Genetic variation in the human leukocyte antigen (HLA) region is thought to influence susceptibility to and severity of a variety of infectious diseases. Several studies have explored a possible relationship between HLA genetics and SARS-CoV-2 infection, although mixed results, small sample sizes, and difficulty controlling for exposure risk have made it difficult to draw firm conclusions. Here, a dataset of 419,234 subjects with HLA genotype data and COVID-19 PCR test results was studied. A baseline analysis was performed to examine the association of non-HLA factors on COVID-19 positivity. Then, multivariate logistic regressions, incorporating single and paired HLA alleles, were performed and then corrected for significant factors from the baseline analysis. Proxies for socioeconomic status and exposure risk were significantly associated with COVID-19 positivity across all ancestry groups studied. Forty-one single HLA alleles displayed significant association with COVID-19 positivity; after controlling for socioeconomic status and exposure risk, only eight significant associations remained. Additionally, two HLA allele pairs were associated with test positivity after correction. Of all variables, socioeconomic status showed the greatest effect size. The results from this study suggest that many, if not all, of the reported associations between HLA alleles and SARS-CoV-2 infection may be spurious, owing to confounding factors.

Understanding the relationships between proteins and specific disease phenotypes contributes to the early detection of diseases and advances the development of personalized medicine. The acquisition of a large amount of proteomics data has facilitated this process. To improve discovery efficiency and reduce the time and financial costs associated with biological experiments, various computational methods have yielded promising results. However, the lack of rich and reliable protein-related information still presents challenges in this process.

In this paper, we propose an ensemble prediction model, named HPOseq, which predicts human protein-phenotype relationships based only on sequence information. HPOseq establishes two base models to achieve objectives. One directly extracts internal information from amino acid sequences as protein features to predict the associated phenotypes. The other builds a protein-protein network based on sequence similarity, extracting information between proteins for phenotype prediction. Ultimately, an ensemble module is employed to integrate the predictions from both base models, resulting in the final prediction.

The results of 5-fold cross-validation reveal that HPOseq outperforms seven baseline methods for predicting protein-phenotype relationships. Moreover, we conduct case studies from the points of phenotype annotation and protein analysis to verify the practical significance of HPOseq.

The SARS-CoV-2 outbreak represents a global health problem. The different infection rates are heavily influenced by host genetic factors, such as variability in the HLA region. The aim of our study was to investigate whether certain HLA alleles in the Bulgarian population contribute to COVID-19 progression and their role in anti-SARS-CoV-2 immunity. We evaluated 76 patients diagnosed with COVID-19 and classified them according to severity as mild, moderate, and severe. Data from a population cohort (n = 539), representative of the Bulgarian population, was used for comparisons. We found that the HLA-DQB1*05:03 (OR = 3.13, pc = 0.0008) allele was significantly associated with COVID-19 severity. Several other class I and class II alleles showed a promising association with a predisposition to disease severity or a protective role in its progression. This is the first study to assess the association between HLA and COVID-19 progression in the Bulgarian population. Despite some limitations, our results suggest that certain HLA alleles play a role in the severity of SARS-CoV-2 infection and it would be interesting to further trace their effect in the context of long COVID.

COVID-19 remains a significant global health problem with uncertain long-term consequences for convalescents. We investigated the relationships between anti-N protein antibody levels, severe acute respiratory syndrome (SARS)-CoV-2-associated TCR repertoire parameters, HLA type and epidemiological information from three cohorts of 524 SARS-CoV-2-infected subjects subgrouped in acute phase, seronegative and seropositive convalescents from the Emilia Romagna region. Epidemiological information and anti-N antibody index were associated with TCR repertoire data. HLA type was inferred from TCR repertoire using the HLA3 tool and its association with clonal breadth (CB) and clonal depth (CD) was assessed. Age above 58 years, male and COVID-19 hospitalisation were significantly and independently associated with seropositivity (p = 0.004; p = 0.004; p = 0.04), suggesting an association between high antibody titres and symptoms' severity. As for the TCR repertoire analysis, we found no difference in CB among the cohorts, while CD was higher in seronegative than acute (p = 0.04). However, clustering analysis supported that seronegative patients are endowed with broader CB and deeper CD indicating a compensatory mechanism without effective seroconversion. The CD calculated on the TCRs associated with the single SARS-CoV-2 ORFs in convalescents is higher when compared to the acute. Lastly, we identified and reported on novel HLAs significantly associated with increased risk of hospitalisation such as HLA-C*07:02 carriers (OR = 3.9, CI = 1.1-13.4, p = 0.03) and on HLAs that associate significantly with lower or higher TCR repertoire parameters in a population exposed for the first time to SARS-CoV-2.

