female , Humans , Immunity, Cellular/genetics , Immunity, Humoral/genetics , Immunogenicity, Vaccine , Immunologic Memory , Male , Middle Aged , RNA-Seq , SARS-CoV-2 , Single-Cell Analysis , Spike Glycoprotein, Coronavirus/immunology , Th1 Cells , Th17 Cells , Vaccines, Synthetic/immunology , Vaccines, Synthetic/therapeutic use , Young Adult , /therapeutic use
7.
Front Immunol ; 12: 733539, 2021.
Article in English | MEDLINE | ID: covidwho-1572288

ABSTRACT

The response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely impacted by the level of virus exposure and status of the host immunity. The nature of protection shown by direct asymptomatic contacts of coronavirus disease 2019 (COVID-19)-positive patients is quite intriguing. In this study, we have characterized the antibody titer, SARS-CoV-2 surrogate virus neutralization, cytokine levels, single-cell T-cell receptor (TCR), and B-cell receptor (BCR) profiling in asymptomatic direct contacts, infected cases, and controls. We observed significant increase in antibodies with neutralizing amplitude in asymptomatic contacts along with cytokines such as Eotaxin, granulocyte-colony stimulating factor (G-CSF), interleukin 7 (IL-7), migration inhibitory factor (MIF), and macrophage inflammatory protein-1α (MIP-1α). Upon single-cell RNA (scRNA) sequencing, we explored the dynamics of the adaptive immune response in few representative asymptomatic close contacts and COVID-19-infected patients. We reported direct asymptomatic contacts to have decreased CD4+ naive T cells with concomitant increase in CD4+ memory and CD8+ Temra cells along with expanded clonotypes compared to infected patients. Noticeable proportions of class switched memory B cells were also observed in them. Overall, these findings gave an insight into the nature of protection in asymptomatic contacts.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , Genomics/methods , SARS-CoV-2/immunology , Single-Cell Analysis/methods , Adaptive Immunity/genetics , Adult , Antibodies, Viral/immunology , COVID-19/genetics , COVID-19/virology , Cytokines/immunology , Cytokines/metabolism , Female , Gene Expression Profiling/methods , Humans , Male , /metabolism , Middle Aged , SARS-CoV-2/physiology , Sequence Analysis, RNA/methods , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/virology , Young Adult
8.
Front Immunol ; 12: 755579, 2021.
Article in English | MEDLINE | ID: covidwho-1556334

ABSTRACT

During the COVID-19 pandemic, a phenomenon emerged in which some patients with severe disease were critically ill and could not be discharged from the ICU even though they exhibited negative viral tests. To explore the underlying mechanism, we collected blood samples from these patients and analyzed the gene expression profiles of peripheral immune cells. We found that all enrolled patients, regardless of changes in genes related to different symptoms and inflammatory responses, showed universally and severely decreased expression of adaptive immunity-related genes, especially those related to T/B cell arms and HLA molecules, and that these patients exhibited long-term secondary infections. In addition, no significant change was found in the expression of classic immunosuppression molecules including PD-1, PD-L1, and CTLA-4, suggesting that the adaptive immune suppression may not be due to the change of these genes. According to the published literatures and our data, this adaptive immunosuppression is likely to be caused by the "dysregulated host response" to severe infection, similar to the immunosuppression that exists in other severely infected patients with sepsis.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , Immune Tolerance/immunology , Adaptive Immunity/genetics , Aged , COVID-19/diagnosis , COVID-19/genetics , Coinfection/diagnosis , Coinfection/genetics , Coinfection/immunology , Cross-Sectional Studies , Cytokine Release Syndrome/genetics , Female , Gene Expression Profiling , Humans , Immune Tolerance/genetics , Inflammation/genetics , Intensive Care Units , Male , Middle Aged , Patient Discharge , SARS-CoV-2/isolation & purification , Smell/genetics , Taste/genetics
9.
Nat Rev Immunol ; 20(9): 518-519, 2020 09.
Article in English | MEDLINE | ID: covidwho-1550304
10.
Front Immunol ; 12: 758154, 2021.
Article in English | MEDLINE | ID: covidwho-1477831

