Influenza A H1N1 mediated pre-existing immunity to SARS-CoV-2 predicts COVID-19 outbreak dynamics

Susceptibility to SARSCoV2 infections is highly variable, ranging from asymptomatic and mild infections in most, to deadly outcome in few. Here, we present evidence that antibodies induced by currently circulating influenza A H1N1 (flu) strains cross react with the most critical receptor binding motif of the SARSCoV2 spike protein that interacts with the ACE2 receptor. About 58 to 68% of blood donors in Stockholm had detectable antibodies to this cross-reactive peptide, NGVEGF, and seasonal flu vaccination trended to enhance binding of inhibitory antibodies to SARSCoV2. This peptide also activated CD8 T cells in 20% of healthy subjects. Eleven additional CD8 T cell peptides that cross react with flu and SARSCoV2 were identified that potentially protect against SARSCoV2 in 40 to 71% of individuals, depending on their HLA type.

Minimal observed impact of HLA genotype on hospitalization and severity of SARS-CoV-2 infection

HLA is a critical component of the viral antigen presentation pathway. We investigated the relationship between severity of SARS-CoV-2 disease and HLA type in 3,235 individuals with confirmed SARS-CoV-2 infection. We found only the DPB1 locus to be associated with the binary outcome of whether an individual developed any COVID-19 symptoms. The number of peptides predicted to bind to an HLA allele had no significant relationship with disease severity both when stratifying individuals by ancestry or age and in a pooled analysis. Age, BMI, asthma status, and autoimmune disorder status were predictive of severity across multiple age and individual ancestry stratificiations. Overall, at the population level, we found HLA type is significantly less predictive of COVID-19 disease severity than certain demographic factors and clinical comorbidities.

A New Human Leukocyte Antigen Typing Algorithm Combined With Currently Available Genotyping Tools Based on Next-Generation Sequencing Data and Guidelines to Select the Most Likely Human Leukocyte Antigen Genotype

BackgroundHigh-precision human leukocyte antigen (HLA) genotyping is crucial for anti-cancer immunotherapy, but existing tools predicting HLA genotypes using next-generation sequencing (NGS) data are insufficiently accurate.Materials and MethodsWe compared availability, accuracy, correction score, and complementary ratio of eight HLA genotyping tools (OptiType, HLA-HD, PHLAT, seq2HLA, arcasHLA, HLAscan, HLA*LA, and Kourami) using 1,005 cases from the 1000 Genomes Project data. We created a new HLA-genotyping algorithm combining tools based on the precision and the accuracy of tools’ combinations. Then, we assessed the new algorithm’s performance in 39 in-house samples with normal whole-exome sequencing (WES) data and polymerase chain reaction–sequencing-based typing (PCR-SBT) results.ResultsRegardless of the type of tool, the calls presented by more than six tools concordantly showed high accuracy and precision. The accuracy of the group with at least six concordant calls was 100% (97/97) in HLA-A, 98.2% (112/114) in HLA-B, 97.3% (142/146) in HLA-C. The precision of the group with at least six concordant calls was over 98% in HLA-ABC. We additionally calculated the accuracy of the combination tools considering the complementary ratio of each tool and the accuracy of each tool, and the accuracy was over 98% in all groups with six or more concordant calls. We created a new algorithm that matches the above results. It was to select the HLA type if more than six out of eight tools presented a matched type. Otherwise, determine the HLA type experimentally through PCR-SBT. When we applied the new algorithm to 39 in-house cases, there were more than six matching calls in all HLA-A, B, and C, and the accuracy of these concordant calls was 100%.ConclusionsHLA genotyping accuracy using NGS data could be increased by combining the current HLA genotyping tools. This new algorithm could also be useful for preliminary screening to decide whether to perform an additional PCR-based experimental method instead of using tools with NGS data.

Impact of HLA type, age and chronic viral infection on peripheral T-cell receptor sharing between unrelated individuals

The human adaptive immune system must generate extraordinary diversity to be able to respond to all possible pathogens. The T-cell repertoire derives this high diversity through somatic recombination of the T-cell receptor (TCR) locus, a random process that results in repertoires that are largely private to each individual. However, factors such as thymic selection and T-cell proliferation upon antigen exposure can affect TCR sharing among individuals. By immunosequencing the TCRβ variable region of 426 healthy individuals, we find that, on average, fewer than 1% of TCRβ clones are shared between individuals, consistent with largely private TCRβ repertoires. However, we detect a significant correlation between increased HLA allele sharing and increased number of shared TCRβ clones, with each additional shared HLA allele contributing to an increase in ~0.01% of the total shared TCRβ clones, supporting a key role for HLA type in shaping the immune repertoire. Surprisingly, we find that shared antigen exposure to CMV leads to fewer shared TCRβ clones, even after controlling for HLA, indicative of a largely private response to major viral antigenic exposure. Consistent with this hypothesis, we find that increased age is correlated with decreased overall TCRβ clone sharing, indicating that the pattern of private TCRβ clonal expansion is a general feature of the T-cell response to other infectious antigens as well. However, increased age also correlates with increased sharing among the lowest frequency clones, consistent with decreased repertoire diversity in older individuals. Together, all of these factors contribute to shaping the TCRβ repertoire, and understanding their interplay has important implications for the use of T cells for therapeutics and diagnostics.