Background and Objectives: Severe COVID-19 still constitutes an important health problem. Taking into account the crucial role of HLA in immune reactions, evaluation of the impact of HLA on COVID-19 risk and clinical course seemed necessary, as the already available data are inconsistent. The aim of the present study was to compare the HLA profiles of patients with symptomatic SARS-CoV-2 infection and a healthy control group, as well as to compare HLA allele frequencies in patients with severe and non-severe courses of COVID-19. Materials and Methods: HLA classes were genotyped using a next-generation sequencing method in 2322 persons, including 2217 healthy hematopoietic stem cell potential donors and 105 patients with symptomatic COVID-19. Results: Symptomatic course of SARS-CoV-2 infection appeared to be associated with the presence of HLA-A*30:01, B*44:02, B*52:01, C*05:01, C*17:01, and DRB1*11:02, while HLA-C*07:04 and DQB1*03:03 seem to play a protective role. Moreover, we demonstrated that the severe symptomatic course of COVID-19 can be associated with the presence of HLA-B*08:01, C*04:01, DRB1*03:01, and DQB1*03:01, while HLA-DRB1*08:01 appeared to be protective against severe COVID-19 disease. Conclusions: Identification of alleles that are potentially associated with symptomatic SARS-CoV-2 infection as well as the severe course of COVID-19 broadens the knowledge on the genetic background of COVID-19 course and can constitute an important step in the development of personalized medicine.

Cytotoxic CD8+ T lymphocytes (CTLs) have been implicated in the severity of COVID-19. The TCR-pMHC ternary complex, formed by the T cell receptor (TCR) and peptide-MHC (major histocompatibility complex), constitutes the molecular basis of CTL responses against SARS-CoV-2. While numerous studies have been conducted on T cell immunity, the molecular mechanisms underlying CTL-mediated immunity against SARS-CoV-2 infection have not been well elaborated. In this review, we described the association between HLA variants and different immune responses to SARS-CoV-2 infection, which may lead to varying COVID-19 outcomes. We also summarized the specific TCR repertoires triggered by certain SARS-CoV-2 CTL epitopes, which might explain the variations in disease outcomes among different patients. Importantly, we have highlighted the primary strategies used by SARS-CoV-2 variants to evade T-cell killing: disrupting peptide-MHC binding, TCR recognition, and antigen processing. This review provides valuable insights into the molecule mechanism of CTL responses during SARS-CoV-2 infection, aiding efforts to control the pandemic and prepare for future challenges.

the human leukocyte antigen (HLA) loci have been widely characterized to be associated with viral infectious diseases. Several studies including various ethnic groups and populations suggested associations between certain HLA alleles and SARS-CoV-2 infection. Despite the numerous associations identified, the role of HLA polymorphisms in determining the individual response to SARS-CoV-2 infection is controversial among different Saudi populations.

Here, we performed HLA typing by next-generation sequencing to investigate if variations in polymorphic HLA genes are linked to COVID-19 severity in the Saudi population. Namely, we analyzed HLA loci at allele level in 575 Saudi patients with SARS-CoV-2 infection. HLA class I and class II frequencies in patients were compared with allele frequency data from healthy Saudi population.

in our cohort HLA-A* 02:01:01 G was associated with mild disease but was not associated with moderate and severe disease. HLA-B* 51:01:01 G was protective from severe disease while HLA-B* 50:01:01 G, HLA-C* 06:02:01 G and HLA-DRB1 * 07:01:01 G were associated with risk to severe disease as well as the total COVID-19 cohort. HLA-DRB1 * 15:01:01 G was associated with risk to all severity groups.

in conclusion, we found significant associations between HLA alleles and COVID-19 disease severity in Saudis. Further studies are warranted to include HLA typing in the workup for any new COVID-19 patients.

Natural infection or vaccination have provided robust immune defense against SARS-CoV-2 invasion, nevertheless, Omicron variants still successfully cause breakthrough infection, and the underlying mechanisms are poorly understood.

Sequential blood samples were continuously collected at different time points from 252 volunteers who were received the CanSino Ad5-nCoV (n= 183) vaccine or the Sinovac CoronaVac inactivated vaccine (n= 69). The anti-SARS-CoV-2 prototype and Omicron BA.5.2 as well as XBB.1.16 variant neutralizing antibodies (Nab) in sera were detected by ELISA. Sera were also used to measure pseudo and live virus neutralization assay. The associations between the anti-prototype Nab levels and different HLA-ABC alleles were analyzed using artificial intelligence (AI)-deep learning techniques. The frequency of B cells in PBMCs was investigated by flow cytometry assay (FACs).

Individuals carrying the HLA-B*15 allele manifested the highest concentrations of anti-SARS-CoV-2 prototype Nab after vax administration. Unfortunately, these volunteers are more susceptible to Omicron BA.5.2 breakthrough infection due to their sera have poorer anti-BA.5.2 Nab and lower levels of viral neutralization efficacy. FACs confirmed that a significant decrease in CD19+CD27+RBD+ memory B cells in these HLA-B*15 population compared to other cohorts. Importantly, generating lower concentrations of cross-reactive anti-XBB.1.16 Nab post-BA.5.2 infection caused HLA-B*15 individuals to be further infected by XBB.1.16 variant.

Individuals carrying the HLA-B*15 allele respond better to COVID-19 vax including the CanSino Ad5-nCoV and the Sinovac CoronaVac inactivated vaccines, but are more susceptible to Omicron variant infection, thus, a novel vaccine against this population is necessary for COVID-19 pandemic control in the future.