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has severely impacted daily life all over the world. Any measures to slow down the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to decrease disease severity are highly requested. Recent studies have reported inverse correlations between plasma levels of vitamin D and susceptibility to SARS-CoV-2 infection and COVID-19 severity. Therefore, it has been proposed to supplement the general population with vitamin D to reduce the impact of COVID-19. However, by studying the course of COVID-19 and the immune response against SARS-CoV-2 in a family with a mutated, non-functional vitamin D receptor, we here demonstrate that vitamin D signaling was dispensable for mounting an efficient adaptive immune response against SARS-CoV-2 in this family. Although these observations might not directly be transferred to the general population, they question a central role of vitamin D in the generation of adaptive immunity against SARS-CoV-2.


Subject(s)
B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Familial Hypophosphatemic Rickets/genetics , Receptors, Calcitriol/genetics , SARS-CoV-2/immunology , Adaptive Immunity/genetics , Adaptive Immunity/immunology , COVID-19/immunology , Familial Hypophosphatemic Rickets/immunology , Female , Humans , Immunologic Memory/immunology , Lymphocyte Count , Vitamin D/blood , Vitamin D/therapeutic use
11.
Front Immunol ; 12: 701273, 2021.
Article in English | MEDLINE | ID: covidwho-1332121

ABSTRACT

SARS-CoV-2 infection leads to a highly variable clinical evolution, ranging from asymptomatic to severe disease with acute respiratory distress syndrome, requiring intensive care units (ICU) admission. The optimal management of hospitalized patients has become a worldwide concern and identification of immune biomarkers predictive of the clinical outcome for hospitalized patients remains a major challenge. Immunophenotyping and transcriptomic analysis of hospitalized COVID-19 patients at admission allow identifying the two categories of patients. Inflammation, high neutrophil activation, dysfunctional monocytic response and a strongly impaired adaptive immune response was observed in patients who will experience the more severe form of the disease. This observation was validated in an independent cohort of patients. Using in silico analysis on drug signature database, we identify differential therapeutics that specifically correspond to each group of patients. From this signature, we propose a score-the SARS-Score-composed of easily quantifiable biomarkers, to classify hospitalized patients upon arrival to adapt treatment according to their immune profile.


Subject(s)
COVID-19/immunology , SARS-CoV-2/physiology , Adaptive Immunity/genetics , Adult , Aged , Antiviral Agents/therapeutic use , Biomarkers , COVID-19/therapy , Cohort Studies , Female , Hospitalization , Humans , Inflammation/genetics , Male , Middle Aged , Precision Medicine , Prospective Studies , Severity of Illness Index , Transcriptome
12.
Cell Commun Signal ; 19(1): 76, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1318284

ABSTRACT

Hypoxia is a pathological condition common to many diseases, although multiple organ injuries induced by hypoxia are often overlooked. There is increasing evidence to suggest that the hypoxic environment may activate innate immune cells and suppress adaptive immunity, further stimulating inflammation and inhibiting immunosurveillance. We found that dysfunctional immune regulation may aggravate hypoxia-induced tissue damage and contribute to secondary injury. Among the diverse mechanisms of hypoxia-induced immune dysfunction identified to date, the role of programmed death-ligand 1 (PD-L1) has recently attracted much attention. Besides leading to tumour immune evasion, PD-L1 has also been found to participate in the progression of the immune dysfunction which mediates hypoxia-induced multiple organ injury. In this review, we aimed to summarise the role of immune dysfunction in hypoxia-induced multiple organ injury, the effects of hypoxia on the cellular expression of PD-L1, and the effects of upregulated PD-L1 expression on immune regulation. Furthermore, we summarise the latest information pertaining to the involvement, diagnostic value, and therapeutic potential of immunosuppression induced by PD-L1 in various types of hypoxia-related diseases, including cancers, ischemic stroke, acute kidney injury, and obstructive sleep apnoea. Video Abstract.


