Immunogenetic landscape of COVID-19 infections related neurological complications

The human leukocyte antigen (HLA) is a critical component of antigen presentation and plays crucial role in conferring differential susceptibility and severity of diseases caused by viruses such as COVID-19. The immunogenetic profile of populations, BCG vaccination status, and a host of lifestyle factors might contribute to the observed variations in mortality rates due to COVID-19. These genetic, epigenetic, and environmental factors could widely influence infection dynamics and immune responses against COVID-19. The aim of this review is to provide an update on HLA association with SARS-CoV-2 infection in global populations and to highlight the possible neurological involvements. We also set out to explore the HLA immunogenetic markers related to COVID‐19 infections that can be used in screening high‐risk individuals for personalized therapies and in community-based vaccine development. © 2023 Elsevier Inc. All rights reserved.

HLA-II immunopeptidome profiling and deep learning reveal features of antigenicity to inform antigen discovery.

CD4+ T cell responses are exquisitely antigen specific and directed toward peptide epitopes displayed by human leukocyte antigen class II (HLA-II) on antigen-presenting cells. Underrepresentation of diverse alleles in ligand databases and an incomplete understanding of factors affecting antigen presentation in vivo have limited progress in defining principles of peptide immunogenicity. Here, we employed monoallelic immunopeptidomics to identify 358,024 HLA-II binders, with a particular focus on HLA-DQ and HLA-DP. We uncovered peptide-binding patterns across a spectrum of binding affinities and enrichment of structural antigen features. These aspects underpinned the development of context-aware predictor of T cell antigens (CAPTAn), a deep learning model that predicts peptide antigens based on their affinity to HLA-II and full sequence of their source proteins. CAPTAn was instrumental in discovering prevalent T cell epitopes from bacteria in the human microbiome and a pan-variant epitope from SARS-CoV-2. Together CAPTAn and associated datasets present a resource for antigen discovery and the unraveling genetic associations of HLA alleles with immunopathologies.

Immunoinformatic prediction of potential immunodominant epitopes from cagW in order to investigate protection against Helicobacter pylori infection based on experimental consequences.

Helicobacter pylori is a leading cause of stomach cancer and peptic ulcers. Thus, identifying epitopes in H. pylori antigens is important for disease etiology, immunological surveillance, enhancing early detection tests, and developing optimal epitope-based vaccines. We used immunoinformatic and computational methods to create a potential CagW epitope candidate for H. pylori protection. The cagW gene of H. pylori was amplified and cloned into pcDNA3.1 (+) for injection into the muscles of healthy BALB/c mice to assess the impact of the DNA vaccine on interleukin levels. The results will be compared to a control group of mice that received PBS or cagW-pcDNA3.1 (+) vaccinations. An analysis of CagW protein antigens revealed 8 CTL and 7 HTL epitopes linked with AYY and GPGPG, which were enhanced by adding B-defensins to the N-terminus. The vaccine's immunogenicity, allergenicity, and physiochemistry were validated, and its strong activation of TLRs (1, 2, 3, 4, and 10) suggests it is antigenic. An in-silico cloning and immune response model confirmed the vaccine's expression efficiency and predicted its impact on the immune system. An immunofluorescence experiment showed stable and bioactive cagW gene expression in HDF cells after cloning the whole genome into pcDNA3.1 (+). In vivo vaccination showed that pcDNA3.1 (+)-cagW-immunized mice had stronger immune responses and a longer plasmid DNA release window than control-plasmid-immunized mice. After that, bioinformatics methods predicted, developed, and validated the three-dimensional structure. Many online services docked it with Toll-like receptors. The vaccine was refined using allergenicity, antigenicity, solubility, physicochemical properties, and molecular docking scores. Virtual-reality immune system simulations showed an impressive reaction. Codon optimization and in-silico cloning produced E. coli-expressed vaccines. This study suggests a CagW epitopes-protected H. pylori infection. These studies show that the proposed immunization may elicit particular immune responses against H. pylori, but laboratory confirmation is needed to verify its safety and immunogenicity.

Positive mental health in Slovenia before and during the COVID-19 pandemic.

