HLA‐DR polymorphism in SARS‐CoV‐2 infection and susceptibility to symptomatic COVID‐19

Kouraki, Afroditi; Chain, Benny; Brooks, Timothy; Abbass, Hakam; Abiodun, Aderonke; Alfarih, Mashael; Alldis, Zoe; Amin, Oliver E.; Andiapen, Mervyn; Artico, Jessica; Augusto, João B.; Baca, Georgiana Luisa; Bailey, Sasha N. L.; Bhuva, Anish; Boulter, Alex; Bowles, Ruth; Bracken, Olivia V; O’Brien, Ben; Bullock, Natalie; Butler, David K.; Captur, Gabriella; Champion, Nicola; Chan, Carmen; Chandran, Aneesh; Collier, David; Sousa, Jorge Couto de; Couto-Parada, Xosé; Cutiño-Moguel, Teresa; Davies, Rhodri H.; Douglas, Brooke; Genova, Cecilia Di; Dieobi‐Anene, Keenan; Diniz, Mariana O.; Ellis, Anaya; Feehan, Karen; Finlay, Malcolm; Fontana, Marianna; Forooghi, Nasim; Gaier, Celia; Gibbons, Joseph M.; Gilroy, Derek W.; Hamblin, Matt; Harker, Gabrielle; Hewson, Jacqueline; Hickling, Lauren M.; Hingorani, Aroon D.; Howes, Lee; Hughes, Alun; Hughes, Gemma; Hughes, Rebecca; Itua, Ivie; Jardim, Victor; Lee, Wing‐Yiu Jason; Jensen, Melaniepetra; Jones, Jessica; Jones, Meleri; Joy, George; Kapil, Vikas; Kurdi, Hibba; Lambourne, Jonathan; Lin, Kai‐Min; Louth, Sarah; Mandadapu, Vineela; Menacho, Katia; Mfuko, Celina; Mitchelmore, Oliver; Moon, Christopher; Munoz-Sandoval, Diana; Murray, Sam M.; Otter, Ashley; Pade, Corinna; Palma, Susana; Parker, Ruth; Patel, Kush; Pawarova, Babita; Petersen, Steffen E.; Piniera, Brian; Pieper, Franziska P.; Pope, Daniel; Prossora, Mary; Rannigan, Lisa; Rapala, Alicja; Reynolds, Catherine J.; Richards, Amy; Robathan, Matthew; Rosenheim, Joshua; Sambile, Genine; Schmidt, Nathalie M.; Semper, Amanda; Seraphim, Andreas; Simion, Mihaela; Smit, Angelique; Sugimoto, Michelle A.; Swadling, Leo; Taylor, Stephen; Temperton, Nigel; Thomas, Stephen J.; Thornton, George; Tucker, Art; Veerapen, Jessry; Vijayakumar, Mohit; Welch, Sophie; Wodehouse, Theresa; Wynne, Lucinda; Zahedi, Dan; Altmann, Daniel M.; Boyton, Rosemary J.; Brooks, Tim; Chain, Benjamin M.; Maini, Mala K.; Manisty, Charlotte; McKnight, Áine; Moon, James; Noursadeghi, Mahdad; Treibel, Thomas A.; Aithal, Guruprasad P.; Ashraf, Waheed; Astbury, Stuart; Ball, Jonathan K.; Chappell, Joseph G.; Craxford, Simon; Cusin, Lola; Duncan, Joshua D.; Ikram, Adeel; Irving, William L.; Jackson, Hannah J.; Kelly, Anthony; Lingaya, Melanie; Marson, Ben; Newham, J. A.; Nightingale, Jessica; Norrish, Alan; B, Nowicka; Ollivere, B.; Tarr, Alexander W.; Tighe, Patrick J.; Tsoleridis, Theocharis; Urbanowicz, Richard A.; Valdes, Ana M.; Vijay, Amrita

doi:10.1111/imm.13450

Cited by 21 publications

(9 citation statements)

References 48 publications

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“…Likewise, another recent paper describing an association of HLA-DRB1 alleles with asymptomatic infection did not genotype for HLA-B . 52 Finally, two other large studies that employed patient questionnaires regarding symptoms did not consider the most mild symptoms common in SARS-CoV-2 infection (e.g. “runny nose” and “scratchy throat”), resulting in a much less stringent definition of asymptomatic infection than we considered here.…”

