Rohn Hana, Elischer Fynn, Larbig Louisa, Jansen Sarah, Schramm Sabine, Otte Mona, Konik Margarethe, Paniskaki Krystallenia, Weber Peter, Reinold Johanna, Gäckler Anja, Krawczyk Adalbert, Wilde Benjamin, Trilling Mirko, Michita Rafael T, Möhlendick Birte, Siffert Winfried, Brenner Thorsten, Dinse Hannah, Skoda Eva M, Horn Peter A, Witzke Oliver, Rebmann Vera
Department of Infectious Diseases, West German Centre for Infectious Diseases (WZI), University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
HLA. 2024 Dec;104(6):e15799. doi: 10.1111/tan.15799.
HLA-G, an important immune-checkpoint (IC) molecule that exerts inhibitory signalling on immune effector cells, has been suggested to represent a key player in regulating the immune response to Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2). Since specific single-nucleotide polymorphisms (SNP) in the HLA-G 3'untranslated region (UTR), which arrange as haplotypes, are crucial for the regulation of HLA-G expression, we analysed the contribution of these genetic variants as host factors in SARS-CoV-2 infection during acute and post-acute phases. HLA-G gene polymorphisms in the 3'UTR were investigated by sequencing in an unvaccinated Coronavirus Disease 2019 (COVID-19) cohort during acute SARS-CoV-2 infection (N = 505) and in the post-acute phase (N = 253). The HLA-G 3'UTR haplotype known as UTR-3 (p = 0.002) and the variant rs17875408 (also known as +3422) T variant (p = 0.004) are independent prognostic risk factors for fatal COVID-19. The +3422T variant (p = 0.006) predicted also the early loss of neutralising SARS-CoV-2 antibodies. In addition, the HLA-G 3'UTR haplotype UTR-7 (p = 0.023) emerged as an independent prognostic factor for increased susceptibility to Long-COVID symptoms after SARS-CoV-2 infection. Our study highlights that due to the variability of the 3'UTR genetic background, HLA-G has the potential to contribute to the progression of SARS-CoV-2 infection, extending to the development of Long-COVID symptoms, despite the likely alterations in the microenvironment and associated HLA-G-specific regulatory elements over the course of the disease. By spotlighting HLA-G, the importance of the genetic background of IC and their pivotal role in modulating immune responses during and after COVID-19 are emphasised.
HLA-G是一种重要的免疫检查点（IC）分子，可对免疫效应细胞发挥抑制信号作用，有人认为它是调节对严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）免疫反应的关键因素。由于HLA-G 3'非翻译区（UTR）中的特定单核苷酸多态性（SNP）以单倍型形式排列，对HLA-G表达的调节至关重要，因此我们分析了这些基因变异作为宿主因素在SARS-CoV-2感染急性期和急性后期的作用。通过对2019冠状病毒病（COVID-19）未接种疫苗队列在急性SARS-CoV-2感染期（N = 505）和急性后期（N = 253）进行测序，研究了3'UTR中的HLA-G基因多态性。被称为UTR-3的HLA-G 3'UTR单倍型（p = 0.002）和rs17875408变异体（也称为+3422）的T变异体（p = 0.004）是致命COVID-19的独立预后危险因素。+3422T变异体（p = 0.006）还预测了中和SARS-CoV-2抗体的早期丧失。此外，HLA-G 3'UTR单倍型UTR-7（p = 0.023）是SARS-CoV-2感染后对长期COVID症状易感性增加的独立预后因素。我们的研究强调，由于3'UTR基因背景的可变性，尽管在疾病过程中微环境和相关的HLA-G特异性调节元件可能发生改变，但HLA-G有可能促进SARS-CoV-2感染的进展，甚至扩展到长期COVID症状的发展。通过关注HLA-G，强调了IC基因背景的重要性及其在调节COVID-19期间和之后免疫反应中的关键作用。