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), long COVID (LC) and post-COVID-19 vaccine syndrome show similarities in their pathophysiology and clinical manifestations. These disorders are related to viral or adjuvant persistence, immunological alterations, autoimmune diseases and hormonal imbalances. A developmental model is postulated that involves the interaction between immune hyperactivation, autoimmune hypophysitis or pituitary hypophysitis, and immune depletion. This process might begin with a deficient CD4 T-cell response to viral infections in genetically predisposed individuals (HLA-DRB1), followed by an uncontrolled immune response with CD8 T-cell hyperactivation and elevated antibody production, some of which may be directed against autoantigens, which can trigger autoimmune hypophysitis or direct damage to the pituitary, resulting in decreased production of pituitary hormones, such as ACTH. As the disease progresses, prolonged exposure to viral antigens can lead to exhaustion of the immune system, exacerbating symptoms and pathology. It is suggested that these disorders could be included in the autoimmune/adjuvant-induced inflammatory syndrome (ASIA) because of their similar clinical manifestations and possible relationship to genetic factors, such as polymorphisms in the HLA-DRB1 gene. In addition, it is proposed that treatment with antivirals, corticosteroids/ginseng, antioxidants, and metabolic precursors could improve symptoms by modulating the immune response, pituitary function, inflammation and oxidative stress. Therefore, the purpose of this review is to suggest a possible autoimmune origin against the adenohypophysis and a possible improvement of symptoms after treatment with corticosteroid replacement therapy.

Long-term immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires the identification of T-cell epitopes affecting host immunogenicity. In this computational study, we explored the CD8+ epitope diversity estimated in 27 of the most common HLA-A and HLA-B alleles, representing most of the United States population. Analysis of 16 SARS-CoV-2 variants [B.1, Alpha (B.1.1.7), five Delta (AY.100, AY.25, AY.3, AY.3.1, AY.44), and nine Omicron (BA.1, BA.1.1, BA.2, BA.4, BA.5, BQ.1, BQ.1.1, XBB.1, XBB.1.5)] in analyzed MHC class I alleles revealed that SARS-CoV-2 CD8+ epitope conservation was estimated at 87.6%-96.5% in spike (S), 92.5%-99.6% in membrane (M), and 94.6%-99% in nucleocapsid (N). As the virus mutated, an increasing proportion of S epitopes experienced reduced predicted binding affinity: 70% of Omicron BQ.1-XBB.1.5 S epitopes experienced decreased predicted binding, as compared with ~3% and ~15% in the earlier strains Delta AY.100-AY.44 and Omicron BA.1-BA.5, respectively. Additionally, we identified several novel candidate HLA alleles that may be more susceptible to severe disease, notably HLA-A*32:01, HLA-A*26:01, and HLA-B*53:01, and relatively protected from disease, such as HLA-A*31:01, HLA-B*40:01, HLA-B*44:03, and HLA-B*57:01. Our findings support the hypothesis that viral genetic variation affecting CD8 T-cell epitope immunogenicity contributes to determining the clinical severity of acute COVID-19. Achieving long-term COVID-19 immunity will require an understanding of the relationship between T cells, SARS-CoV-2 variants, and host MHC class I genetics. This project is one of the first to explore the SARS-CoV-2 CD8+ epitope diversity that putatively impacts much of the United States population.

The diversity of clinical manifestations in COVID-19 has been observed not only among individuals but also among various populations in globally. HLA molecules play a central role in physiology, protective immunity, and deleterious, disease-related autoimmune reactivity or overreaction. This study exploited the association between HLA frequencies and SARS-CoV-2 susceptibility and disease severity among the Vietnamese cohort (159 patients and 52 controls). A significant difference in frequency of both HLA class I and II in mild, moderate, and severe/fatal COVID-19 patients and negative exposure individuals - the controls were observed. Regarding SARS-CoV-2 sensitivity, HLA-A*03:01, 30:01, HLA-DQA1*01:02, DRB1*15:01, and DRB5*02:02 presented higher frequency in the control group compared with infected patients but DRB1 09:01 frequency was higher in infected patients. Regarding COVID-19 severity, HLA-F*01:01, 01:03 and DPA1*01:03 and 02:01, DPB1*04:01, DQA1*01:02, and DQB1*05:02 alleles were detected with higher frequency in severe patients but DOB*01:01, DRB1*05:01 and 09:01 had a significantly higher frequency in the mild group than remaining groups. Surprisingly, HLA-DQA1*01:02 and DRB1*09:01 alleles were identified with both inversely potential roles in protective function and severe risk. The obtained data herein will contribute to explore on the role of host genetic background in the pathology of COVID-19 disease.

The coronavirus disease 2019 (COVID-19) has left a devasting effect on various regions globally. Africa has exceptionally high rates of other infectious diseases, such as tuberculosis (TB), human immunodeficiency virus (HIV), and malaria, and was not impacted by COVID-19 to the extent of other continents Globally, COVID-19 has caused approximately 7 million deaths and 700 million infections thus far. COVID-19 disease severity and susceptibility vary among individuals and populations, which could be attributed to various factors, including the viral strain, host genetics, environment, lifespan, and co-existing conditions. Host genetics play a substantial part in COVID-19 disease severity among individuals. Human leukocyte antigen (HLA) was previously been shown to be very important across host immune responses against viruses. HLA has been a widely studied gene region for various disease associations that have been identified. HLA proteins present peptides to the cytotoxic lymphocytes, which causes an immune response to kill infected cells. The HLA molecule serves as the central region for infectious disease association; therefore, we expect HLA disease association with COVID-19. Therefore, in this narrative review, we look at the HLA gene region, particularly, HLA class I, to understand its role in COVID-19 disease.