Section: Discussionmentioning

confidence: 99%

A common allele of HLA mediates asymptomatic SARS-CoV-2 infection

Augusto

Yusufali

Peyser

et al. 2021

Preprint

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Background. Evidence has shown that a large proportion of SARS-CoV-2 infected individuals do not experience symptomatic disease. Owing to its critical role in immune response, we hypothesized that variation in the human leukocyte antigen (HLA) loci may underly asymptomatic infection. Methods. We enrolled 29,947 individuals registered in the National Marrow Donor Program for whom high-resolution HLA genotyping data were available in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Among 21,893 individuals who completed the baseline survey, our discovery (N=640) and replication (N=788) cohorts were comprised of self-identified White subjects who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci (HLA-A, -B, -C, -DRB1, -DQB1) with asymptomatic vs. symptomatic infection. Results. HLA-B*15:01 was significantly increased in asymptomatic individuals in the discovery cohort compared to symptomatic (OR = 2.45; 95%CI 1.38-4.24, p = 0.0016, pcorr = 0.048), and we reproduced this association in the replication cohort (OR= 2.32; 95%CI = 1.10-4.43, p = 0.017). We found robust association of HLA-B*15:01 in the combined dataset (OR=2.40 95% CI = 1.54-3.64; p = 5.67 x10-5) and observed that homozygosity of this allele increases more than eight times the chance of remaining asymptomatic after SARS-CoV-2 infection (OR = 8.58, 95%CI = 1.74-34.43, p = 0.003). Finally, we demonstrated the association of HLA-B*15:01 with asymptomatic SARS-Cov-2 infection is enhanced by the presence of HLA-DRB1*04:01 Conclusion. HLA-B*15:01 is strongly associated with asymptomatic infection with SARS-CoV-2 and is likely to be involved in the mechanism underlying early viral clearance.

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Section: Discussionmentioning

confidence: 99%

A common allele of HLA mediates asymptomatic SARS-CoV-2 infection

Augusto

Yusufali

Peyser

et al. 2021

Preprint

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“…The HLA-DR is an important regulator of antigen presentation that influences the immunological T cell response and disease prognosis. 17 As a result, the goal of this investigation was to assess if there was a link between monocyte HLA-DR expression, the T lymphocyte frequency, and the COVID-19 course diversity.…”

Section: Discussionmentioning

confidence: 99%

“…This is reinforced by recent research by Astbury et al who documented that HLADR polymorphisms influence COVID-19 outcome. 17 Both helper T (Th) cells and cytotoxic T cells have also been shown to play an important antiviral role by balancing the fight against the virus with the risk of developing autoimmunity or overwhelming inflammation. Locally and systemically, their absence will result in uncontrolled inflammatory innate reactions and detrimental tissue damage.…”

Section: Discussionmentioning

confidence: 99%

Utility of Monocyte Expression of HLA-DR versus T Lymphocyte Frequency in the Assessment of COVID-19 Outcome

Hammad¹,

Kotb²,

Eldesoky³

et al. 2022

IJGM

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Background Dysregulated immunity is a hallmark of SARS-CoV-2 infection. Immune suppression is indicated by low monocyte expression of human leukocyte antigen D-related (mHLA-DR). T cells are important antiviral cells. We aimed to assess the role of mHLA-DR and T lymphocyte frequency in predicting COVID-19 severity. Patients and Methods This cross-sectional study enrolled 97 SARS-CoV-2 positive patients, including mild to moderate (n = 49) and severe cases admitted to intensive care unit (ICU) (n = 48). These ICU cases were further subdivided into survivors (n = 35) and non-survivors (n = 13). Results Severe cases had a significant decrease in the mHLA-DR mean fluorescence intensity (MFI) and T lymphocyte percentage compared to mild to moderate cases ( P <0.001). Non-survivors had a lower T lymphocyte percentage ( P =0.004) than survivors. The mHLA-DR MFI and T lymphocyte percentage correlated with oxygen saturation (r=0.632, P <0.001) and (r=0.669, P <0.001), respectively. According to the ROC curves, mHLA-DR MFI, at a cutoff of 143 and an AUC of 0.9, is a reliable biomarker for distinguishing severe COVID-19 cases, with 89.6% sensitivity and 81.6% specificity, while T lymphocyte frequency had 81.3% sensitivity and 81.6% specificity at a cutoff of 54.4% and an AUC of 0.9. The T lymphocyte percentage as a predictor of ICU survival at a cutoff of 38.995% exhibited 100% sensitivity and 57.1% specificity. According to multivariate regression analysis, reduced mHLA-DR MFI and T lymphocyte percentage are independent predictors of COVID-19 severity (OR = 0.976, 95% CI: 0.955–0.997, P = 0.025) and (OR = 0.849, 95% CI: 0.741–0.972, P = 0.018), respectively. Conclusion Reduced mHLA-DR expression and T-lymphocyte percentage are independent predictors of COVID-19 severity. Oxygen saturation percentage is correlated with mHLA-DR MFI and T lymphocyte frequency. The T lymphocyte frequency is a proposed predictor of COVID-19 survival in ICU admitted patients.

