Periodic Reporting for period 1 - UNDINE (The human genetic and immunological determinants of the clinical manifestations of SARS-CoV-2 infection: Towards personalised medicine)
Período documentado: 2022-06-01 hasta 2023-11-30
Since the start of the COVID-19 pandemic, in December 2019, more than 750 million people have been infected with SARS-CoV-2, resulting in more than 9 million deaths worldwide. The consequences of exposure to SARS-CoV-2 vary greatly in the general population. While most exposed individuals are infected, some individuals are not infected despite repeated exposure. The consequences of infection range from silent infection to lethal disease, with a variety of clinical presentations in between. This immense inter-individual clinical variability in disease severity and consequences is the key scientific and medical enigma in the field. UNDINE aims to unravel the pathogenesis of COVID-19 and to understand the tremendous variation in the susceptibility to suffer from severe disease, including COVID-19 pneumonia, multisystem inflammatory syndrome of children (MIS-C) and adults (MIS-A), neurological forms of COVID, and Long-COVID. In general, we hypothesize that most patients with one or another clinical manifestation of SARS-CoV-2 infection have pre-existing and causal genetic and/or immunological anomalies. In addition, we also tackle challenges like the clinical implications of novel SARS-CoV-2 variants and the occurrence of life-threatening COVID-19 pneumonia despite vaccination (“breakthrough cases”). UNDINE aims for new discoveries that expand the genetic knowledge and deepening the immunological insight to both innate and adaptive immunity with the aim to generate new diagnostic tests and personalized medicine approaches. To achieve our goals, we conduct studies on human genetics and immunology of SARS-CoV-2 infection in humans from single cells to the whole organism, building on established clinical cohorts of patients with different disease manifestations and state-of-the-art and innovative genetic, molecular and immunological techniques in seven interrelated work packages.
Work package 1 has been coordinating the recruitment of patient material from all participating clinics and continues to monitor the supply of samples for the other six. Work packages 2-7 have all successfully recruited scientific personnel and started their research activities according to the DoA in the first reporting period (Month 1-18). Work package 2 has been investigating the variation in immune responses to SARS-CoV-2 between human populations worldwide, including the quantification of respective contributions of sex and age. It can now also present first results on the potential contribution of host genetic factors to the variation in immune responses to the different strains of SARS-CoV-2. In work package 3, we have been trying to identify individuals resistant to SARS-CoV-2 infection and the genetic basis hereof. In the first reporting period, a cohort of resistors has been established. We started to further investigate the monogenic basis of inborn resistance, and ongoing work is assessing the immunological and functional consequences of candidate variants, with the ultimate aim to identify biological markers of resistance to infection with SARS-CoV-2. Elucidating the genetics and the immunity of critical COVID-19 pneumonia is the centre of work package 4. Using large-scale human genome sequencing followed by a characterization of genetic variant biochemistry, expression and cellular localization we try to unravel a causal relationship between identified variants and cellular and clinical phenotype. Here, first results in the reporting period have identified a number of candidate genes with potential disease-causing effect in relation to COVID-19 pneumonia, which are currently undergoing biochemical, cellular and immunological evaluation. Work package 5 tests for the presence and neutralizing activity of auto-Antibodies against type I IFNs or other cytokines in various COVID-19 conditions particularly related to critical COVID-19 pneumonia (WP4), MIS-C (WP6), and LongCOVID (WP7). UNDINE’s industry partner bioMérieux has developed a first prototype test for auto-Abs to type I IFNs. A first test kit has been designed in the reporting period and will be further investigated towards its suitability for being used as a routine diagnostic assay. Whole genome and exome sequencing is used in work package 6 to study the human genetics and immunology of MIS-C/A a. During the first reporting period, we have identified several genetic candidates underlying clinical manifestations of MIS-C. These candidate variants are currently being characterized at the molecular level, cellular and immunological levels. Finally, work package 7 focuses on the wide field of Long-COVID. The aim is to unravel the genetics and immunology of Long-COVID. Again, through whole genome and exome sequencing, followed by functional analyses of genetic variants, we try to assess the specificity and quality of adaptive immune responses to SARS-CoV-2 in patients with Long COVID. As a first step, we have defined what constitutes the clinical presentation of Long-COVID. Moreover, in the first reporting period, several candidate genes have been identified that are likely to be associated with Long-COVID, which are now being further investigated biochemically and immunologically.
The UNDINE project is progressing well and according to the originally outlined time plan. In the first reporting period, we have engaged in several public dissemination activities and first results have been communicated to the scientific community via conference contributions and research papers. Within the first 18 months, 35 papers have been published that present data resulting from research conducted in UNDINE. All Milestones have been reached and all Deliverables have been submitted.
The UNDINE project is progressing well and according to the originally outlined time plan. In the first reporting period, we have engaged in several public dissemination activities and first results have been communicated to the scientific community via conference contributions and research papers. Within the first 18 months, 35 papers have been published that present data resulting from research conducted in UNDINE. All Milestones have been reached and all Deliverables have been submitted.
Major results beyond the state of the art have not yet been identified. The first test kit prototype for detecting auto-Abs to type I IFNs, developed by UNDINE’s industry partner bioMérieux, may become a routine diagnostic assay in the future and is undergoing some preclinical testing in France. However, additional investigations are necessary to ascertain the suitability, sensitivity and specificity of the kit as a reliable test tool. Moreover, the genetic variants presently identified to underlie critical COVID-19 pneumonia and MIS-C are a focus for potential clinical testing in a genetic targeted panel, either testing of family members of patients with critical infection or of individuals at a larger scale prior to infection or after infection intensify prophylactic and therapeutic measures, respectively. So far commercialisation and IPR issues have not appeared.