Which genetic factors make some children particularly susceptible to severe RSV infections?

What is this research project about?

Newborns are particularly susceptible to infections.


What is this research project about?

The Respiratory Syncytial Virus (RSV) is a globally distributed respiratory pathogen. In the winter season it causes epidemic respiratory infections in all age groups. Among healthy adults, RSV infections are generally mild with common cold-like symptoms. However, primary RSV infections among infants can take a severe course. In fact, RSV is the most frequent cause of lower respiratory tract infections among infants and it causes significant morbidity and mortality in this age group. The course and outcome of primary RSV infection are highly variable. While some children have only mild symptoms such as during a common cold, others are severely ill and need hospitalization. Pre-term birth is one important known risk factor for severe RSV infection. However, most cases of a severe primary RSV infection occur among infants that do not have any known risk factors. Globally the most severe cases are responsible for more than 3 million hospital admissions and 59.600 in hospital deaths every year.

To the pictures: Figure 1 shows uninfected cells (purple nuclei). Figures 2, 3 and 4 show progressive RSV infection; the cells were infected with a virus (green) and a viral protein was stained (orange/red); in the superposition of both colours they appear yellow; as the infection progresses neighbouring cells fuse. Source: Svenja Sake/Twincore


Figure 1

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What’s the current status?

The determinants controlling severe primary RSV disease are poorly defined. Genetic variation in some genes involved in various immune functions has been associated with severe courses of infection. It is generally assumed that genetic variants in multiple genes may contribute to RSV disease severity. However, genome-wide and comprehensive studies are missing. Vaccines or directly acting antivirals to prevent or treat RSV infections are not available. A prophylactic monoclonal antibody is used to protect infants at very high risk (e.g. due to pre-term birth) in the first year of their life. However, this prophylaxis is expensive and its cost-effective administration is compromised by incomplete knowledge about those children at greatest risk for severe RSV infection. Thus, precise information about host determinants responsible for severe courses of primary RSV infection opens new opportunities for diagnosing infants with a high risk of severe RSV disease and for personalized prophylaxis.

Nasal epithelial cells with cilia movement of the ciliated epithelium. These cells are the preferred target cells of an RSV infection. © Dr. Martin Wetzke | MHH Children’s Hospital

What are the project goals?

The objective of our project is to discover genetic factors that control the course and severity of an RSV infection among infants. We aim to identify the genes that contribute to RSV infectious disease susceptibility and to understand how genetic variation in these genes influences RSV infection and immune control. Building on this information we aim to develop diagnostic procedures that allow prediction of the risk for severe RSV disease. Ultimately, such diagnostic tests would enable identification of children with a risk for severe infection and thus allow tailored distribution of prophylactic antibodies for protection of these vulnerable infants.

How do we get there?

Over the past years, we have established a cohort of 160 infants aged less than two years suffering from severe RSV infection (IRIS cohort, Infection with Respiratory Syncytial Virus), completed whole exome sequencing (WES), and identified 346 SNPs that are significantly associated with severe RSV infection. Patients were included based on stringent inclusion/exclusion criteria and extensively clinically profiled including quantitative parameters of disease severity (e.g. duration of hospitalization, and oxygen support). Bio specimen (nasal fluid and serum) were stored in the Hannover Unified Biobank. RSV infection including possible co-infection by other viruses was confirmed by RT-PCR. Mechanistic follow up has highlighted novel RSV dependency and restriction factors that are targeted by associated coding SNPs (Patent application Hansen, Wetzke, Haid, Pietschmann EP17195522.2).

Electron microscope image: An RSV particle releases parts of the filamentous genome (source: RKI)


Project title: Genetic Determinants of severe respiratory syncytial virus infection among infants

Prof. Dr. Thomas Pietschmann

Projekte: A1, B10

Prof. Dr. Gesine Hansen

Projekte: A1, B1

Project A1 Publications

Publications of the Year 2023:

Non-Appearance of the RSV Season 2020/21 During the COVID-19 Pandemic–Prospective, Multicenter Data on the Incidence of Respiratory Syncytial Virus (RSV) Infection. Lange M, Happle C, Hamel J, Dördelmann M, Bangert M, Kramer R, Eberhardt F, Panning M, Heep A, Hansen G, Wetzke M.  Dtsch Arztebl Int. 2021 Aug 23;118(33-34):561-562.

Pathogen spectra in hospitalised and nonhospitalised children with community-acquired pneumonia. Wetzke M, Schütz K, Kopp MV, Seidenberg J, Vogelberg C, Ankermann T, Happle C, Voigt G, Köster H, Illig T, Lex C, Schuster A, Maier R, Panning M, Barten G, Rohde G, Welte T, Hansen G. ERJ Open Res. 2023 Mar 13;9(2):00286-2022.

Virucidal activity of oral, hand, and surface disinfectants against respiratory syncytial virus. Meister TL, Friesland M, Frericks N, Wetzke M, Haid S, Steinmann J, Todt D, Pietschmann T, Steinmann E.  J Hosp Infect. 2023 Aug 23;141:25-32.

Publications of the Year 2022:

IRIS: Infection with RespIratory Syncytial Virus in infants-a prospective observational cohort study. Wetzke M, Funken D, Lange M, Bejo L, Haid S, Monteiro JGT, Schütz K, Happle C, Schulz TF, Seidenberg J, Pietschmann T, Hansen G. BMC Pulm Med. 2022 Mar 15;22(1):88.

