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1.
Curr Opin Immunol ; 72: 126-134, 2021 10.
Article in English | MEDLINE | ID: covidwho-1606183

ABSTRACT

Membrane cofactor protein (MCP; CD46), a ubiquitously expressed complement regulatory protein, serves as a cofactor for serine protease factor I to cleave and inactivate C3b and C4b deposited on host cells. However, CD46 also plays roles in human reproduction, autophagy, modulating T cell activation and effector functions and is a member of the newly identified intracellular complement system (complosome). CD46 also is a receptor for 11 pathogens ('pathogen magnet'). While CD46 deficiencies contribute to inflammatory disorders, its overexpression in cancers and role as a receptor for some adenoviruses has led to its targeting by oncolytic agents and adenoviral-based therapeutic vectors, including coronavirus disease of 2019 (COVID-19) vaccines. This review focuses on recent advances in identifying disease-causing CD46 variants and its pathogen connections.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Membrane Cofactor Protein/metabolism , SARS-CoV-2/physiology , T-Lymphocytes/immunology , Animals , Autophagy , Complement Activation , Host-Pathogen Interactions , Humans , Lymphocyte Activation , Membrane Cofactor Protein/genetics , Oncolytic Virotherapy , Polymorphism, Genetic , Reproduction
2.
In Vivo ; 36(1): 13-29, 2022.
Article in English | MEDLINE | ID: covidwho-1593602

ABSTRACT

Chronic and acute respiratory diseases pose a major problem for public health worldwide due to the high morbidity and mortality rates, while treatment options remain mostly symptomatic. The renin-angiotensin system (RAS) plays an important role in lung tissue, regulating pulmonary circulation and blood pressure, but also contributing to normal pulmonary function and development. Angiotensin-converting enzyme (ACE) and its homologous angiotensin-converting enzyme 2 (ACE2) are considered to be amongst the main RAS regulators and are highly expressed in the pulmonary vascular endothelium. This review discusses the impact of ACE and ACE2 functional gene polymorphisms on seven major pulmonary diseases, in terms of predisposition, course, and outcome, revealing their potential utility as both genetic markers and biomarkers. The discussed conditions include chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), asthma, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), lung cancer and pulmonary sarcoidosis (PS), as well as SARS-CoV-2 viral infection and COVID-19 disease.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Peptidyl-Dipeptidase A , Humans , Peptidyl-Dipeptidase A/genetics , Polymorphism, Genetic , Renin-Angiotensin System/genetics , SARS-CoV-2
3.
Exp Biol Med (Maywood) ; 246(21): 2332-2337, 2021 11.
Article in English | MEDLINE | ID: covidwho-1507096

ABSTRACT

The coronavirus disease COVID-19 has been the cause of millions of deaths worldwide. Among the SARS-CoV-2 proteins, the non-structural protein 1 (NSP1) has great importance during the virus infection process and is present in both alpha and beta-CoVs. Therefore, monitoring of NSP1 polymorphisms is crucial in order to understand their role during infection and virus-induced pathogenicity. Herein, we analyzed how mutations detected in the circulating SARS-CoV-2 in the population of the city of Manaus, Amazonas state, Brazil could modify the tertiary structure of the NSP1 protein. Three mutations were detected in the SARS-CoV-2 NSP1 gene: deletion of the amino acids KSF from positions 141 to 143 (delKSF), SARS-CoV-2, lineage B.1.195; and two substitutions, R29H and R43C, SARS-CoV-2 lineage B.1.1.28 and B.1.1.33, respectively. The delKSF was found in 47 samples, whereas R29H and R43C were found in two samples, one for each mutation. The NSP1 structures carrying the mutations R43C and R29H on the N-terminal portion (e.g. residues 10 to 127) showed minor backbone divergence compared to the Wuhan model. However, the NSP1 C-terminal region (residues 145 to 180) was severely affected in the delKSF and R29H mutants. The intermediate variable region (residues 144 to 148) leads to changes in the C-terminal region, particularly in the delKSF structure. New investigations must be carried out to analyze how these changes affect NSP1 activity during the infection. Our results reinforce the need for continuous genomic surveillance of SARS-CoV-2 to better understand virus evolution and assess the potential impact of the viral mutations on the approved vaccines and future therapies.


