Ped-COVID-19 Study

COVID-19 is an infectious disease caused by the new strain of coronavirus SARS-CoV-2. It was first identified in 2019 in Wuhan, China, and has since spread globally, resulting in the 2019–20 coronavirus pandemic. Common symptoms include fever and cough, however disease symptoms as well as disease course and outcome are highly variable ranging from asymptomatic cases to severe pneumonia and death. While children are likely to have milder symptoms than adults, children of all ages are susceptible to COVID-19 and can suffer from severe disease. Until now it is unknown why children show a different course of disease compared to adults.

Studying the immune response to SARS-CoV-2 in children is therefore critical to rapidly advance our understanding of the pathophysiology of COVID-19 both in children and adults. Children offer a unique possibility to study host-related factors that determine COVID-19 severity in the absence of ageing and comorbidity-related interactions, which are largely determining the disease course in adults.

We have therefore initiated a functional genetics and genomics COVID-19 study to examine the genetic and environmental risk factors of COVID-19 in pediatric and adult patients. Our group integrates deep immune profiling with multi-omics across multiple molecular levels (genome, transcriptome, proteome, metabolome) to enhance our understanding of the human immune response to SARS-CoV-2. Following questions will be addressed:

- Why does SARS-CoV-2 affect children differently compared to adults?

- What are the genetic and immunological risk factors that contribute to this difference?

- Can we use these factors to identify those children who will become severely affected?

As part of the Child Health Alliance Munich (CHANCE) initiative this prospective study is performed at the Dr. von Hauner Children’s Hospital of the Ludwig-Maximilians University (LMU) Munich and the Department of Pediatrics of the Technical University of Munich School of Medicine (TUM). The study is also actively involved in national (Deutsche COVID-19 OMICS Initiative) and international (COVID-19 Host Genetics Initiative) COVID-19 initiatives to join forces in combating this pandemic.

Selected publications:

1. Flynn, E., Tsu, A., Kasela, S., Kim-Hellmuth, S., Aguet, F., Ardlie, K. G., Bussemaker, H. J., Mohammadi, P. & Lappalainen, T. Transcription factor regulation of eQTL activity across individuals and tissues. Plos Genet 18, e1009719 (2022).

2. Brandt, M. K., Kim-Hellmuth, S., Ziosi, M., Gokden, A., Wolman, A., Lam, N., Recinos, Y., Hornung, V. K., Schumacher, J. & Lappalainen, T. An autoimmune disease riskvariant: A trans master regulatory effect mediated by IRF1 under immune stimulation? PLoS Genet 17(7), (2021). 

3. Warnat-Herresthal, S., Schultze, H., Shastry, K. L., Manamohan, S., Mukherjee, S., Garg, V., Sarveswara, R., Händler, K., Pickkers, P., Aziz, N. A., Ktena, S., Tran, F., Bitzer, M., Ossowski, S., Casadei, N., Herr, C., Petersheim, D., Behrends, U., Kern, F., Fehlmann, T., Schommers, P., Lehmann, C., Augustin, M., Rybniker, J., Altmüller, J., Mishra, N., Bernardes, J. P., Krämer, B., Bonaguro, L., Schulte-Schrepping, J., Domenico, E. D., Siever, C., Kraut, M., Desai, M., Monnet, B., Saridaki, M., Siegel, C. M., Drews, A., Nuesch-Germano, M., Theis, H., Heyckendorf, J., Schreiber, S., Kim-Hellmuth, S., […], Deutsche COVID-19 Omics Initiative (DeCOI), Giamarellos-Bourboulis, E. J., Kox, M., Becker, M., Cheran, S., Woodacre, M. S., Goh, E. L. & Schultze, J. L. Swarm Learning for decentralized and confidential clinical machine learning. Nature 1–7 (2021). 

4. de Goede, O. M., Nachun, D. C., Ferraro, N. M., Gloudemans, M. J., Rao, A. S., Smail, C., Eulalio, T. Y., Aguet, F., Ng, B., Xu, J., Barbeira, A. N., Castel, S. E., Kim-Hellmuth, S., Park, Y., Scott, A. J., Strober, B. J., GTEx Consortium, Brown, C. D., Wen, X., Hall, I. M., Battle, A., Lappalainen, T., Im, H. K., Ardlie, K. G., Mostafavi, S., Quertermous, T., Kirkegaard, K. & Montgomery, S. B. Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease. Cell (2021).

5. GTEx Consortium#. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science 369, 1318-1330 (2020). #Lead analyst: Kim-Hellmuth, S.