Subject(s)
Adaptive Immunity/genetics , B7-H1 Antigen/immunology , Inflammation/immunology , Tumor Hypoxia/genetics , Acute Kidney Injury/genetics , Acute Kidney Injury/immunology , Adaptive Immunity/immunology , B7-H1 Antigen/genetics , Humans , Immunity, Innate/genetics , Inflammation/genetics , Ischemic Stroke/genetics , Ischemic Stroke/immunology , Monitoring, Immunologic , Neoplasms/genetics , Neoplasms/immunology , Sleep Apnea, Obstructive/genetics , Sleep Apnea, Obstructive/immunology , Tumor Hypoxia/immunology
13.
Cells ; 10(6)2021 05 23.
Article in English | MEDLINE | ID: covidwho-1243956

ABSTRACT

The recent SARS-CoV-2 pandemic has refocused attention to the betacoronaviruses, only eight years after the emergence of another zoonotic betacoronavirus, the Middle East respiratory syndrome coronavirus (MERS-CoV). While the wild source of SARS-CoV-2 may be disputed, for MERS-CoV, dromedaries are considered as source of zoonotic human infections. Testing 100 immune-response genes in 121 dromedaries from United Arab Emirates (UAE) for potential association with present MERS-CoV infection, we identified candidate genes with important functions in the adaptive, MHC-class I (HLA-A-24-like) and II (HLA-DPB1-like), and innate immune response (PTPN4, MAGOHB), and in cilia coating the respiratory tract (DNAH7). Some of these genes previously have been associated with viral replication in SARS-CoV-1/-2 in humans, others have an important role in the movement of bronchial cilia. These results suggest similar host genetic pathways associated with these betacoronaviruses, although further work is required to better understand the MERS-CoV disease dynamics in both dromedaries and humans.


Subject(s)
Adaptive Immunity/genetics , Camelus/virology , Communicable Diseases, Emerging/immunology , Coronavirus Infections/immunology , Immunity, Innate/genetics , Zoonoses/immunology , Animals , Antibodies, Viral , Bronchi/cytology , Bronchi/physiology , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Camelus/genetics , Camelus/immunology , Cilia/physiology , Communicable Diseases, Emerging/genetics , Communicable Diseases, Emerging/transmission , Communicable Diseases, Emerging/virology , Coronavirus Infections/genetics , Coronavirus Infections/transmission , Coronavirus Infections/virology , Disease Reservoirs/virology , Female , Genetic Predisposition to Disease , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , Male , Middle East Respiratory Syndrome Coronavirus/immunology , Middle East Respiratory Syndrome Coronavirus/isolation & purification , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Respiratory Mucosa/cytology , Respiratory Mucosa/physiology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , United Arab Emirates , Virus Replication/genetics , Virus Replication/immunology , Zoonoses/genetics , Zoonoses/transmission , Zoonoses/virology
14.
Sci Rep ; 11(1): 4243, 2021 02 19.
Article in English | MEDLINE | ID: covidwho-1091458

ABSTRACT

SARS-CoV-2 infection ranges from asymptomatic to severe with lingering symptomatology in some. This prompted investigation of whether or not asymptomatic disease results in measurable immune activation post-infection. Immune activation following asymptomatic SARS-CoV-2 infection was characterized through a comparative investigation of the immune cell transcriptomes from 43 asymptomatic seropositive and 52 highly exposed seronegative individuals from the same community 4-6 weeks following a superspreading event. Few of the 95 individuals had underlying health issues. One seropositive individual reported Cystic Fibrosis and one individual reported Incontinentia pigmenti. No evidence of immune activation was found in asymptomatic seropositive individuals with the exception of the Cystic Fibrosis patient. There were no statistically significant differences in immune transcriptomes between asymptomatic seropositive and highly exposed seronegative individuals. Four positive controls, mildly symptomatic seropositive individuals whose blood was examined 3 weeks following infection, showed immune activation. Negative controls were four seronegative individuals from neighboring communities without COVID-19. All individuals remained in their usual state of health through a five-month follow-up after sample collection. In summary, whole blood transcriptomes identified individual immune profiles within a community population and showed that asymptomatic infection within a super-spreading event was not associated with enduring immunological activation.