Subject(s)
COVID-19/epidemiology , SARS-CoV-2/genetics , Viral Nonstructural Proteins/genetics , Amino Acid Sequence/genetics , Amino Acid Substitution/genetics , Brazil/epidemiology , Humans , Polymorphism, Genetic/genetics , Sequence Deletion/genetics
4.
Front Cell Infect Microbiol ; 11: 753721, 2021.
Article in English | MEDLINE | ID: covidwho-1505764

ABSTRACT

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has currently spread worldwide, leading to high morbidity and mortality. As the putative receptor of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) is widely distributed in various tissues and organs of the human body. Simultaneously, ACE2 acts as the physiological counterbalance of ACE providing homeostatic regulation of circulating angiotensin II levels. Given that some ACE2 variants are known to cause an increase in the ligand-receptor affinity, their roles in acquisition, progression and severity of COVID-19 disease have aroused widespread concerns. Therefore, we summarized the latest literature and explored how ACE2 variants and epigenetic factors influence an individual's susceptibility to SARS-CoV-2 infection and disease outcome in aspects of ethnicity, gender and age. Meanwhile, the possible mechanisms for these phenomena were discussed. Notably, recombinant human ACE2 and ACE2-derived peptides may have special benefits for combating SARS-CoV-2 variants and further studies are warranted to confirm their effects in later stages of the disease process. As the uncertainty regarding the severity and transmissibility of disease rises, a more in-depth understanding of the host genetics and functional characteristics of ACE2 variants will not only help explain individual clinical differences of the disease, but also contribute to providing effective measures to develop solutions and manage future outbreaks of SARS-CoV-2.


Subject(s)
COVID-19 , Angiotensin-Converting Enzyme 2 , Humans , Polymorphism, Genetic , SARS-CoV-2
5.
Sci Rep ; 11(1): 20837, 2021 10 21.
Article in English | MEDLINE | ID: covidwho-1479820

ABSTRACT

Vitamin D is a fundamental regulator of host defences by activating genes related to innate and adaptive immunity. Previous research shows a correlation between the levels of vitamin D in patients infected with SARS-CoV-2 and the degree of disease severity. This work investigates the impact of the genetic background related to vitamin D pathways on COVID-19 severity. For the first time, the Portuguese population was characterized regarding the prevalence of high impact variants in genes associated with the vitamin D pathways. This study enrolled 517 patients admitted to two tertiary Portuguese hospitals. The serum concentration of 25 (OH)D, was measured in the hospital at the time of patient admission. Genetic variants, 18 variants, in the genes AMDHD1, CYP2R1, CYP24A1, DHCR7, GC, SEC23A, and VDR were analysed. The results show that polymorphisms in the vitamin D binding protein encoded by the GC gene are related to the infection severity (p = 0.005). There is an association between vitamin D polygenic risk score and the serum concentration of 25 (OH)D (p = 0.04). There is an association between 25 (OH)D levels and the survival and fatal outcomes (p = 1.5e-4). The Portuguese population has a higher prevalence of the DHCR7 RS12785878 variant when compared with its prevalence in the European population (19% versus 10%). This study shows a genetic susceptibility for vitamin D deficiency that might explain higher severity degrees in COVID-19 patients. These results reinforce the relevance of personalized strategies in the context of viral diseases.Trial registration: NCT04370808.