Severe acute respiratory syndrome coronavirus 2 was first reported in December 2019 and it has spread globally ever since. The HLA system is crucial in directing anti-viral immunity and recent studies are investigating the possible involvement of the HLA genes on the severity of immune inflammation in different phases of COVID-19.

In this cross-sectional study, peripheral blood-extracted genomic DNAs of 109 COVID-19 patients and 70 healthy controls were genotyped for different alleles of HLA-A, HLA-B, and HLA-DRB1 loci using sequence-specific primer PCR method.

The results indicated that frequencies of HLA-DRB1*11:01 and HLA-DRB1*04:03 were significantly higher in severe patients rather than moderates (p: <0.001 and 0.004, respectively). Also, it was observed that HLA-DRB1*04:01 was more frequent in moderate patients and healthy controls (p:0.002). In addition, HLA-B*07:35, and HLA-DRB1*07:01 showed higher frequencies in patients compared with controls (p: 0.031 and 0.003 respectively). Inversely, due to the higher frequencies of HLA-B*51:01 (p:0.027), HLA-DRB1*11:05 (p:0.003), HLA-DRB1*13:05 (p:0.022), and HLA-DRB1*14:01 (p:0.006) in healthy individuals rather than patients, they may be associated with COVID-19 resistance.

The results show that, based on the population differences, the type of alleles related to the severity of COVID-19 is different, which should be clarified by designing large-scale studies in order to develop HLA-based treatments and vaccines.

In this study, we aimed to investigate whether specific HLA alleles found in patients from Romania and the Republic of Moldova were associated with the severity of COVID-19 infection and its associated mortality. We analyzed the HLA alleles at the -A, -B, -C, -DRB1, and -DQB1 loci in a cohort of 130 individuals with severe and extremely severe forms of COVID-19, including 44 individuals who died. We compared these findings to a control group consisting of individuals who had either not been diagnosed with COVID-19 or had experienced mild forms of the disease. Using multivariate logistic regression models, we discovered that the B*27 and B*50 alleles were associated with an increased susceptibility to developing a severe form of COVID-19. The A*33 and C*15 alleles showed potential for offering protection against the disease. Furthermore, we identified two protective alleles (A*03 and DQB1*02) against the development of extremely severe forms of COVID-19. By utilizing score statistics, we established a statistically significant association between haplotypes and disease severity (p = 0.021). In summary, this study provides evidence that HLA genotype plays a role in influencing the clinical outcome of COVID-19 infection.

Long Covid-19 syndrome (LCS) manifests with a wide range of clinical symptoms, yet the factors associated with LCS remain poorly understood. The current study aimed to investigate the relationships that demographic characteristics, clinical history, laboratory indicators, and the frequency of HLA-I alleles have with the likelihood of developing LCS. We extracted the demographic characteristics and clinical histories from the medical records of 88 LCS cases (LCS+ group) and 96 individuals without LCS (LCS- group). Furthermore, we evaluated the clinical symptoms, serum levels of interleukin (IL)-6 and tumor necrosis factor-α, laboratory parameters, and the frequencies of HLA-I alleles. Following this we used multiple logistic regression to investigate the association these variables had with LCS. Subjects in the LCS+ group were more likely to have experienced severe Covid-19 symptoms and had higher body mass index (BMI), white blood cell, lymphocyte counts, C-reactive protein (CRP), and IL-6 levels than those in the LCS- group (for all: P < 0.05). Moreover, the frequencies of the HLA-A*11, -B*14, -B*38, -B*50, and -C*07 alleles were higher in the LCS+ group (for all: P < 0.05). After adjusting for the most important variables, the likelihood of suffering from LCS was significantly associated with BMI, CRP, IL-6, the HLA-A*11, and -C*07 alleles, as well as a positive history of severe Covid-19 (for all: P < 0.05). Our study showed that a history of severe Covid-19 during the acute phase of the disease, the HLA-A*11, and -C*07 alleles, higher BMI, as well as elevated serum CRP and IL-6 levels, were all associated with an increased likelihood of LCS.

The COVID-19 pandemic has had a profound global impact, with variations in susceptibility, severity, and mortality rates across different regions. While many factors can contribute to the spread and impact of the disease, specifically human leukocyte antigen (HLA) genetic variants have emerged as potential contributors to COVID-19 outcomes.

In this comprehensive narrative review, we conducted a thorough literature search to identify relevant studies investigating the association between HLA genetic variants and COVID-19 outcomes. Additionally, we analyzed allelic frequency data from diverse populations to assess differences in COVID-19 incidence and severity.