Subject(s)
COVID-19/immunology , SARS-CoV-2/immunology , Transcriptome/immunology , Adaptive Immunity/genetics , Adolescent , Adult , Aged , Antibodies, Viral/blood , Antibodies, Viral/isolation & purification , Asymptomatic Infections , Austria , COVID-19/blood , COVID-19/diagnosis , COVID-19/transmission , COVID-19 Serological Testing/statistics & numerical data , Child , Child, Preschool , Contact Tracing/statistics & numerical data , Family Characteristics , Female , Follow-Up Studies , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , Immunity, Innate/genetics , Infant , Male , Middle Aged , RNA-Seq/statistics & numerical data , SARS-CoV-2/isolation & purification , Young Adult
15.
Dev Growth Differ ; 63(3): 219-227, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1088005

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a pandemic as of early 2020. Upon infection, SARS-CoV-2 attaches to its receptor, that is, angiotensin-converting enzyme 2 (ACE2), on the surface of host cells and is then internalized into host cells via enzymatic machineries. This subsequently stimulates immune response factors. Since the host immune response and severity of COVID-19 vary among individuals, genetic risk factors for severe COVID-19 cases have been investigated. Our research group recently conducted a survey of genetic variants among SARS-CoV-2-interacting molecules across populations, noting near absence of difference in allele frequency spectrum between populations in these genes. Recent genome-wide association studies have identified genetic risk factors for severe COVID-19 cases in a segment of chromosome 3 that involves six genes encoding three immune-regulatory chemokine receptors and another three molecules. The risk haplotype seemed to be inherited from Neanderthals, suggesting genetic adaptation against pathogens in modern human evolution. Therefore, SARS-CoV-2 uses highly conserved molecules as its virion interaction, whereas its immune response appears to be genetically biased in individuals to some extent. We herein review the molecular process of SARS-CoV-2 infection as well as our further survey of genetic variants of its related immune effectors. We also discuss aspects of modern human evolution.


Subject(s)
Adaptive Immunity , COVID-19 , Evolution, Molecular , Genetic Variation , Host-Pathogen Interactions , SARS-CoV-2/genetics , Adaptive Immunity/genetics , Adaptive Immunity/immunology , Animals , COVID-19/epidemiology , COVID-19/genetics , COVID-19/immunology , Conserved Sequence , Genome-Wide Association Study , Host Adaptation/genetics , Host Adaptation/immunology , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Pandemics , SARS-CoV-2/immunology , Sequence Analysis, RNA
16.
Am J Physiol Heart Circ Physiol ; 320(1): H296-H304, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-961166

ABSTRACT

Biological sex is increasingly recognized as a critical determinant of health and disease, particularly relevant to the topical COVID-19 pandemic caused by the SARS-CoV-2 coronavirus. Epidemiological data and observational reports from both the original SARS epidemic and the most recent COVID-19 pandemic have a common feature: males are more likely to exhibit enhanced disease severity and mortality than females. Sex differences in cardiovascular disease and COVID-19 share mechanistic foundations, namely, the involvement of both the innate immune system and the canonical renin-angiotensin system (RAS). Immunological differences suggest that females mount a rapid and aggressive innate immune response, and the attenuated antiviral response in males may confer enhanced susceptibility to severe disease. Furthermore, the angiotensin-converting enzyme 2 (ACE2) is involved in disease pathogenesis in cardiovascular disease and COVID-19, either to serve as a protective mechanism by deactivating the RAS or as the receptor for viral entry, respectively. Loss of membrane ACE2 and a corresponding increase in plasma ACE2 are associated with worsened cardiovascular disease outcomes, a mechanism attributed to a disintegrin and metalloproteinase (ADAM17). SARS-CoV-2 infection also leads to ADAM17 activation, a positive feedback cycle that exacerbates ACE2 loss. Therefore, the relationship between cardiovascular disease and COVID-19 is critically dependent on the loss of membrane ACE2 by ADAM17-mediated proteolytic cleavage. This article explores potential mechanisms involved in COVID-19 that may contribute to sex-specific susceptibility focusing on the innate immune system and the RAS, namely, genetics and sex hormones. Finally, we highlight here the added challenges of gender in the COVID-19 pandemic.