Subject(s)
COVID-19/blood , COVID-19/diagnosis , Polymorphism, Genetic , Vitamin D Deficiency/blood , Vitamin D/analogs & derivatives , Vitamin D/blood , Vitamin D/genetics , Aged , Biomarkers , Cholestanetriol 26-Monooxygenase/genetics , Cytochrome P450 Family 2/genetics , Female , Genetic Predisposition to Disease , Hospitalization , Humans , Male , Middle Aged , Oxidoreductases Acting on CH-CH Group Donors/genetics , Portugal/epidemiology , Prevalence , Severity of Illness Index , Vesicular Transport Proteins/genetics , Vitamin D-Binding Protein/genetics , Vitamin D3 24-Hydroxylase/genetics
6.
Cells ; 10(10)2021 10 18.
Article in English | MEDLINE | ID: covidwho-1477931

ABSTRACT

Several recent reports have highlighted the onset of vaccine-induced thrombotic thrombocytopaenia (VITT) in some recipients (approximately 1 case out of 100k exposures) of the ChAdOx1 nCoV-19 vaccine (AstraZeneca). Although the underlying events leading to this blood-clotting phenomenon has yet to be elucidated, several critical observations present a compelling potential mechanism. Thrombus formation requires the von Willebrand (VWF) protein to be in ultra-large multimeric state. The conservation of this state is controlled by the ADAMTS13 enzyme, whose proteolytic activity reduces the size of VWF multimers, keeping blood clotting at bay. However, ADAMTS13 cannot act on VWF that is bound to platelet factor 4 (PF4). As such, it is of particular interest to note that a common feature between subjects presenting with VITT is high titres of antibodies against PF4. This raises the possibility that these antibodies preserve the stability of ultra-large VWF complexes, leading to the formation of endothelium-anchored VWF strings, which are capable of recruiting circulating platelets and causing uncontrolled thrombosis in terminal capillaries. Here, we share our viewpoint about the current understanding of the VITT pathogenesis involving the prevention of ADAMTS13's activity on VWF by PF4 antibody-mediated stabilisation/ protection of the PF4-VWF complex.


Subject(s)
ADAMTS13 Protein/metabolism , COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Thrombocytopenia/immunology , Antibodies , Autoantibodies/immunology , Blood Platelets/metabolism , Crystallography, X-Ray , Endothelial Cells/immunology , Humans , Platelet Factor 4/metabolism , Polymorphism, Genetic , Protein Domains , Thrombocytopenia/etiology , Thrombosis/etiology , von Willebrand Factor/metabolism
8.
Genes (Basel) ; 12(10)2021 10 01.
Article in English | MEDLINE | ID: covidwho-1444159

ABSTRACT

The renin-angiotensin-aldosterone system (RAAS) appears to play an important role in SARS-CoV-2 infection. Polymorphisms within the genes that control this enzymatic system are candidates for elucidating the pathogenesis of COVID-19, since COVID-19 is not only a pulmonary disease but also affects many organs and systems throughout the body in multiple ways. Most striking is the fact that ACE2, one of the major components of the RAAS, is a prerequisite for SARS-COV-2 infection. Recently, we and other groups reported an association between a polymorphism of the ACE1 gene (a homolog of ACE2) and the phenotypic expression of COVID-19, particularly in its severity. The ethnic difference in ACE1 insertion (I)/deletion (D) polymorphism seems to explain the apparent difference in mortality between the West and East Asia. The purpose of this review was to further evaluate the evidence linking ACE1 polymorphisms to COVID-19. We searched the Medline database (2019-2021) for reference citations of relevant articles and selected studies on the clinical outcome of COVID-19 related to ACE1 I/D polymorphism. Although the numbers of patients are not large enough yet, most available evidence supports the notion that the DD genotype adversely influences COVID-19 symptoms. Surprisingly, small studies conducted in several countries yielded opposite results, suggesting that the ACE1 II genotype is a risk factor. This contradictory result may be the case in certain geographic areas, especially in subgroups of patients. It may also be due to interactions with other genes or to yet unexplained biochemical mechanisms. According to our hypothesis, such candidates are genes that are functionally involved in the pathophysiology of COVID-19, can act in concert with the ACE1 DD genotype, and that show differences in their frequency between the West and East Asia. For this, we conducted research focusing on Alu-related genes. The current study on the ACE1 genotype will provide potentially new clues to the pathogenesis, treatment, and diagnosis of SARS-CoV-2 infections.


