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Electroporation-mediated delivery of FER gene enhances innate immune response and improves survival in a murine model of pneumonia

Gene Therapy volume 25, pages 359–375 (2018)Cite this article

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Abstract

Previously, we reported that electroporation-mediated (EP) delivery of the FER gene improved survival in a combined trauma-pneumonia model. The mechanism of this protective effect is unknown. In this paper, we performed a pneumonia model in C57/BL6 mice with 500 CFU of Klebsiella pneumoniae. After inoculation, a plasmid encoding human FER was delivered by EP into the lung (PNA/pFER-EP). Survival of FER-treated vs. controls (PNA; PNA/EP-pcDNA) was recorded. In parallel cohorts, bronchial alveolar lavage (BAL) and lung were harvested at 24 and 72 h with markers of infection measured. FER-EP-treated animals reduced bacterial counts and had better 5-day survival compared to controls (80 vs. 20 vs. 25%; p < 0.05). Pre-treatment resulted in 100% survival. With FER, inflammatory monocytes were quickly recruited into BAL. These cells had increased surface expression for Toll-receptor 2 and 4, and increased phagocytic and myeloperoxidase activity at 24 h. Samples from FER electroporated animals had increased phosphorylation of STAT transcription factors, varied gene expression of IL1β, TNFα, Nrf2, Nlrp3, Cxcl2, HSP90 and increased cytokine production of TNF-α, CCL-2, KC, IFN-γ, and IL-1RA. In a follow-up experiment, using Methicillin-resistant Staphylococcus aureus (MRSA) similar bacterial reduction effects were obtained with FER gene delivery. We conclude that FER overexpression improves survival through STAT activation enhancing innate immunity and accelerating bacterial clearance in the lung. This constitutes a novel mechanism of inflammatory regulation with therapeutic potential in the setting of hospital-acquired pneumonia.

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Acknowledgements

We gratefully acknowledge the support from the National Institutes of Health-R01GM111305 (KR) and K12HL133304 (DMA), as well as from the Michigan Center for Integrative Research in Critical Care (DMA). We also thank Dr. Eric White (Gift of Life of Michigan) and John Erby Wilkinson (Department of Pathology/ULAM, University of Michigan Medical School) for their help in obtaining, processing, and staining human lung tissue.

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  1. Division of Acute Care Surgery, University of Michigan, 1500 E Medical Center Dr, UH-1C421, SPC 5033, Ann Arbor, MI, 48109-5033, USA

    Vladislav Dolgachev, Sreehari Panicker, Sanjay Balijepalli, Lane Kelly McCandless, Yue Yin, Samantha Swamy, M. V. Suresh, Matthew J. Delano, Mark R. Hemmila, Krishnan Raghavendran & David Machado-Aranda

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  1. Vladislav Dolgachev
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Correspondence to David Machado-Aranda.

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Dolgachev, V., Panicker, S., Balijepalli, S. et al. Electroporation-mediated delivery of FER gene enhances innate immune response and improves survival in a murine model of pneumonia. Gene Ther 25, 359–375 (2018). https://doi.org/10.1038/s41434-018-0022-y

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