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Comparison of IP-10 production induced by ex-vivo stimulation with Respiratory Syncytial Virus (RSV) and the TLR3 agonist Poly I: C in human and non-human primate lung tissues

: Twisterling, Elaine S.; Dahlmann, Franziska; Dehmel, Susann; Wronski, Sabine; Braubach, Peter; Jonigk, Danny; Warnecke, G.; Krüger, M.; Zardo, P.; Sewald, Katherina; Braun, Armin

Allergy. European journal of allergy and clinical immunology 73 (2018), Supplement 105, Abstract 1117
ISSN: 0105-4538
ISSN: 1398-9995
European Academy of Allergy and Clinical Immunology (EAACI Congress) <2018, Munich>
Fraunhofer ITEM ()

Background: Human Respiratory Syncytial virus (HRSV) is a major cause of respiratory disease young children and is known as a risk factor for asthma. HRSV and the viral mimic Poly I:C activate toll‐like receptor 3 (TLR3), initiating an innate response with release of immune mediators, e.g. interferon gamma‐induced protein 10 (IP‐10). In this work, we aimed to perform an ex vivo HRSV infection in precision‐cut lung slices (PCLS) from human, rhesus, and cynomolgus macaques, comparing whenever possible the response with the viral surrogate poly I:C.
Method: PCLS containing airways were prepared from lung sections of human, rhesus, and cynomolgus macaques. The slices were inoculated with HRSV‐A2 106 IU/mL, UV‐inactivated HRSV, or vehicle control for 48 hours. Macaque slices were also incubated with Poly I:C 100 μg/mL with and without the immunosuppressive dexamethasone 50 μg/mL. Viral replication, tissue viability, and immune response assays were assessed in supernatants, lysates, or slices.
Results: The inoculum infectivity of 106 IU/mL as well the UV‐inactivation were confirmed by plaque‐assay on Hep‐2 cells Immunofluorescence staining using a FITC‐labeled anti‐RSV showed the presence of infected macrophages in PCLS, but not in mock infected samples. HRSV stimulation slightly decreased tissue viability, as seen by Live/DEAD staining and LDH assay. The viral infection increased IP‐10 production in PCLS of human, rhesus, and cynomolgus macaques, reaching respectively 13.3, 3.4, and 1.7 fold‐increase in comparison to the vehicle controls. Poly I:C stimulation caused IP10 response comparable to HRSV in rhesus and cynomolgus PCLS. The IP‐10 production ratio comparing HRSV/Poly I:C was 1.1 in rhesus and 0.9 in cynomolgus PCLS.
Conclusion: HRSV infects ex vivo PCLS of human and non‐human primates, inducing the release of the pro‐inflammatory chemokine IP‐10. This response is comparable to the viral surrogate poly I:C. In the future, these systems can be used to further investigate host response to HRSV, especially in the context of asthma development.