Subject(s)
COVID-19 , Gene Expression Regulation, Viral , Genotype , INDEL Mutation , Peptidyl-Dipeptidase A , Polymorphism, Genetic , SARS-CoV-2/metabolism , COVID-19/genetics , COVID-19/metabolism , Humans , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Risk Factors
9.
Virus Res ; 305: 198551, 2021 11.
Article in English | MEDLINE | ID: covidwho-1440397

ABSTRACT

Samples from complete genomes of SARS-CoV-2 isolated during the first wave (December 2019-July 2020) of the global COVID-19 pandemic from 21 countries (Asia, Europe, Middle East and America) around the world, were analyzed using the phylogenetic method with molecular clock dating. Results showed that the first cases of COVID-19 in the human population appeared in the period between July and November 2019 in China. The spread of the virus into other countries of the world began in the autumn of 2019. In mid-February 2020, the virus appeared in all the countries we analyzed. During this time, the global population of SARS-CoV-2 was characterized by low levels of the genetic polymorphism, making it difficult to accurately assess the pathways of infection. The rate of evolution of the coding region of the SARS-CoV-2 genome equal to 7.3 × 10-4 (5.95 × 10-4-8.68 × 10-4) nucleotide substitutions per site per year is comparable to those of other human RNA viruses (Measles morbillivirus, Rubella virus, Enterovirus C). SARS-CoV-2 was separated from its known close relative, the bat coronavirus RaTG13 of the genus Betacoronavirus, approximately 15-43 years ago (the end of the 20th century).


Subject(s)
COVID-19/epidemiology , Evolution, Molecular , Genome, Viral , Mutation Rate , SARS-CoV-2/genetics , Animals , Asia/epidemiology , COVID-19/history , COVID-19/transmission , COVID-19/virology , Chiroptera/virology , Europe/epidemiology , Genomics/methods , History, 20th Century , History, 21st Century , Humans , Middle East/epidemiology , North America/epidemiology , Phylogeny , Polymorphism, Genetic , SARS-CoV-2/classification , SARS-CoV-2/pathogenicity , South America/epidemiology
10.
BMC Genomics ; 22(1): 662, 2021 Sep 14.
Article in English | MEDLINE | ID: covidwho-1430394

ABSTRACT

BACKGROUND: Deer mice (genus Peromyscus) are the most common rodents in North America. Despite the availability of reference genomes for some species, a comprehensive database of polymorphisms, especially in those maintained as living stocks and distributed to academic investigators, is missing. In the present study we surveyed two populations of P. maniculatus that are maintained at the Peromyscus Genetic Stock Center (PGSC) for polymorphisms across their 2.5 × 109 bp genome. RESULTS: High density of variation was identified, corresponding to one SNP every 55 bp for the high altitude stock (SM2) or 207 bp for the low altitude stock (BW) using snpEff (v4.3). Indels were detected every 1157 bp for BW or 311 bp for SM2. The average Watterson estimator for the BW and SM2 populations is 248813.70388 and 869071.7671 respectively. Some differences in the distribution of missense, nonsense and silent mutations were identified between the stocks, as well as polymorphisms in genes associated with inflammation (NFATC2), hypoxia (HIF1a) and cholesterol metabolism (INSIG1) and may possess value in modeling pathology. CONCLUSIONS: This genomic resource, in combination with the availability of P. maniculatus from the PGSC, is expected to promote genetic and genomic studies with this animal model.