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“…Ob SARS-CoV-2-spezifische T‑Zellen wirklich die Fähigkeit haben, sich gegen körpereigene Antigene zu richten, bedarf jedoch weiterer Studien. Ebenso muss der Einfluss des Human-leukocyte-antigen(HLA)-Typs auf den COVID-19-Erkrankungsverlauf im Zuge größerer genetischer Studien untersucht werden [ 4 ].…”

Section: Ursachenunclassified

Post-COVID-Syndrom – Fokus Fatigue

Hellwig

Domschke

2022

Nervenarzt

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Die Weltgesundheitsorganisation (WHO) definiert Post-COVID-19(„coronavirus disease 2019“) als Zustand, der bei Personen mit einer anamnestisch wahrscheinlichen oder bestätigten SARS-CoV-2(„severe acute respiratory syndrome coronavirus type 2“)-Infektion 3 Monate nach Beginn der COVID-19-Symptome und mindestens 2 Monate andauernd vorhanden ist und durch eine alternative Diagnose nicht erklärbar ist. Kernsymptome des Post-COVID-Syndroms umfassen Atemnot, Fatigue und kognitive Dysfunktion, welche das alltägliche Funktionsniveau beeinflussen. Neuropsychiatrische Spätfolgen sind bei COVID-19-Patienten mit Inzidenzraten von über 30 % häufig. Neben den genannten Kernsymptomen zeigen Schlafstörungen, Depression und Angsterkrankungen erhöhte Inzidenzen. Nach gegenwärtiger Meinung werden assoziierte neuropsychiatrische Symptome sowohl unter dem Begriff Post-COVID-Syndrom subsumiert, aber auch als Komorbiditäten interpretiert, welche die Manifestation eines Post-COVID-Syndroms begünstigen können. So zeigt das Kernsymptom Fatigue Symptomüberlappung und Komorbidität mit psychischen Erkrankungen. Bildgebungsstudien deuten auf ein organisches Korrelat der Fatigue bei Post-COVID-Patienten hin, darüber hinaus wurden psychosoziale Aspekte und psychiatrische Komorbiditäten wie Depression und Angsterkrankungen als modulierende und damit potenziell behandelbare Faktoren identifiziert. Die Therapie der Fatigue umfasst neben dem pharmakologischen Management mit u. a. Stimulanzien und Antidepressiva auch nichtpharmakologische Strategien, hier vor allem die kognitive Verhaltenstherapie sowie körper- und bewegungsfokussierte Interventionen. Die Evidenz hierfür erwächst aus Metaanalysen bei tumorassoziierter oder postviraler Fatigue.

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HLA‐DR polymorphism in SARS‐CoV‐2 infection and susceptibility to symptomatic COVID‐19

Abstract: are joint senior author. *The members of the COVIDsortium investigators and COVIDsortium immune correlates network can be found at the end of the Acknowledgements.

Cited by 21 publications

References 48 publications

A common allele of HLA mediates asymptomatic SARS-CoV-2 infection

A common allele of HLA mediates asymptomatic SARS-CoV-2 infection

Utility of Monocyte Expression of HLA-DR versus T Lymphocyte Frequency in the Assessment of COVID-19 Outcome

Post-COVID-Syndrom – Fokus Fatigue

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