Can HLA type I and II alleles presence be associated with the clinical spectrum of CHIKV infection?

Host immune response as well as virulence factors are key in disease susceptibility. There are no known association studies of HLA class I and II alleles with chikungunya (CHIKV) infection in Latin American population. We aim to identify Human Leukocyte Antigen (HLA) alleles present in patients with CHIKV infection when compared to healthy controls, as well as allele association with the clinical spectrum of the disease. A cross-sectional analysis nested in a community cohort was carried out. We included patients 18 years and older with serological confirmation of CHIKV infection. HLA typing of HLA-A, HLA-B and HLA-DRB1 alleles was performed. Two-by-two tables were used to establish associations between allele presence and clinical characteristics. Data from 65 patients with confirmed CHIKV infection were analyzed for HLA typing. CHIKV infection was associated with the presence of HLA-A*68, HLA-B*35, HLA-DRB*01, HLA-DRB1*04 and HLA-DRB1*13 alleles with statistical significance when compared to healthy subjects. A statistically significant relationship was found between the presence of rash in the face or the abdomen and the presence of HLA-DRB1*04. Our study demonstrated that in our cohort, HLA type I as well as type II alleles are associated with CHIKV infection, and specifically an HLA type II allele with dermatological symptoms. Further research is needed to set a path for future investigation on genes outside the HLA system to improve knowledge in the pathophysiology of CHIKV infection and its host-pathogen interaction.

HLA Type and Chronic Viral Infection Impact Peripheral T-cell Receptor Sharing Between Unrelated Individuals

The human adaptive immune system must generate extraordinary diversity to be able to respond to all possible pathogens. The T-cell repertoire derives this high diversity through somatic recombination of the T-cell receptor (TCR) locus, a random process that results in repertoires that are largely private to each individual. However, certain factors such as low junctional diversity, thymic selection, and T-cell proliferation upon antigen exposure can affect TCR sharing among individuals. By immunosequencing the TCRβ variable region of 426 healthy individuals, we find that fewer than 1% of TCRβ clones are shared between individuals on average, consistent with largely private TCRβ repertoires. However, we detect a significant correlation between increased HLA allele sharing and increased number of shared TCRβ clones, with each additional shared HLA allele contributing to an increase in ~0.01% of the total TCRβ clones being shared, supporting a key role for HLA type in shaping the immune repertoire. Surprisingly, we find that shared antigen exposure to CMV leads to fewer shared TCRβ clones, even after controlling for HLA, indicative of a largely private response to major viral antigenic exposure. Consistent with this hypothesis, we find that increased age is correlated with decreased overall TCRβ clone sharing, indicating that the pattern of private TCRβ clonal expansion is a general feature of the T-cell response to other infectious antigens. All of these factors contribute to shaping the TCRβ repertoire, and understanding their interplay has important implications for the use of T cells for therapeutics and diagnostics.

Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers

BackgroundInfection with Salmonella enterica serovars Typhi and Paratyphi A cause an estimated 14 million cases of enteric fever annually. Here the controlled nature of challenge studies is exploited to identify genetic variants associated with enteric fever susceptibility.MethodsHuman challenge participants were genotyped by Illumina OmniExpress-24 BeadChip array (n=176) and/or transcriptionally profiled by RNA-sequencing (n=178).ResultsTwo SNPs within CAPN14 and MIATNB were identified with p<10−5 for association with development of symptoms or bacteraemia following oral S. Typhi or S. Paratyphi A challenge. Imputation of classical human leukocyte antigen (HLA) types from genomic and transcriptomic data identified HLA-B*27:05, previously associated with non-typhoidal Salmonella-induced reactive arthritis, as the HLA type most strongly associated with enteric fever susceptibility (p=0.012). Genes related to the unfolded protein response and heat shock were over-represented in HLA-B*27:05+ participants following challenge (p=0.01). Furthermore, intracellular replication of S. Typhi is higher in C1R cells transfected with HLA-B*27:05 (p=0.02).ConclusionThese data suggest that activation of the unfolded protein response by HLA-B*27:05 misfolding may create an intracellular environment conducive to S. Typhi replication, increasing susceptibility to enteric fever.