Subject(s)
Altitude , Peromyscus , Animals , Genomics , Models, Animal , Peromyscus/genetics , Polymorphism, Genetic
11.
J Renin Angiotensin Aldosterone Syst ; 2021: 5509280, 2021.
Article in English | MEDLINE | ID: covidwho-1430254

ABSTRACT

Introduction: The coronavirus disease 2019 (COVID-19), that is caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), has spread rapidly worldwide since December 2019. The SARS-CoV-2 virus has a great affinity for the angiotensin-converting enzyme-2 (ACE-2) receptor, which is an essential element of the renin-angiotensin system (RAS). This study is aimed at assessing the impact of the angiotensin-converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphisms, on the susceptibility and clinical outcomes of the COVID-19 immunoinflammatory syndrome. Patients and Methods. A total of 112 patients diagnosed with COVID-19 between 1 and 15 May 2020 were enrolled in the study. ACE gene allele frequencies were compared to the previously reported Turkish population comprised of 300 people. Results: The most common genotype in the patients and control group was DI with 53% and II with 42%, respectively. The difference in the presence of the D allele between the patient and control groups was statistically significant (67% vs. 42%, respectively, p < 0.0001). Severe pneumonia was observed more in patients with DI allele (31%) than DD (8%) and II (0%) (p = 0.021). The mortality rate, time to defervescence, and the hospitalization duration were not different between the genotype groups. Conclusion: Genotype DI of ACE I/D polymorphism is associated with the infectious rate particularly severe pneumonia in this study conducted in the Turkish population. Therefore, ACE D/I polymorphism could affect the clinical course of COVID-19.


Subject(s)
COVID-19/genetics , Peptidyl-Dipeptidase A/genetics , Adult , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Gene Frequency , Genetic Association Studies , Humans , INDEL Mutation , Male , Middle Aged , Polymorphism, Genetic , Renin-Angiotensin System , Young Adult
12.
Arch Virol ; 166(11): 3117-3126, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1404655

ABSTRACT

Evidence supports a role of host genetic diversity in the clinical course of coronavirus disease 2019 (COVID-19). Variation in the cannabinoid CB2 receptor gene (CNR2) could affect the regulatory action of endocannabinoids on the immune system, resulting in an increased risk of various inflammatory diseases. The present study investigated the relationship between the CNR2-Q63R variant and COVID-19 severity. A total of 200 Iranian COVID-19 patients were enrolled in the study and genotyped using a TaqMan assay. The co-dominant, dominant, recessive, over-dominant, and additive inheritance models were analyzed using SNPStats software. In silico molecular docking was also performed to simulate the effects of the Q63R variation on CB2 binding with a ligand and with the G-protein. A significant difference in the Q63R allele and genotype distribution was found between expired and discharged COVID-19 patients in co-dominant, recessive, and additive inheritance models. The molecular docking results showed that the predicted structure of mutant CB2 (63R type) could not bind to the G-protein in the correct position. The data indicated that the Q63R variation in the CNR2 gene may affect the severity of COVID-19. Identification of genes related to susceptibility and severity of COVID-19 may lead to specific targets for drug repurposing or development.


Subject(s)
COVID-19/genetics , Genetic Predisposition to Disease/genetics , Receptor, Cannabinoid, CB2/genetics , COVID-19/diagnosis , Case-Control Studies , Female , GTP-Binding Proteins/metabolism , Gene Frequency , Genotype , Humans , Iran , Male , Middle Aged , Models, Molecular , Molecular Docking Simulation , Polymorphism, Genetic , Protein Binding , Receptor, Cannabinoid, CB2/chemistry , Receptor, Cannabinoid, CB2/metabolism , SARS-CoV-2 , Severity of Illness Index
14.
PLoS Genet ; 16(12): e1009272, 2020 12.
Article in English | MEDLINE | ID: covidwho-1388879

ABSTRACT

The Betacoronaviruses comprise multiple subgenera whose members have been implicated in human disease. As with SARS, MERS and now SARS-CoV-2, the origin and emergence of new variants are often attributed to events of recombination that alter host tropism or disease severity. In most cases, recombination has been detected by searches for excessively similar genomic regions in divergent strains; however, such analyses are complicated by the high mutation rates of RNA viruses, which can produce sequence similarities in distant strains by convergent mutations. By applying a genome-wide approach that examines the source of individual polymorphisms and that can be tested against null models in which recombination is absent and homoplasies can arise only by convergent mutations, we examine the extent and limits of recombination in Betacoronaviruses. We find that recombination accounts for nearly 40% of the polymorphisms circulating in populations and that gene exchange occurs almost exclusively among strains belonging to the same subgenus. Although experimental studies have shown that recombinational exchanges occur at random along the coronaviral genome, in nature, they are vastly overrepresented in regions controlling viral interaction with host cells.