Background: Mental health has been heavily affected during the COVID-19 pandemic. In this study we compared the prevalence of flourishing and languishing mental health during the pandemic and examined which factors are associated with either category of positive mental health respectively. Methods: Data from two cross-sectional surveys with nationally representative samples of adult population in Slovenia conducted in 2019 (n = 9,047) and in 2021 (n = 3,429) are used. Positive mental health was measured with Mental Health Continuum-Short Form instrument. Logistic regression was used to examine the associations between flourishing and languishing mental health and relevant COVID-19 specific and other health-related factors. Results: There was a substantial decrease in the prevalence of flourishing and an increase in the prevalence of languishing mental health during the pandemic. Distribution of both flourishing and languishing mental health followed the socio-economic gradient. Resilience, COVID-19 literacy and changes in family relations, social interactions, and dietary habits were associated with both flourishing and languishing mental health. Conclusion: Positive mental health of the population worsened during the pandemic, more so in traditionally disadvantaged populations. Public health efforts need to be focused appropriately with an increased emphasis on strengthening resilience and health literacy.

Transcriptome in Human Mycoses

Mycoses are infectious diseases caused by fungi, which incidence has increased in recent decades due to the increasing number of immunocompromised patients and improved diagnostic tests. As eukaryotes, fungi share many similarities with human cells, making it difficult to design drugs without side effects. Commercially available drugs act on a limited number of targets and have been reported fungal resistance to commonly used antifungal drugs. Therefore, elucidating the pathogenesis of fungal infections, the fungal strategies to overcome the hostile environment of the host, and the action of antifungal drugs is essential for developing new therapeutic approaches and diagnostic tests. Large-scale transcriptional analyses using microarrays and RNA sequencing (RNA-seq), combined with improvements in molecular biology techniques, have improved the study of fungal pathogenicity. Such techniques have provided insights into the infective process by identifying molecular strategies used by the host and pathogen during the course of human mycoses. This chapter will explore the latest discoveries regarding the transcriptome of major human fungal pathogens. Further we will highlight genes essential for host–pathogen interactions, immune response, invasion, infection, antifungal drug response, and resistance. Finally, we will discuss their importance to the discovery of new molecular targets for antifungal drugs. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2014, 2022.

Immune Profile of SARS-CoV-2 Variants of Concern.

The spread of the current Sars-Cov-2 pandemics leads to the development of mutations that are constantly monitored because they could affect the efficacy of vaccines. Three recently identified mutated strains, known as variants of concern, are rapidly spreading worldwide. Here, we study possible effects of these mutations on the immune response to Sars-Cov-2 infection using NetTepi a computational method based on artificial neural networks that considers binding and stability of peptides obtained by proteasome degradation for widely represented HLA class I alleles present in human populations as well as the T-cell propensity of viral peptides that measures their immune response. Our results show variations in the number of potential highly ranked peptides ranging between 0 and 20% depending on the specific HLA allele. The results can be useful to design more specific vaccines.

Enhanced inhibition of MHC-I expression by SARS-CoV-2 Omicron subvariants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) possess mutations that confer resistance to neutralizing antibodies within the Spike protein and are associated with breakthrough infection and reinfection. By contrast, less is known about the escape from CD8+ T cell-mediated immunity by VOC. Here, we demonstrated that all SARS-CoV-2 VOCs possess the ability to suppress major histocompatibility complex class I (MHC-I) expression. We identified several viral genes that contribute to the suppression of MHC I expression. Notably, MHC-I upregulation was strongly inhibited after SARS-CoV-2 but not influenza virus infection in vivo. While earlier VOCs possess similar capacity as the ancestral strain to suppress MHC-I, the Omicron subvariants exhibited a greater ability to suppress surface MHC-I expression. We identified a common mutation in the E protein of Omicron that further suppressed MHC-I expression. Collectively, our data suggest that in addition to escaping from neutralizing antibodies, the success of Omicron subvariants to cause breakthrough infection and reinfection may in part be due to its optimized evasion from T cell recognition.

Interferons and Resistance Mechanisms in Tumors and Pathogen-Driven Diseases-Focus on the Major Histocompatibility Complex (MHC) Antigen Processing Pathway.