Subject(s)
Adaptive Immunity/immunology , Androgens/immunology , Angiotensin-Converting Enzyme 2/genetics , COVID-19/immunology , Estrogens/immunology , Immunity, Innate/immunology , Receptors, Coronavirus/genetics , ADAM17 Protein/metabolism , Adaptive Immunity/genetics , Androgens/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , COVID-19/metabolism , COVID-19/mortality , Cardiovascular Diseases/genetics , Cardiovascular Diseases/immunology , Estrogens/metabolism , Female , Genes, X-Linked/genetics , Genes, X-Linked/immunology , Humans , Immunity, Innate/genetics , Male , Promoter Regions, Genetic , Receptors, Coronavirus/metabolism , Renin-Angiotensin System/genetics , Renin-Angiotensin System/immunology , Response Elements/genetics , SARS-CoV-2/metabolism , Severity of Illness Index , Sex Characteristics , Sex Factors , X Chromosome Inactivation
17.
Immunol Cell Biol ; 99(2): 177-191, 2021 02.
Article in English | MEDLINE | ID: covidwho-894767

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a zoonosis like most of the great plagues sculpting human history, from smallpox to pandemic influenza and human immunodeficiency virus. When viruses jump into a new species the outcome of infection ranges from asymptomatic to lethal, historically ascribed to "genetic resistance to viral disease." People have exploited these differences for good and bad, for developing vaccines from cowpox and horsepox virus, controlling rabbit plagues with myxoma virus and introducing smallpox during colonization of America and Australia. Differences in resistance to viral disease are at the core of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) crisis, yet our understanding of the mechanisms in any interspecies leap falls short of the mark. Here I review how the two key parameters of viral disease are countered by fundamentally different genetic mechanisms for resistance: (1) virus transmission, countered primarily by activation of innate and adaptive immune responses; and (2) pathology, countered primarily by tolerance checkpoints to limit innate and adaptive immune responses. I discuss tolerance thresholds and the role of CD8 T cells to limit pathological immune responses, the problems posed by tolerant superspreaders and the signature coronavirus evasion strategy of eliciting only short-lived neutralizing antibody responses. Pinpointing and targeting the mechanisms responsible for varying pathology and short-lived antibody were beyond reach in previous zoonoses, but this time we are armed with genomic technologies and more knowledge of immune checkpoint genes. These known unknowns must now be tackled to solve the current COVID-19 crisis and the inevitable zoonoses to follow.


Subject(s)
COVID-19 , Immune Tolerance/immunology , Immunity, Innate/genetics , SARS-CoV-2/immunology , Virus Diseases/immunology , Adaptive Immunity/genetics , Adaptive Immunity/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/physiology , Antibodies, Viral/immunology , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Humans , Immune Tolerance/genetics , Rabbits , SARS-CoV-2/genetics , Viral Zoonoses/genetics , Viral Zoonoses/immunology , Virus Diseases/genetics
18.
Front Immunol ; 11: 2147, 2020.
Article in English | MEDLINE | ID: covidwho-776207

ABSTRACT

The novel severe acute respiratory syndrome coronavirus 2, the cause of the coronavirus disease 2019 (COVID-19) pandemic, has ravaged the world, with over 22 million total cases and over 770,000 deaths worldwide as of August 18, 2020. While the elderly are most severely affected, implicating an age bias, a striking factor in the demographics of this deadly disease is the gender bias, with higher numbers of cases, greater disease severity, and higher death rates among men than women across the lifespan. While pre-existing comorbidities and social, behavioral, and lifestyle factors contribute to this bias, biological factors underlying the host immune response may be crucial contributors. Women mount stronger immune responses to infections and vaccinations and outlive men. Sex-based biological factors underlying the immune response are therefore important determinants of susceptibility to infections, disease outcomes, and mortality. Despite this, gender is a profoundly understudied and often overlooked variable in research related to the immune response and infectious diseases, and it is largely ignored in drug and vaccine clinical trials. Understanding these factors will not only help better understand the pathogenesis of COVID-19, but it will also guide the design of effective therapies and vaccine strategies for gender-based personalized medicine. This review focuses on sex-based differences in genes, sex hormones, and the microbiome underlying the host immune response and their relevance to infections with a focus on coronaviruses.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Host-Pathogen Interactions/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , Adaptive Immunity/genetics , COVID-19 , Coronavirus Infections/virology , Female , Genetic Predisposition to Disease , Gonadal Steroid Hormones/immunology , Host-Pathogen Interactions/genetics , Humans , Immunity, Innate/genetics , Male , Microbiota/immunology , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2 , Sex Factors
19.
Physiol Genomics ; 52(9): 401-407, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-772149