Subject(s)
Betacoronavirus/classification , Betacoronavirus/genetics , Recombination, Genetic/genetics , Spike Glycoprotein, Coronavirus/genetics , Crossing Over, Genetic/genetics , Genes, Viral/genetics , Genome, Viral/genetics , Host Specificity/genetics , Models, Genetic , Polymorphism, Genetic , SARS-CoV-2/classification , SARS-CoV-2/genetics , Viral Tropism/genetics
15.
Infect Genet Evol ; 95: 105043, 2021 11.
Article in English | MEDLINE | ID: covidwho-1364361

ABSTRACT

Coronavirus 2019 (COVID-19) is a viral disease caused by severe acute respiratory syndrome coronavirus-2 (SARS CoV-2). The disease resulted in global morbidity and mortality that led to considering as pandemic. The human body response to COVID-19 infection was massively different from being asymptomatic to developing severe symptoms. Host genetic factors are thought to be one of the reasons for these disparities in body responses. Few studies have suggested that Apolipoprotein Epsilon (Apo E) is a candidate gene for playing roles in the development of the disease symptoms. This work aims to find an association between different Apo E genotypes and alleles to COVID-19 infection comparing a general population and a group of COVID-19 patients. For the first time, the results found that Apo E4 is associated with COVID-19 disease in a Kurdish population of Iraq. Further study is required to reveal this association in different ethnic backgrounds all over the world.


Subject(s)
Apolipoprotein E4/genetics , COVID-19/epidemiology , Genetic Predisposition to Disease , Polymorphism, Genetic , SARS-CoV-2/pathogenicity , Adult , Aged , Alleles , Apolipoprotein E4/immunology , Asymptomatic Diseases , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Cohort Studies , Female , Gene Expression , Gene Frequency , Humans , Iraq/epidemiology , Male , Middle Aged , SARS-CoV-2/growth & development , Severity of Illness Index
16.
J Med Virol ; 93(9): 5446-5451, 2021 09.
Article in English | MEDLINE | ID: covidwho-1363689

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a global health issue and develops into a broad range of illnesses from asymptomatic to fatal respiratory diseases. SARS-CoV-2 infection is associated with oxidative stress that triggers cytokine production, inflammation, and other pathophysiological processes. Glutathione-S-transferase (GST) is an important enzyme that catalyzes the conjugation of glutathione (GSH) with electrophiles to protect the cell from oxidative damage and participates in the antioxidant defense mechanism in the lungs. Thus, in this study, we investigated the role of GSTM1 and GSTT1 gene polymorphism with COVID-19 susceptibility, as well as its outcome. The study included 269 RT-PCR confirmed COVID-19 patients with mild (n = 149) and severe (n = 120) conditions. All subjects were genotyped for GSTM1 and GSTT1 by multiplex polymerase chain reaction (mPCR) followed by statistical analysis. The frequency of GSTM1-/- , GSTT1-/- and GSTM1-/- /GSTT1-/- was higher in severe COVID-19 patients as compared to mild patients but we did not observe a significant association. In the Cox hazard model, death was significantly 2.28-fold higher in patients with the GSTT1-/- genotype (p = 0.047). In combination, patients having GSTM1+/+ and GSTT1-/- genotypes showed a poor survival rate (p = 0.02). Our results suggested that COVID-19 patients with the GSTT1-/- genotype showed higher mortality.