Interferons (IFNs), divided into type I, type II, and type III IFNs represent proteins that are secreted from cells in response to various stimuli and provide important information for understanding the evolution, structure, and function of the immune system, as well as the signaling pathways of other cytokines and their receptors. They exert comparable, but also distinct physiologic and pathophysiologic activities accompanied by pleiotropic effects, such as the modulation of host responses against bacterial and viral infections, tumor surveillance, innate and adaptive immune responses. IFNs were the first cytokines used for the treatment of tumor patients including hairy leukemia, renal cell carcinoma, and melanoma. However, tumor cells often develop a transient or permanent resistance to IFNs, which has been linked to the escape of tumor cells and unresponsiveness to immunotherapies. In addition, loss-of-function mutations in IFN signaling components have been associated with susceptibility to infectious diseases, such as COVID-19 and mycobacterial infections. In this review, we summarize general features of the three IFN families and their function, the expression and activity of the different IFN signal transduction pathways, and their role in tumor immune evasion and pathogen clearance, with links to alterations in the major histocompatibility complex (MHC) class I and II antigen processing machinery (APM). In addition, we discuss insights regarding the clinical applications of IFNs alone or in combination with other therapeutic options including immunotherapies as well as strategies reversing the deficient IFN signaling. Therefore, this review provides an overview on the function and clinical relevance of the different IFN family members, with a specific focus on the MHC pathways in cancers and infections and their contribution to immune escape of tumors.

Modular adjuvant-free pan-HLA-DR-immunotargeting subunit vaccine against SARS-CoV-2 elicits broad sarbecovirus-neutralizing antibody responses.

Subunit vaccines typically require co-administration with an adjuvant to elicit protective immunity, adding development hurdles that can impede rapid pandemic responses. To circumvent the need for adjuvant in a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subunit vaccine, we engineer a thermostable immunotargeting vaccine (ITV) that leverages the pan-HLA-DR monoclonal antibody 44H10 to deliver the viral spike protein receptor-binding domain (RBD) to antigen-presenting cells. X-ray crystallography shows that 44H10 binds to a conserved epitope on HLA-DR, providing the basis for its broad HLA-DR reactivity. Adjuvant-free ITV immunization in rabbits and ferrets induces robust anti-RBD antibody responses that neutralize SARS-CoV-2 variants of concern and protect recipients from SARS-CoV-2 challenge. We demonstrate that the modular nature of the ITV scaffold with respect to helper T cell epitopes and diverse RBD antigens facilitates broad sarbecovirus neutralization. Our findings support anti-HLA-DR immunotargeting as an effective means to induce strong antibody responses to subunit antigens without requiring an adjuvant.

HLA Variation and SARS-CoV-2 Specific Antibody Response.

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.

Novel pro-and eukaryotic expression plasmid expressing omicron antigens delivered via Salmonella elicited MHC class I and II based protective immunity.

The latest omicron variants are emerging with mutations in the receptor binding domain (RBD) that confer immune evasion and resistance against current vaccines. Such variants have raised the peril of future vaccine effectiveness, as leading vaccines target the spike protein. Type-IV hypersensitivity, and other ailments due to the dominant Th1 response by leading vaccines, is also to be resolved. Therefore, vaccine that target diverse SARS-CoV-2 proteins and provide broad-spectrum protection and a balanced Th1 and Th2 response is an indispensable armament against the pandemic. In that prospect, a novel dual expression plasmid pJHL270 was developed and demonstrated the expression of omicron antigens exogenously from Salmonella and endogenously in the host cells. The simultaneous activation of MHC class I and II molecules culminated in a balanced Th1 and Th2 response, which was evident through the upsurge of IgG, IgA antibodies, IgG2a/IgG1 ratio, cytokine responses and CD4+, CD8+ T-lymphocytes. The level of CD44+ cells showed the trigger for Th1 and Th2 balance and memory-cell activation for long-lasting immunity. The level of IFN-γ + cells and neutralizing antibodies signifies the anti-viral response. The vaccine protected the hamsters from BA.5 and BA.2.75 omicron viral-challenge, exhibited a significant reduction in lung viral-load and histopathological lesions. In addition to two-way antigen expression and bilateral immune elicitation, this Salmonella-based vaccine delivery system can be prospectively applied to humans and a broad range of animals as a convenient alternative to viral and chemical vaccine delivery approaches.

