IGF1R is protective in pneumococcal pneumonia

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Item Type:	Preprint
Title:	IGF1R is protective in pneumococcal pneumonia
Creators Name:	Felten, M., Teixeira Alves, L.G., Letsiou, E., Arnedo, E.A., Piñeiro-Hermida, S., López, I.P., Dietert, K., Firsching, T., Gruber, A.D., Fatykhova, D., Hocke, A., Lingscheid, T., Lienau, J., Rohde, G., Pichel, J.G. and Witzenrath, M.
Abstract:	BACKGROUND: Streptococcus pneumoniae (S.pn) is the most prevalent causal bacterial pathogen in community-acquired pneumonia. Despite appropriate antimicrobial therapy, pneumococcal pneumonia can progress to acute respiratory distress syndrome where actual therapies are mainly supportive, and the discovery of new molecular targets is needed. OBJECTIVE: To investigate the role of IGF1R (Insulin-like Growth Factor 1 Receptor) in pneumococcal pneumonia. METHODS: Igf1r-deficient (UBC-CreERT2; Igf1rfl/fl) and control (Igf1rfl/fl) mice were infected with 5×106 S.pn (PN36) or PBS (sham infected). Mice were sacrificed 48 h after infection. Pulmonary permeability, local inflammatory response, and pulmonary and extra-pulmonary bacterial loads were analyzed. Further, IGF1R protein expression was determined in human lung tissue after S.pn infection and IGF1 and IGF1R levels were determined serum of pneumonia patients. RESULTS: In patients and mice infected with S.pn, IGF1 signaling was significantly altered. Igf1r-deficient mice had significantly increased pulmonary permeability after infection with increased pulmonary inflammatory cytokine levels, while inflammatory cell recruitment was not altered compared to infected Igf1rfl/fl control animals. Pulmonary bacterial load was significantly higher in Igf1r-deficient mice, and histological analysis confirmed increased alveolar edema and necrosis compared to infected Igf1rfl/fl control and sham-infected mice. Ex vivo, S.pn caused a decrease in IGF1R protein expression in human lung tissue. CONCLUSION: Our results demonstrate a significant regulation of IGF1R in ex-vivo infected human lung tissue and in serum of S.pn pneumonia patients. Moreover, pneumonia severity was increased in Igf1r-deficient mice upon S.pn infection compared to Igf1rfl/fl control mice, suggesting that IGF1R plays a protective role in pneumococcal pneumonia.
Keywords:	Animals, Mice
Source:	bioRxiv
Publisher:	Cold Spring Harbor Laboratory Press
Article Number:	2024.09.11.612370
Date:	11 September 2024
Official Publication:	https://doi.org/10.1101/2024.09.11.612370

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