Our review provides insights into the immunological mechanisms involving HLA-mediated responses to COVID-19 and highlights potential research directions and therapeutic interventions. We found evidence suggesting that certain HLA alleles, such as HLA-A02, may confer a lower risk of COVID-19, while others, like HLA-C04, may increase the risk of severe symptoms and mortality. Furthermore, our analysis of allele frequency distributions revealed significant variations among different populations.

Considering host genetic variations, particularly HLA genetic variants, is crucial for understanding COVID-19 susceptibility and severity. These findings have implications for personalized treatment and interventions based on an individual's genetic profile. However, further research is needed to unravel the precise mechanisms underlying the observed associations and explore the potential for targeted therapies or preventive measures based on HLA genetic variants.

Extreme polymorphism of HLA and killer-cell immunoglobulin-like receptors (KIR) differentiates immune responses across individuals. Additional to T cell receptor interactions, subsets of HLA class I act as ligands for inhibitory and activating KIR, allowing natural killer (NK) cells to detect and kill infected cells. We investigated the impact of HLA and KIR polymorphism on the severity of COVID-19. High resolution HLA class I and II and KIR genotypes were determined from 403 non-hospitalized and 1575 hospitalized SARS-CoV-2 infected patients from Italy collected in 2020. We observed that possession of the activating KIR2DS4*001 allotype is associated with severe disease, requiring hospitalization (OR = 1.48, 95% CI 1.20-1.85, pc  = 0.017), and this effect is greater in individuals homozygous for KIR2DS4*001 (OR = 3.74, 95% CI 1.75-9.29, pc  = 0.003). We also observed the HLA class II allotype, HLA-DPB1*13:01 protects SARS-CoV-2 infected patients from severe disease (OR = 0.49, 95% CI 0.33-0.74, pc  = 0.019). These association analyses were replicated using logistic regression with sex and age as covariates. Autoantibodies against IFN-α associated with COVID-19 severity were detected in 26% of 156 hospitalized patients tested. HLA-C*08:02 was more frequent in patients with IFN-α autoantibodies than those without, and KIR3DL1*01502 was only present in patients lacking IFN-α antibodies. These findings suggest that KIR and HLA polymorphism is integral in determining the clinical outcome following SARS-CoV-2 infection, by influencing the course both of innate and adaptive immunity.

Understanding how human leukocyte antigen (HLA) polymorphism affects both the susceptibility and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection will help to identify individuals at higher risk to better manage and prioritize vaccination at the clinical level and explain the differences in epidemic trends in different regions at the epidemiological level. This study compared the frequencies of HLA class I alleles (HLA-A, B) in 214 coronavirus disease 2019 (COVID-19) patients with different disease severity and 35 healthy controls and analyzed the correlations between specific HLA alleles and disease severity and T cell memory. The results showed no significant difference in HLA allele frequencies between COVID-19 patients and healthy controls (P > 0.05). The allele HLA-B*13:02 was significantly correlated with the disease severity of COVID-19 patients (P = 0.006). After adjustment for age and disease severity, the T cell responses of COVID-19 convalescents with the allele HLA-B*40:01 may be lower at six months (P = 0.044) and 12 months (P = 0.069). Moreover, these results may be due to their rare peptide anchors by analyzing the binding peptide motifs of these HLA alleles. The study may be valuable for investigating the potential association of specific HLA alleles with SARS-CoV-2 infection.

Replicating SARS-CoV-2 has been shown to degrade HLA class I on target cells to evade the cytotoxic T-cell (CTL) response. HLA-I downregulation can be sensed by NK cells to unleash killer cell immunoglobulin-like receptor (KIR)-mediated self-inhibition by the cognate HLA-I ligands. Here, we investigated the impact of HLA and KIR genotypes and HLA-KIR combinations on COVID-19 outcome. We found that the peptide affinities of HLA alleles were not correlated with COVID-19 severity. The predicted poor binders for SARS-CoV-2 peptides belong to HLA-B subtypes that encode KIR ligands, including Bw4 and C1 (introduced by B*46:01), which have a small F pocket and cannot accommodate SARS-CoV-2 CTL epitopes. However, HLA-Bw4 weak binders were beneficial for COVID-19 outcome, and individuals lacking the HLA-Bw4 motif were at higher risk for serious illness from COVID-19. The presence of the HLA-Bw4 and KIR3DL1 combination had a 58.8% lower risk of developing severe COVID-19 (OR = 0.412, 95% CI = 0.187-0.904, p = 0.02). This suggests that HLA-Bw4 alleles that impair their ability to load SARS-CoV-2 peptides will become targets for NK-mediated destruction. Thus, we proposed that the synergistic responsiveness of CTLs and NK cells can efficiently control SARS-CoV-2 infection and replication, and NK-cell-mediated anti-SARS-CoV-2 immune responses being mostly involved in severe infection when the level of ORF8 is high enough to degrade HLA-I. The HLA-Bw4/KIR3DL1 genotype may be particularly important for East Asians undergoing COVID-19 who are enriched in HLA-Bw4-inhibitory KIR interactions and carry a high frequency of HLA-Bw4 alleles that bind poorly to coronavirus peptides.

