Periodic Reporting for period 2 - UNDINE (The human genetic and immunological determinants of the clinical manifestations of SARS-CoV-2 infection: Towards personalised medicine)
Berichtszeitraum: 2023-12-01 bis 2025-05-31
Since the start of the COVID-19 pandemic, in December 2019, more than 778 million people have been infected with SARS-CoV-2, resulting in more than 7.1 million deaths worldwide. The consequences of exposure to SARS-CoV-2 vary greatly in the general population. While most exposed individuals are infected, rare 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 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), Neuro-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. 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.
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), Neuro-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. 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.
We conduct studies on human genetics and immunology of SARS-CoV-2 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 coordinates the recruitment of patient material from all participating clinics and monitors the supply of samples for the other six. Work packages 2-7 have progressed their research activities according to the DoA in the second reporting period (Month 1-18) without any major deviations. Work package 2 has been investigating the variation in immune responses to SARS-CoV-2 between human populations, including the quantification of a respective contribution of sex and age. It further presents 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 with a first candidate gene indicated in the second reporting period. At the same time, we continue to further investigate the monogenic basis of inborn resistance, 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 their biochemistry, expression and cellular localization we try to unravel a causal relationship between identified variants and cellular and clinical phenotype. In the second reporting period we have increased the number of candidate genes identified with potential disease-causing effect in relation to COVID-19 pneumonia. Biochemical, cellular and immunological evaluation is continuing. 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. UNDINE’s industry partner bioMérieux has developed a prototype test for auto-Abs to type I IFNs in the first reporting period and has manufactured a batch of tests in the second period now to be assessed for their efficiency as a reliable platform. Whole genome and exome sequencing is used in work package 6 to study the human genetics and immunology of MIS-C/A. During the second 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 complex field of Long-COVID. The aim is to unravel the genetics and immunology of Long-COVID symptomatology. In the first reporting period, several candidate genes have been identified that are likely to be associated with Long-COVID, which have been analysed by NGS in the second reporting period and are further investigated biochemically and immunologically.
The UNDINE project is still progressing well and according to the outlined time plan. In the second reporting period, we have expanded our engagement in communication and dissemination activities and In the first 36 months, 73 papers have been published that present data resulting from research conducted in UNDINE. All but one Milestones have been reached and all Deliverables have been submitted.
state-of-the-art and innovative genetic, molecular and immunological techniques in seven interrelated work packages. Work package 1 coordinates the recruitment of patient material from all participating clinics and monitors the supply of samples for the other six. Work packages 2-7 have progressed their research activities according to the DoA in the second reporting period (Month 1-18) without any major deviations. Work package 2 has been investigating the variation in immune responses to SARS-CoV-2 between human populations, including the quantification of a respective contribution of sex and age. It further presents 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 with a first candidate gene indicated in the second reporting period. At the same time, we continue to further investigate the monogenic basis of inborn resistance, 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 their biochemistry, expression and cellular localization we try to unravel a causal relationship between identified variants and cellular and clinical phenotype. In the second reporting period we have increased the number of candidate genes identified with potential disease-causing effect in relation to COVID-19 pneumonia. Biochemical, cellular and immunological evaluation is continuing. 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. UNDINE’s industry partner bioMérieux has developed a prototype test for auto-Abs to type I IFNs in the first reporting period and has manufactured a batch of tests in the second period now to be assessed for their efficiency as a reliable platform. Whole genome and exome sequencing is used in work package 6 to study the human genetics and immunology of MIS-C/A. During the second 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 complex field of Long-COVID. The aim is to unravel the genetics and immunology of Long-COVID symptomatology. In the first reporting period, several candidate genes have been identified that are likely to be associated with Long-COVID, which have been analysed by NGS in the second reporting period and are further investigated biochemically and immunologically.
The UNDINE project is still progressing well and according to the outlined time plan. In the second reporting period, we have expanded our engagement in communication and dissemination activities and In the first 36 months, 73 papers have been published that present data resulting from research conducted in UNDINE. All but one 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. bioMérieux has now manufactured a batch of tests in the second reporting period, which is to be assessed for their efficiency as a reliable platform. 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.