Subject(s)
COVID-19/genetics , Genetic Predisposition to Disease , Glutathione Transferase/genetics , Polymorphism, Genetic , SARS-CoV-2/pathogenicity , Adult , Aged , Alleles , COVID-19/mortality , COVID-19/pathology , COVID-19/virology , COVID-19 Nucleic Acid Testing , Female , Follow-Up Studies , Gene Expression , Gene Frequency , Glutathione/metabolism , Humans , Male , Middle Aged , Oxidative Stress , Proportional Hazards Models , Severity of Illness Index
17.
Front Immunol ; 12: 669357, 2021.
Article in English | MEDLINE | ID: covidwho-1344263

ABSTRACT

Development of adaptive immunity after COVID-19 and after vaccination against SARS-CoV-2 is predicated on recognition of viral peptides, presented on HLA class II molecules, by CD4+ T-cells. We capitalised on extensive high-resolution HLA data on twenty five human race/ethnic populations to investigate the role of HLA polymorphism on SARS-CoV-2 immunogenicity at the population and individual level. Within populations, we identify wide inter-individual variability in predicted peptide presentation from structural, non-structural and accessory SARS-CoV-2 proteins, according to individual HLA genotype. However, we find similar potential for anti-SARS-CoV-2 cellular immunity at the population level suggesting that HLA polymorphism is unlikely to account for observed disparities in clinical outcomes after COVID-19 among different race/ethnic groups. Our findings provide important insight on the potential role of HLA polymorphism on development of protective immunity after SARS-CoV-2 infection and after vaccination and a firm basis for further experimental studies in this field.


Subject(s)
COVID-19/immunology , Histocompatibility Antigens Class II/genetics , Immunity, Cellular , SARS-CoV-2/immunology , Antigen Presentation , CD4-Positive T-Lymphocytes/immunology , COVID-19/genetics , Genotype , Histocompatibility Antigens Class II/immunology , Humans , Peptides/immunology , Polymorphism, Genetic , Proteome/immunology , Viral Proteins/immunology
18.
HLA ; 98(4): 370-379, 2021 10.
Article in English | MEDLINE | ID: covidwho-1334517

ABSTRACT

The experience of individuals with Coronavirus Disease 2019 (COVID-19) ranges from asymptomatic to life threatening multi-organ dysfunction. Specific HLA alleles may affect the predisposition to severe COVID-19 because of their role in presenting viral peptides to launch the adaptive immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this population-based case-control study in the midwestern United States, we performed high-resolution HLA typing of 234 cases hospitalized for COVID-19 in the St. Louis metropolitan area and compared their HLA allele frequencies with those of 22,000 matched controls from the National Marrow Donor Program (NMDP). We identified two predisposing alleles, HLA-DRB1*08:02 in the Hispanic group (OR = 9.0, 95% confidence interval: 2.2-37.9; adjusted p = 0.03) and HLA-A*30:02 in younger African Americans with ages below the median (OR = 2.2, 1.4-3.6; adjusted p = 0.01), and several candidate alleles with potential associations with COVID-19 in African American, White, and Hispanic groups. We also detected risk-associated amino acid residues in the peptide binding grooves of some of these alleles, suggesting the presence of functional associations. These findings support the notion that specific HLA alleles may be protective or predisposing factors to COVID-19. Future consortium analysis of pooled cases and controls is warranted to validate and extend these findings, and correlation with viral peptide binding studies will provide additional evidence for the functional association between HLA alleles and COVID-19.