We present an integrated immunopeptidomics and proteomics study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to comprehensively decipher the changes in host cells in response to viral infection. Immunopeptidomics analysis identified viral antigens presented by host cells through both class I and class II MHC system for recognition by the adaptive immune system. The host proteome changes were characterized by quantitative proteomics and glycoproteomics and from these data, the activation of toll-like receptor 3-interferon pathway was identified. Glycosylation analysis of human leukocyte antigen (HLA) proteins from the elution and flow-through of immunoprecipitation revealed that SARS-CoV-2 infection changed the glycosylation pattern of certain HLA alleles with different HLA alleles, showing distinct dynamic changes in relative abundance. The difference in the glycosylation and abundance of HLA alleles changed the number of strong binding antigens each allele presented, suggesting the impact of SARS-CoV-2 infection on antigen presentation is allele-specific. These results could be further exploited to explain the imbalanced response from innate and adaptive immune system in coronavirus disease 2019 cases, which would be helpful for the development of therapeutics and vaccine for coronavirus disease 2019 and preparation for future pandemic.

Three and a half years after the pandemic outbreak, now that WHO has formally declared that the emergency is over, COVID-19 is still a significant global issue. Here, we focus on recent developments in genetic and genomic research on COVID-19, and we give an outlook on state-of-the-art therapeutical approaches, as the pandemic is gradually transitioning to an endemic situation. The sequencing and characterization of rare alleles in different populations has made it possible to identify numerous genes that affect either susceptibility to COVID-19 or the severity of the disease. These findings provide a beginning to new avenues and pan-ethnic therapeutic approaches, as well as to potential genetic screening protocols. The causative virus, SARS-CoV-2, is still in the spotlight, but novel threatening virus could appear anywhere at any time. Therefore, continued vigilance and further research is warranted. We also note emphatically that to prevent future pandemics and other world-wide health crises, it is imperative to capitalize on what we have learnt from COVID-19: specifically, regarding its origins, the world's response, and insufficient preparedness. This requires unprecedented international collaboration and timely data sharing for the coordination of effective response and the rapid implementation of containment measures.

Human Leukocyte Antigen (HLA) system is a highly polymorphic genetic system associated with the prognosis of several infectious diseases. The aim of this study is to investigate the association of HLA polymorphism with the outcome of coronavirus disease 2019 (COVID-19) in Tunisian critically ill patients.

this retrospective cross-sectional study included 42 consecutive patients hospitalized in intensive care unit (ICU) for COVID-19 in March 2021. Genotyping of HLA loci was performed by LABType™ sequence-specific oligonucleotide (SSO) typing kits (One lambda Inc, USA). Statistical analyses were performed using Statistical Package for Social Sciences (SPSS®) version 23.0. A p-value <0.05 was considered significant. Multivariable regression analysis was performed for the association between HLA polymorphism with adverse outcomes with adjustment for potential confounders such as age, sex, co-morbidities and blood type.

patients included in our study had a mean age of 64.5 ± 11.5 (34-83) years and were mainly men (64.3%; (n=27)). The most common cardiovascular risk factors were obesity (61.9%; (n=26)) and hypertension (26.2%; (n=11)). Thirty-two patients died (76.2%). Eleven patients (26.2%) required intubation during hospitalization. We found that HLA DQB1*06 allele was significantly associated with protection against mortality aOR: 0.066, 95% CI 0.005-0.821; p = 0.035. HLA DQB1*03 allele was significantly associated with protection against intubation aOR: 0.151, 95% CI 0.023-0.976; p = 0.047.

it was found that there are 2 protective HLA alleles against COVID-19 severity and mortality in critically ill patients. This could allow focusing on people genetically predisposed to develop severe forms of COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic caused by the novel beta coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) crippled the whole world and has resulted in large number of morbidity and mortality. The origin of the SARS-CoV-2 is still disputed. The risk of infection with SARS-CoV-2 is dependent on several risk factors as observed in many studies. The severity of the disease depends on many factors including the viral strain, host immunogenetics, environmental factors, host genetics, host nutritional status and presence of comorbidities like hypertension, diabetes, Chronic Obstructive Pulmonary Disease, cardiovascular disease, renal impairment. Diabetes is a metabolic disorder mainly characterized by hyperglycemia. Diabetic individuals are intrinsically prone to infections. SARS-CoV-2 infection in patients with diabetes result in β-cell damage and cytokine storm. Damage to the cells impairs the equilibrium of glucose, leading to hyperglycemia. The ensuing cytokine storm causes insulin resistance, especially in the muscles and liver, which also causes a hyperglycemic state. All of these increase the severity of COVID-19. Genetics also play pivotal role in disease pathogenesis. This review article focuses from the probable sources of coronaviruses and SARS-CoV-2 to its impacts on individuals with diabetes and host genetics in pre- and post-pandemic era.