6. Kim-Hellmuth, S.†*, Aguet, F.*, Oliva, M., Muñoz-Aguirre, M., Kasela, S., Wucher, V., Castel, S. E., Hamel, A. R., Viñuela, A., Roberts, A. L., Mangul, S., Wen, X., Wang, G., Barbeira, A. N., Garrido-Martin, D., Nadel, B., Zou, Y., Bonazzola, R., Quan, J., Brown, A., Martinez-Perez, A., Soria, J. M., GTEx Consortium, Getz, G., Dermitzakis, E., Small, K. S., Stephens, M., Xi, H. S., Im, H. K., Guigó, R., Segre, A. V., Stranger, B. E., Ardlie, K. G. & Lappalainen, T.  Cell type specific genetic regulation of gene expression across human tissues. Science 369 (2020). 

7. Oliva, M.*, Muñoz-Aguirre, M.*, Kim-Hellmuth, S.*, Wucher, V., Gewirtz, A., Cotter, D., Parsana, P., Kasela, S., Balliu, B., Viñuela, A., Castel, S. E., Mohammadi, P., Aguet, F., Zou, Y., Khramtsova, E., Skol, A., Garrido-Martin, D., Reverter, F., Brown, A., Evans, P., Gamazon, E., Payne, A., Bonazzola, R., Barbeira, A. N., Hamel, A. R., Martinez-Perez, A., Soria, J. M., GTEx Consortium, Pierce, B., Stephens, M., Eskin, E., Dermitzakis, E., Segre, A. V., Im, H. K., Engelhardt, B., Ardlie, K. G., Montegomery, S., Battle, A., Lappalainen, T., Guigó, R. & Stranger, B. E. The impact of sex on gene expression and its genetic regulation across human tissues. Science 369 (2020). 

8. Demanelis, K., Jasmine, F., Chen, L. S., Chernoff, M., Tong, L., Delgado, D., Zhang, C., Shinkle, J., Sabarinathan, M., Lin, H., Ramirez, E., Oliva, M., Kim-Hellmuth, S., Stranger, B. E., Lai, T.-P., Aviv, A., Ardlie, K. G., Aguet, F., Ahsan, H., GTEx Consortium, Doherty, J. A., Kibriya, M. G. & Pierce, B. L. Determinants of telomere length across human tissues. Science 369 (2020). 

9. Kim-Hellmuth, S.*, Hermann, M.*, Eilenberger, J., Ley-Zaporozhan, J., Fischer, M., Hauck, F., Klein, C., Haas, N., Kappler, M., Huebner, J., Jakob, A. & Both, von, U. SARS-CoV-2 Triggering Severe Acute Respiratory Distress Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in a 3-Year-Old Child With Down Syndrome. Journal of the Pediatric Infectious Diseases Society 146, e2020009399–4 (2020).

10. Kim-Hellmuth, S.†, Bechheim, M., Pütz, B., Mohammadi, P., Nédélec, Y., Giangreco, N., Becker, J., Kaiser, V., Fricker, N., Beier, E., Boor, P., Castel, S. E., Nöthen, M. M., Barreiro, L. B., Pickrell, J. K., Müller-Myhsok, B., Lappalainen, T., Schumacher, J. & Hornung, V. Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations. Nat Commun 8, 266 (2017).

11. Kim-Hellmuth, S. & Lappalainen, T. Concerted Genetic Function in Blood Traits. Cell 167, 1167–1169 (2016).

12. Kim, S., Becker, J., Bechheim, M., Kaiser, V., Noursadeghi, M., Fricker, N., Beier, E., Klaschik, S., Boor, P., Hess, T., Hofmann, A., Holdenrieder, S., Wendland, J. R., Fröhlich, H., Hartmann, G., Nöthen, M. M., Müller-Myhsok, B., Pütz, B., Hornung, V. & Schumacher, J. Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes. Nat Commun 5, 5236 (2014).

13. Kim, S., Kaiser, V., Beier, E., Bechheim, M., Guenthner-Biller, M., Ablasser, A., Berger, M., Endres, S., Hartmann, G. & Hornung, V. Self-priming determines high type I IFN production by plasmacytoid dendritic cells. Eur. J. Immunol. 44, 807–818 (2014).

14. Kim, S., Bauernfeind, F., Ablasser, A., Hartmann, G., Fitzgerald, K. A., Latz, E. & Hornung, V. Listeria monocytogenes is sensed by the NLRP3 and AIM2 inflammasome. Eur. J. Immunol. 40, 1545–1551 (2010).

15. Hornung, V., Ellegast, J., Kim, S., Brzózka, K., Jung, A., Kato, H., Poeck, H., Akira, S., Conzelmann, K.-K., Schlee, M., Endres, S. & Hartmann, G. 5'-Triphosphate RNA is the ligand for RIG-I. Science 314, 994–997 (2006).

†Corresponding author, *Equally contributing author

Complete list of publications