Association of HLA Class I Genotype with Mortality in Patients with Diabetes Mellitus and COVID-19.

Numerous studies showed that diabetes mellitus (DM) increases the risk of death from COVID-19 by five times. It is generally accepted that the high lethality of COVID-19 against the background of DM is due to the main complications of this disease: micro- and macroangiopathies, as well as heart and kidney failure. In addition, it was shown that acute respiratory viral infection increases the production of interferon gamma, increases muscle resistance to insulin, and modulates the activity of effector CD8+ T cells. The ability of CD8+ T cells to recognize SARS-CoV-2-infected cells depends not only on humoral factors but also on individual genetic characteristics, including the individual set of major histocompatibility complex class I (MHC-I) molecules. In this study, the relationship of the MHC-I genotype of patients with DM aged less than 60 years with the outcome of COVID-19 was studied using a sample of 222 patients. It was shown that lethal outcomes of COVID-19 in patients with DM are associated with the low affinity of the interaction of an individual set of MHC-I molecules with SARS-CoV-2 peptides.

MHC class I links with severe pathogenicity in C57BL/6N mice infected with SARS-CoV-2/BMA8.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes non-symptomatic infection, mild influenza-like symptoms to pneumonia, severe acute respiratory distress syndrome, and even death, reflecting different clinical symptoms of viral infection. However, the mechanism of its pathogenicity remains unclear. Host-specific traits have a breakthrough significance for studying the pathogenicity of SARS-CoV-2. We previously reported SARS-CoV-2/BMA8, a mouse-adapted strain, was lethal to aged BALB/c mice but not to aged C57BL/6N mice. Here, we further investigate the differences in pathogenicity of BMA8 strain against wild-type aged C57BL/6N and BALB/c mice. METHODS: Whole blood and tissues were collected from mice before and after BMA8 strain infection. Viral replication and infectivity were assessed by detection of viral RNA copies and viral titers; the degree of inflammation in mice was tested by whole blood cell count, ELISA and RT-qPCR assays; the pathogenicity of SARS-CoV-2/BMA8 in mice was measured by Histopathology and Immunohistochemistry; and the immune level of mice was evaluated by flow cytometry to detect the number of CD8+ T cells. RESULTS: Our results suggest that SARS-CoV-2/BMA8 strain caused lower pathogenicity and inflammation level in C57BL/6N mice than in BALB/c mice. Interestingly, BALB/c mice whose MHC class I haplotype is H-2Kd showed more severe pathogenicity after infection with BMA8 strain, while blockade of H-2Kb in C57BL/6N mice was also able to cause this phenomenon. Furthermore, H-2Kb inhibition increased the expression of cytokines/chemokines and accelerated the decrease of CD8+ T cells caused by SARS-CoV-2/BMA8 infection. CONCLUSIONS: Taken together, our work shows that host MHC molecules play a crucial role in the pathogenicity differences of SARS-CoV-2/BMA8 infection. This provides a more profound insight into the pathogenesis of SARS-CoV-2, and contributes enlightenment and guidance for controlling the virus spread.

Spheromers reveal robust T cell responses to the Pfizer/BioNTech vaccine and attenuated peripheral CD8+ T cell responses post SARS-CoV-2 infection.

T cells are a critical component of the response to SARS-CoV-2, but their kinetics after infection and vaccination are insufficiently understood. Using "spheromer" peptide-MHC multimer reagents, we analyzed healthy subjects receiving two doses of the Pfizer/BioNTech BNT162b2 vaccine. Vaccination resulted in robust spike-specific T cell responses for the dominant CD4+ (HLA-DRB1∗15:01/S191) and CD8+ (HLA-A∗02/S691) T cell epitopes. Antigen-specific CD4+ and CD8+ T cell responses were asynchronous, with the peak CD4+ T cell responses occurring 1 week post the second vaccination (boost), whereas CD8+ T cells peaked 2 weeks later. These peripheral T cell responses were elevated compared with COVID-19 patients. We also found that previous SARS-CoV-2 infection resulted in decreased CD8+ T cell activation and expansion, suggesting that previous infection can influence the T cell response to vaccination.

SARS-CoV-2 ORF8 dimerization and binding mode analysis with class I MHC: computational approaches to identify COVID-19 inhibitors.