Differences in SARS-CoV-2-specific immune responses have been observed between individuals following natural infection or vaccination. In addition to already known factors, such as age, sex, COVID-19 severity, comorbidity, vaccination status, hybrid immunity, and duration of infection, inter-individual variations in SARS-CoV-2 immune responses may, in part, be explained by structural differences brought about by genetic variation in the human leukocyte antigen (HLA) molecules responsible for the presentation of SARS-CoV-2 antigens to T effector cells. While dendritic cells present peptides with HLA class I molecules to CD8+ T cells to induce cytotoxic T lymphocyte responses (CTLs), they present peptides with HLA class II molecules to T follicular helper cells to induce B cell differentiation followed by memory B cell and plasma cell maturation. Plasma cells then produce SARS-CoV-2-specific antibodies. Here, we review published data linking HLA genetic variation or polymorphisms with differences in SARS-CoV-2-specific antibody responses. While there is evidence that heterogeneity in antibody response might be related to HLA variation, there are conflicting findings due in part to differences in study designs. We provide insight into why more research is needed in this area. Elucidating the genetic basis of variability in the SARS-CoV-2 immune response will help to optimize diagnostic tools and lead to the development of new vaccines and therapeutics against SARS-CoV-2 and other infectious diseases.

Reports of mortality-associated risk factors in patients with the novel coronavirus disease 2019 (COVID-19) are limited.

We evaluated the clinical features that were associated with mortality among patients who died during hospitalization (n = 158) and those who were alive at discharge (n = 2,736) from the large-scale, multicenter, retrospective, observational cohort CLOT-COVID study, which enrolled consecutively hospitalized COVID-19 patients from 16 centers in Japan from April to September 2021. Data from 2,894 hospitalized COVID-19 participants of the CLOT-COVID study were analyzed in this study.

Patients who died were older (71.1 years vs 51.6 years, P < 0.001), had higher median D-dimer values on admission (1.7 µg/mL vs 0.8 µg/mL, P < 0.001), and had more comorbidities. On admission, the patients who died had more severe COVID-19 than did those who survived (mild: 16% vs 63%, moderate: 47% vs 31%, and severe: 37% vs 6.2%, P < 0.001). In patients who died, the incidence of thrombosis and major bleeding during hospitalization was significantly higher than that in those who survived (thrombosis: 8.2% vs 1.5%, P < 0.001; major bleeding: 12.7% vs 1.4%, P < 0.001). Multivariable logistic regression analysis revealed that age >70 years, high D-dimer values on admission, heart disease, active cancer, higher COVID-19 severity on admission, and development of major bleeding during hospitalization were independently associated with a higher mortality risk.

This large-scale observational study in Japan identified several independent risk factors for mortality in hospitalized patients with COVID-19 that could facilitate appropriate risk stratification of patients with COVID-19.

In the biological immune process, the major histocompatibility complex (MHC) plays an indispensable role in the expression of HLA molecules in the human body when viral infection activates the T-cell response to remove the virus. Since the first case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in 2019, how to address and prevent SARS-CoV-2 has become a common problem facing all mankind. The T-cell immune response activated by MHC peptides is a way to construct a defense line and reduce the transmission and harm of the virus. Presentation of SARS-CoV-2 antigen is associated with different types of HLA phenotypes, and different HLA phenotypes induce different immune responses. The prediction of SARS-CoV-2 mutation information and the design of vaccines based on HLAs can effectively activate autoimmunity and cope with virus mutations, which can provide some references for the prevention and treatment of SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) pandemic has caused human tragedy through the global spread of the viral pathogen SARS-CoV-2. Although the underlying factors for the severity of COVID-19 in different people are still unknown, several gene variants can be used as predictors of disease severity, particularly variations in viral receptor genes such as angiotensin-converting enzyme 2 (ACE2) or major histocompatibility complex (MHC) genes. The reaction of the immune system, as the most important defense strategy in the case of viruses, plays a decisive role. The innate immune system is important both as a primary line of defense and as a trigger of the acquired immune response. The HLA-mediated acquired immune response is linked to the acquired immune system. In various diseases, it has been shown that genetic alterations in components of the immune system can play a crucial role in how the body responds to pathogens, especially viruses. One of the most important host genetic factors is the human leukocyte antigen (HLA) profile, which includes HLA classes I and II and may be symbolic of the diversity of immune response and genetic predisposition in disease progression. COVID-19 will have direct contact with the acquired immune system as an intracellular pathogen after exposure to the proteasome and its components through class I HLA. Therefore, it is assumed that in different genotypes of the HLA-I class, an undesirable supply causes an insufficient activation of the immune system. Insufficient binding of antigen delivered by class I HLA to host lymphocytes results in uncertain identification and insufficient activation of the acquired immune system. The absence of secretion of immune cytokines such as interferons, which play an important role in controlling viral infection in the early stages, is a complication of this event. Understanding the allelic diversity of HLA in people infected with coronavirus compared with uninfected people of one race not only allows identification of people with HLA susceptible to COVID-19 but also provides better insight into the behavior of the virus, which helps to take effective preventive and curative measures earlier.

COVID-19 is a respiratory disease caused by a novel coronavirus called as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Detected for the first time in December 2019 in Wuhan and it has quickly spread all over the world in a couple of months and becoming a world pandemic. Symptoms of the disease and clinical outcomes are very different in infected people. These differences highlight the paramount need to study and understand the human genetic variation that occurring viral infections. Human leukocyte antigen (HLA) is an important component of the viral antigen presentation pathway, and it plays an essential role in conferring differential viral susceptibility and severity of diseases. HLA alleles have been involved in the immune response to viral diseases such as SARS-CoV-2.

