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ZKSCAN3 in severe bacterial lung infection and sepsis-induced immunosuppression

Abstract

The mortality rates among patients who initially survive sepsis are, in part, associated with a high risk of secondary lung infections and respiratory failure. Given that phagolysosomes are important for intracellular killing of pathogenic microbes, we investigated how severe lung infections associated with post-sepsis immunosuppression affect phagolysosome biogenesis. In mice with P. aeruginosa-induced pneumonia, we found a depletion of both phagosomes and lysosomes, as evidenced by decreased amounts of microtubule associated protein light chain 3-II (LC3-II) and lysosomal-associated membrane protein (LAMP1). We also found a loss of transcription factor E3 (TFE3) and transcription factor EB (TFEB), which are important activators for transcription of genes encoding autophagy and lysosomal proteins. These events were associated with increased expression of ZKSCAN3, a repressor for transcription of genes encoding autophagy and lysosomal proteins. Zkscan3−/− mice had increased expression of genes involved in the autophagy-lysosomal pathway along with enhanced killing of P. aeruginosa in the lungs, as compared to wild-type mice. These findings highlight the involvement of ZKSCAN3 in response to severe lung infection, including susceptibility to secondary bacterial infections due to immunosuppression.

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Fig. 1: The effects of endotoxin-induced acute lung injury and P. aeruginosa-mediated pneumonia on autophagy, phagolysosomal and lysosomal regulatory components in mouse lung.
Fig. 2: The effects of endotoxin-induced acute lung injury and P. aeruginosa-induced pneumonia on TFEB, TFE3 and ZKSCAN3 levels in lungs of mice.
Fig. 3: ZKSCAN3 deficiency improved bacterial killing in lung of mice.
Fig. 4: Comparison of lung histology between wild-type and Zkscan3−/− mice.

Data availability

All data is available.

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Acknowledgements

This study is funded by: US Department of Defense grant W81XWH-17-1-0577 (J.W.Z.); NIH 1R01HL139617-01 (J.W.Z.); Nathan Shock Center NIH AG050886 (V.D.U., J.Z.).

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X.O., E.B., N.B.B., M.S.J., and J.C. performed experiments and interpreted data. W.X.Z. contributed to key reagents. V.D.U., J.W.Z. and J.Z. designed the experiments and interpreted the data. E.B., N.B.B., V.D.U., J.W.Z. and J.Z. wrote the manuscript. All authors read and edited the manuscript.

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Correspondence to Jaroslaw W. Zmijewski or Jianhua Zhang.

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Ouyang, X., Becker Jr., E., Bone, N.B. et al. ZKSCAN3 in severe bacterial lung infection and sepsis-induced immunosuppression. Lab Invest (2021). https://doi.org/10.1038/s41374-021-00660-z

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