SARS-CoV-2 encodes eight accessory proteins, one of which, ORF8, has a poorly conserved sequence with SARS-CoV and its role in viral pathogenicity has recently been identified. ORF8 in SARS-CoV-2 has a unique functional feature that allows it to form a dimer structure linked by a disulfide bridge between Cys20 and Cys20 (S-S). This study provides structural characterization of natural mutant variants as well as the identification of potential drug candidates capable of binding directly to the interchain disulfide bridge. The lead compounds reported in this work have a tendency to settle in the dimeric interfaces by direct interaction with the disulfide bridge. These molecules may disturb the dimer formation and may have an inhibition impact on its potential functional role in host immune evasion and virulence pathogenicity. This work provides detailed insights on the sequence and structural variability through computational mutational studies, as well as potent drug candidates with the ability to interrupt the intermolecular disulfide bridge formed between Cys20 and Cys20. Furthermore, the interactions of ORF8 peptides complexed with MHC-1 is studied, and the binding mode reveals that certain ORF8 peptides bind to MHC-1 in a manner similar to other viral peptides. Overall, this study is a narrative of various computational approaches used to provide detailed structural insights into SARS-CoV-2 ORF8 interchain disulfide bond disruptors.

Inhibition of major histocompatibility complex-I antigen presentation by sarbecovirus ORF7a proteins.

Viruses employ a variety of strategies to escape or counteract immune responses, including depletion of cell surface major histocompatibility complex class I (MHC-I), that would ordinarily present viral peptides to CD8+ cytotoxic T cells. As part of a screen to elucidate biological activities associated with individual severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral proteins, we found that ORF7a reduced cell surface MHC-I levels by approximately fivefold. Nevertheless, in cells infected with SARS-CoV-2, surface MHC-I levels were reduced even in the absence of ORF7a, suggesting additional mechanisms of MHC-I down-regulation. ORF7a proteins from a sample of sarbecoviruses varied in their ability to induce MHC-I down-regulation and, unlike SARS-CoV-2, the ORF7a protein from SARS-CoV lacked MHC-I downregulating activity. A single amino acid at position 59 (T/F) that is variable among sarbecovirus ORF7a proteins governed the difference in MHC-I downregulating activity. SARS-CoV-2 ORF7a physically associated with the MHC-I heavy chain and inhibited the presentation of expressed antigen to CD8+ T cells. Specifically, ORF7a prevented the assembly of the MHC-I peptide loading complex and caused retention of MHC-I in the endoplasmic reticulum. The differential ability of ORF7a proteins to function in this way might affect sarbecovirus dissemination and persistence in human populations, particularly those with infection- or vaccine-elicited immunity.

Immunoinformatics approach of epitope prediction for SARS-CoV-2.

BACKGROUND: The novel coronavirus (SARS-CoV-2) caused lethal infections worldwide during an unprecedented pandemic. Identification of the candidate viral epitopes is the first step in the design of vaccines against the viral infection. Several immunoinformatic approaches were employed to identify the SARS-CoV-2 epitopes that bind specifically with the major histocompatibility molecules class I (MHC-I). We utilized immunoinformatic tools to analyze the whole viral protein sequences, to identify the SARS-CoV-2 epitopes responsible for binding to the most frequent human leukocyte antigen (HLA) alleles in the Egyptian population. These alleles were also found with high frequency in other populations worldwide. RESULTS: Molecular docking approach showed that using the co-crystallized MHC-I and T cell receptor (TCR) instead of using MHC-I structure only, significantly enhanced docking scores and stabilized the conformation, as well as the binding affinity of the identified SARS-CoV-2 epitopes. Our approach directly predicts 7 potential vaccine subunits from the available SARS-CoV-2 spike and ORF1ab protein sequence. This prediction has been confirmed by published experimentally validated and in silico predicted spike epitope. On the other hand, we predicted novel epitopes (RDLPQGFSA and FCLEASFNY) showing high docking scores and antigenicity response with both MHC-I and TCR. Moreover, antigenicity, allergenicity, toxicity, and physicochemical properties of the predicted SARS-CoV-2 epitopes were evaluated via state-of-the-art bioinformatic approaches, showing high efficacy of the proposed epitopes as a vaccine candidate. CONCLUSION: Our predicted SARS-CoV-2 epitopes can facilitate vaccine development to enhance the immunogenicity against SARS-CoV-2 and provide supportive data for further experimental validation. Our proposed molecular docking approach of exploiting both MHC and TCR structures can be used to identify potential epitopes for most microbial pathogens, provided the crystal structure of MHC co-crystallized with TCR.