Herein, we sought to evaluate this hypothesis by summarizing the association between HLA class I and class II alleles with COVID-19 susceptibility and/or severity reported in previous studies among different populations (Chinese, Italian, Iranian, Japanese, Spanish, etc.). The findings of all selected articles showed that several alleles have been found associated with COVID-19 susceptibility and severity. Even results across articles have been inconsistent and, in some cases, conflicting, highlighting that the association between the HLA system and the COVID-19 outcome might be ethnic-dependent, there were some alleles in common between some populations such as HLA-DRB1*15 and HLA-A*30:02.

These contradictory findings warrant further large, and reproducible studies to decipher any possible genetic predisposition underlying susceptibility to SARS-COV-2 and disease progression and host immune response.

Background: Single nucleotide polymorphisms provide information on individuals' potential reactions to environmental factors, infections, diseases, as well as various therapies. A study on SNPs that influence SARS-CoV-2 susceptibility and severity may provide a predictive tool for COVID-19 outcomes and improve the customized coronavirus treatment. Aim: To evaluate the role of human leukocyte antigens DP/DQ and IFNλ4 polymorphisms on COVID-19 outcomes among Egyptian patients. Participants and Methods: The study involved 80 patients with severe COVID-19, 80 patients with mild COVID-19, and 80 non-infected healthy volunteers. Genotyping and allelic discrimination of HLA-DPrs3077 (G/A), HLA-DQrs7453920 (A/G), and IFNλ4 rs73555604 (C/T) SNPs were performed using real-time PCR. Results: Ages were 47.9 ± 8, 44.1 ± 12.1, and 45.8 ± 10 years in severe, mild and non-infected persons. There was a statistically significant association between severe COVID-19 and male gender (p = 0.002). A statistically significant increase in the frequency of HLA-DPrs3077G, HLA-DQrs7453920A, and IFNλ4rs73555604C alleles among severe COVID-19 patients when compared with other groups (p < 0.001). Coexistence of these alleles in the same individual increases the susceptibility to severe COVID-19 by many folds (p < 0.001). Univariate and multivariate logistic regression analysis for the studied parameters showed that old age, male gender, non-vaccination, HLA-DQ rs7453920AG+AA, HLA-DPrs3077GA+GG, and IFNλ4rs73555604CT+CC genotypes are independent risk factors for severe COVID-19 among Egyptian patients. Conclusion: HLA-DQ rs7453920A, HLA-DPrs3077G, and IFNλ4rs73555604C alleles could be used as markers of COVID-19 severity.

Aim: More data is required regarding the association between HLA allele and red blood cell (RBC) antigen expression in regard to SARS-CoV-2 infection and COVID-19 susceptibility. Methods: ABO, RhD, 37 other RBC antigens and HLA-A, B, C, DRB1, DQB1 and DPB1 were determined using high throughput platforms in 90 Caucasian convalescent plasma donors. Results: The AB group was significantly increased (1.5×, p = 0.018) and some HLA alleles were found to be significantly overrepresented (HLA-B*44:02, C*05:01, DPB1*04:01, DRB1*04:01 and DRB1*07:01) or underrepresented (A*01:01, B51:01 and DPB1*04:02) in convalescent individuals compared with the local bone marrow registry population. Conclusion: Our study of infection-susceptible but non-hospitalized Caucasian COVID-19 patients contributes to the global understanding of host genetic factors associated with SARS-CoV-2 infection and severity.

Due to their pivotal role in orchestrating the immune response, HLA loci were recognized as candidates for genetic association studies related to the severity of COVID-19. Since the findings on the effects of HLA alleles on the outcome of SARS-CoV-2 infection remain inconclusive, we aimed to elucidate the potential involvement of genetic variability within HLA loci in the molecular genetics of COVID-19 by classifying the articles according to different disease severity/outcomes and by conducting a systematic review with meta-analysis. Potentially eligible studies were identified by searching PubMed, Scopus and Web of Science literature databases. A total of 28 studies with 13,073 participants were included in qualitative synthesis, while the results of 19 studies with 10,551 SARS-CoV-2-positive participants were pooled in the meta-analysis. According to the results of quantitative data synthesis, association with COVID-19 severity or with the lethal outcome was determined for the following alleles and allele families: HLA-A*01, HLA-A*03, HLA-A*11, HLA-A*23, HLA-A*31, HLA-A*68, HLA-A*68:02, HLA-B*07:02, HLA-B*14, HLA-B*15, HLA-B*40:02, HLA-B*51:01, HLA-B*53, HLA-B*54, HLA-B*54:01, HLA-C*04, HLA-C*04:01, HLA-C*06, HLA-C*07:02, HLA-DRB1*11, HLA-DRB1*15, HLA-DQB1*03 and HLA-DQB1*06 (assuming either allelic or dominant genetic model). We conclude that alleles of HLA-A, -B, -C, -DRB1 and -DQB1 loci may represent potential biomarkers of COVID-19 severity and/or mortality, which needs to be confirmed in a larger set of studies.