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic, infecting over 16 million people worldwide with a significant mortality rate. However, there is no current Food and Drug Administration-approved drug that treats coronavirus disease 2019 (COVID-19). Damage to T lymphocytes along with the cytokine storm are important factors that lead to exacerbation of clinical cases. Here, we are proposing intravenous oxytocin (OXT) as a candidate for adjunctive therapy for COVID-19. OXT has anti-inflammatory and proimmune adaptive functions. Using the Library of Integrated Network-Based Cellular Signatures (LINCS), we used the transcriptomic signature for carbetocin, an OXT agonist, and compared it to gene knockdown signatures of inflammatory (such as interleukin IL-1ß and IL-6) and proimmune markers (including T cell and macrophage cell markers like CD40 and ARG1). We found that carbetocin's transcriptomic signature has a pattern of concordance with inflammation and immune marker knockdown signatures that are consistent with reduction of inflammation and promotion and sustaining of immune response. This suggests that carbetocin may have potent effects in modulating inflammation, attenuating T cell inhibition, and enhancing T cell activation. Our results also suggest that carbetocin is more effective at inducing immune cell responses than either lopinavir or hydroxychloroquine, both of which have been explored for the treatment of COVID-19.


Subject(s)
Adaptive Immunity/drug effects , Anti-Inflammatory Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Gene Expression Profiling , Oxytocin/analogs & derivatives , Pneumonia, Viral/drug therapy , T-Lymphocytes/drug effects , Adaptive Immunity/genetics , Betacoronavirus/immunology , COVID-19 , Cell Line , Coronavirus Infections/genetics , Coronavirus Infections/immunology , Coronavirus Infections/virology , Databases, Genetic , Host-Pathogen Interactions , Humans , Oxytocin/pharmacology , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2 , T-Lymphocytes/immunology , T-Lymphocytes/virology , Transcriptome
20.
J Autoimmun ; 114: 102506, 2020 11.
Article in English | MEDLINE | ID: covidwho-599328

ABSTRACT

Coronavirus disease 2019 (COVID-19) has been categorized as evolving in overlapping phases. First, there is a viral phase that may well be asymptomatic or mild in the majority, perhaps 80% of patients. The pathophysiological mechanisms resulting in minimal disease in this initial phase are not well known. In the remaining 20% of cases, the disease may become severe and/or critical. In most patients of this latter group, there is a phase characterized by the hyperresponsiveness of the immune system. A third phase corresponds to a state of hypercoagulability. Finally, in the fourth stage organ injury and failure occur. Appearance of autoinflammatory/autoimmune phenomena in patients with COVID-19 calls attention for the development of new strategies for the management of life-threatening conditions in critically ill patients. Antiphospholipid syndrome, autoimmune cytopenia, Guillain-Barré syndrome and Kawasaki disease have each been reported in patients with COVID-19. Here we present a scoping review of the relevant immunological findings in COVID-19 as well as the current reports about autoinflammatory/autoimmune conditions associated with the disease. These observations have crucial therapeutic implications since immunomodulatory drugs are at present the most likely best candidates for COVID-19 therapy. Clinicians should be aware of these conditions in patients with COVID-19, and these observations should be considered in the current development of vaccines.


Subject(s)
Autoimmune Diseases/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Pneumonia, Viral/immunology , Adaptive Immunity/genetics , Autoimmune Diseases/diagnosis , Autoimmune Diseases/therapy , Autoimmune Diseases/virology , Betacoronavirus/isolation & purification , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Critical Illness , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/therapy , Cytokine Release Syndrome/virology , Female , Genetic Predisposition to Disease , Humans , Immunity, Innate/genetics , Immunization, Passive/methods , Inflammation Mediators/blood , Inflammation Mediators/immunology , Macrophage Activation/genetics , Macrophage Activation/immunology , Male , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , Risk Factors , SARS-CoV-2 , Severity of Illness Index , Sex Factors
SELECTION OF CITATIONS
SEARCH DETAIL