Relationship of Covid-19 Severity with SARS-CoV-2 NS8 Protein Mutations Depending on Virus Strain.

In mid-2021, the Delta strain of SARS-CoV-2 caused the third wave of the COVID-19 pandemic. Huge efforts have been devoted to studying the effect of its mutations on the effectiveness of neutralizing antibodies. Much less attention was paid to the individual features of the presentation of its peptides by molecules of the major histocompatibility complex class I (MCHC-I). In this study, the correlation of the HLA-I genotype of patients under the age of 60 years with the severity of COVID-19 caused by the two most common variants of the SARS-CoV-2 Delta strain in the summer of 2021: AY.122 and B.1.617.2 was studied. Analysis of the severity of the course of COVID-19 revealed a more severe course of the disease caused by the AY.122 variant. Comparison of the mutation profile of the two most common variants of the Delta strain showed that that the G8R mutation in the NS8 protein makes the greatest contribution to the ability of MHC-I to present viral peptides. Given that the NS8 protein is able to suppress the maturation of MHC-I molecules, the appearance of a mutation in one of its immunogenic epitopes could make a significant contribution to the prevalence of the AY.122 variant in the Russian population.

Immunogenetic Predisposition to SARS-CoV-2 Infection.

Herein, we included 527 individuals from two Hospitals, Chemnitz and University-Hospital Leipzig. In total, 199 were negative for PCR and 328 were positive upon first admission. We used next generation sequencing for HLA-A, B, C, DRB1, DRB345, DQA1, DQB1, DPA1, and DPB1, and in some cases, HLA-E, F, G, and H. Furthermore, we molecularly defined 22 blood group systems comprising 26 genes and 5 platelet antigen genes. We observed a significant enrichment of homozygosity for DQA/DQB in the positive group. Within the negative subjects, HLA-B*57:01, HLA-B*55:01, DRB1*13:01, and DRB1*01:01 were enriched, and in the positive group, homozygosity for DQA/DQB, DRB1*09:01, and DRB1*15:01 was observed. DQA1*01:01, DQA1*02:01, and DQA1*01:03 were enriched in the negative group. HLA-DQB1*06:02 was enriched in the positive group, and HLA-DQB1*05:01 and HLA-DQB1*06:03 were enriched in the negative group. For the blood group systems MNS, RH, LE, FY, JK, YT, DO, and KN, enrichment was seen in both groups, depending on the antigen under observation. Homozygosity for D-positive RHD alleles, as well as the phenotypes M-N+ of the MNS blood group system and Yk(a-) of the KN system, were enriched in the positive group. All of these significances disappeared upon correction. Subjects who carried homozygous HPA-1a were more frequent in the negative group, contrasting with the finding that HPA-1ab was enriched in the positive group.

Weighted gene co-expression network-based identification of genetic effect of mRNA vaccination and previous infection on SARS-CoV-2 infection.

To investigate the effect conferred by vaccination and previous infection against SARS-CoV-2 infection in molecular level, weighted gene co-expression network analysis was applied to screen vaccination, prior infection and Omicron infection-related gene modules in 46 Omicron outpatients and 8 controls, and CIBERSORT algorithm was used to infer the proportions of 22 subsets of immune cells. 15 modules were identified, where the brown module showed positive correlations with Omicron infection (r = 0.35, P = 0.01) and vaccination (r = 0.62, P = 1 × 10-6). Enrichment analysis revealed that LILRB2 was the unique gene shared by both phosphatase binding and MHC class I protein binding. Pathways including "B cell receptor signaling pathway" and "FcγR-mediated phagocytosis" were enriched in the vaccinated samples of the highly correlated LILRB2. LILRB2 was also identified as the second hub gene through PPI network, after LCP2. In conclusion, attenuated LILRB2 transcription in PBMC might highlight a novel target in overcoming immune evasion and improving vaccination strategies.