Subject(s)
COVID-19 , HLA-A Antigens , HLA-DRB1 Chains , Alleles , Case-Control Studies , Gene Frequency , Genetic Predisposition to Disease , HLA-A Antigens/genetics , HLA-DRB1 Chains/genetics , Humans , Polymorphism, Genetic , SARS-CoV-2
19.
Front Immunol ; 12: 690416, 2021.
Article in English | MEDLINE | ID: covidwho-1317226

ABSTRACT

The AID (activation-induced cytidine deaminase)/APOBEC (apolipoprotein B mRNA editing enzyme catalytic subunit) family with its multifaceted mode of action emerges as potent intrinsic host antiviral system that acts against a variety of DNA and RNA viruses including coronaviruses. All family members are cytosine-to-uracil deaminases that either have a profound role in driving a strong and specific humoral immune response (AID) or restricting the virus itself by a plethora of mechanisms (APOBECs). In this article, we highlight some of the key aspects apparently linking the AID/APOBECs and SARS-CoV-2. Among those is our discovery that APOBEC4 shows high expression in cell types and anatomical parts targeted by SARS-CoV-2. Additional focus is given by us to the lymphoid structures and AID as the master regulator of germinal center reactions, which result in antibody production by plasma and memory B cells. We propose the dissection of the AID/APOBECs gene signature towards decisive determinants of the patient-specific and/or the patient group-specific antiviral response. Finally, the patient-specific mapping of the AID/APOBEC polymorphisms should be considered in the light of COVID-19.


Subject(s)
APOBEC-1 Deaminase/genetics , COVID-19/enzymology , COVID-19/immunology , Cytidine Deaminase/genetics , SARS-CoV-2/genetics , Transcriptome , Antibodies, Viral/immunology , B-Lymphocytes/immunology , COVID-19/virology , Germinal Center/immunology , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , Immunity, Humoral/genetics , Plasma Cells/immunology , Polymorphism, Genetic , RNA Editing/genetics , RNA, Viral/genetics
20.
PLoS One ; 16(7): e0254920, 2021.
Article in English | MEDLINE | ID: covidwho-1315894

ABSTRACT

BACKGROUND: We evaluated measures to protect healthcare workers (HCWs) in Vancouver, Canada, where variants of concern (VOC) went from <1% VOC in February 2021 to >92% in mid-May. Canada has amongst the longest periods between vaccine doses worldwide, despite Vancouver having the highest P.1 variant rate outside Brazil. METHODS: With surveillance data since the pandemic began, we tracked laboratory-confirmed SARS-CoV-2 infections, positivity rates, and vaccine uptake in all 25,558 HCWs in Vancouver Coastal Health, by occupation and subsector, and compared to the general population. Cox regression modelling adjusted for age and calendar-time calculated vaccine effectiveness (VE) against SARS-CoV-2 in fully vaccinated (≥ 7 days post-second dose), partially vaccinated infection (after 14 days) and unvaccinated HCWs; we also compared with unvaccinated community members of the same age-range. FINDINGS: Only 3.3% of our HCWs became infected, mirroring community rates, with peak positivity of 9.1%, compared to 11.8% in the community. As vaccine coverage increased, SARS-CoV-2 infections declined significantly in HCWs, despite a surge with predominantly VOC; unvaccinated HCWs had an infection rate of 1.3/10,000 person-days compared to 0.89 for HCWs post first dose, and 0.30 for fully vaccinated HCWs. VE compared to unvaccinated HCWs was 37.2% (95% CI: 16.6-52.7%) 14 days post-first dose, 79.2% (CI: 64.6-87.8%) 7 days post-second dose; one dose provided significant protection against infection until at least day 42. Compared with community infection rates, VE after one dose was 54.7% (CI: 44.8-62.9%); and 84.8% (CI: 75.2-90.7%) when fully vaccinated. INTERPRETATION: Rigorous droplet-contact precautions with N95s for aerosol-generating procedures are effective in preventing occupational infection in HCWs, with one dose of mRNA vaccination further reducing infection risk despite VOC and transmissibility concerns. Delaying second doses to allow more widespread vaccination against severe disease, with strict public health, occupational health and infection control measures, has been effective in protecting the healthcare workforce.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Health Personnel/statistics & numerical data , Infection Control/statistics & numerical data , Occupational Health/statistics & numerical data , SARS-CoV-2/genetics , Vaccination/statistics & numerical data , COVID-19/epidemiology , COVID-19/virology , Canada , Humans , Polymorphism, Genetic
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