Target capture sequencing reveals a monoclonal outbreak of respiratory syncytial virus B infections among adult hematologic patients. Baier C, Huang J, Reumann K, Indenbirken D, Thol F, Koenecke C, Ebadi E, Heim A, Bange FC, Haid S, Pietschmann T, Fischer N. Antimicrob Resist Infect Control.

Respiratory Syncytial Virus Two-Step Infection Screen Reveals Inhibitors of Early and Late Life Cycle Stages. Sake SM, Kosch C, Blockus S, Haid S, Gunesch AP, Zhang X, Friesland M, Trummer SB, Grethe C, Kühnel A, Rückert J, Duprex WP, Huang J, Rameix-Welti MA, Empting M, Fischer N, Hirsch AKH, Schulz TF, Pietschmann T. Antimicrob Agents Chemother. 2022 Nov 8:e0103222. doi: 10.1128/aac.01032-22. Epub ahead of print.

Publications of the Year 2021:

Tim-3 is dispensable for allergic inflammation and respiratory tolerance in experimental asthma. Boehne C, Behrendt AK, Meyer-Bahlburg A, Boettcher M, Drube S, Kamradt T, Hansen G. PLoS One. 2021 Apr 6;16(4):e0249605. doi: 10.1371/journal.pone.0249605. eCollection 2021.
PMID: 33822811

Reverse genetics systems for contemporary isolates of respiratory syncytial virus enable rapid evaluation of antibody escape mutants. Jo WK, Schadenhofer A, Habierski A, Kaiser FK, Saletti G, Ganzenmueller T, Hage E, Haid S, Pietschmann T, Hansen G, Schulz TF, Rimmelzwaan GF, Osterhaus ADME, Ludlow M. Proc Natl Acad Sci U S A. 2021 Apr 6;118(14):e2026558118.

Publications of the Year 2020:

Labyrinthopeptins as virolytic inhibitors of respiratory syncytial virus cell entry. Blockus S, Sake SM, Wetzke M, Grethe C, Graalmann T, Pils M, Le Goffic R, Galloux M, Prochnow H, Rox K, Hüttel S, Rupcic Z, Wiegmann B, Dijkman R, Rameix-Welti MA, Eléouët JF, Duprex WP, Thiel V, Hansen G, Brönstrup M, Haid S, Pietschmann T. Antiviral Res. 2020 May;177:104774. doi: 10.1016/j.antiviral.2020.104774. Epub 2020 Mar 18. PMID: 32197980.

IL-17 regulates DC migration to the peribronchial LNs and allergen presentation in experimental allergic asthma. Jirmo AC, Busse M, Happle C, Skuljec J, Dalüge K, Habener A, Grychtol R, DeLuca DS, Breiholz OD, Prinz I, Hansen G.Eur J Immunol. 2020 Jul;50(7):1019-1033. doi: 10.1002/eji.201948409. Epub 2020 Mar 29. PMID: 32142593.

Differential expression patterns of glycosphingolipids and C-type lectin receptors on immune cells in absence of functional regulatory T cells. Jirmo AC, Rossdam C, Grychtol R, Happle C, Gerardy-Schahn R, Buettner FFR, Hansen G. Immun Inflamm Dis. 2020 Dec;8(4):512-522. doi: 10.1002/iid3.334. Epub 2020 Aug 1. PMID: 32737949; PMCID: PMC7654419.

Regulatory B cells control airway hyperreactivity and lung remodeling in a murine asthma model. Dipl-Biol AH, Happle C, Grychtol RM, Skuljec J, Busse M, Dalüge K, Obernolte H, Sewald K, Braun A, Meyer-Bahlburg A, Hansen G. J Allergy Clin Immunol. 2020 Nov 27:S0091-6749(20)31634-1. doi: 10.1016/j.jaci.2020.09.041. Epub ahead of print. PMID: 33249168.

Protecting-Group-Mediated Diastereoselective Synthesis of C4′-Methylated Uridine Analogs and Their Activity against the Human Respiratory Syncytial Virus. Köllmann C, Sake SM, Jones PG, Pietschmann T, Werz DB.  J Org Chem. 2020 Mar 20;85(6):4267-4278. doi: 10.1021/acs.joc.9b03425. Epub 2020 Feb 26. PMID: 32036652.

Publications of the Year 2019:

PedCAPNETZ – prospective observational study on community acquired pneumonia in children and adolescents. Wetzke M, Kopp MV, Seidenberg J, Vogelberg C, Ankermann T, Happle C, Voigt G, Köster H, Illig T, Lex C, Schuster A, Panning M, Barten G, Rohde G, Welte T, Hansen G; pedCAPNETZ Study Group. BMC Pulm Med. 2019 Dec 9;19(1):238. doi: 10.1186/s12890-019-1013-5.

Synthesis of 4’/5′-Spirocyclopropanated Uridine and d-Xylouridine Derivatives and Their Activity against the Human Respiratory Syncytial Virus. Köllmann C, Wiechert SM, Jones PG, Pietschmann T, Werz DB. Org Lett. 2019 Sep 6;21(17):6966-6971. doi: 10.1021/acs.orglett.9b02555. Epub 2019 Aug 21. PMID: 31433193.

Publications of the Project A1