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The extracellular domain of Staphylococcus aureus LtaS binds insulin and induces insulin resistance during infection

Nature Microbiology volume 3, pages 622–631 (2018)Cite this article

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Abstract

Insulin resistance is a risk factor for obesity and diabetes and predisposes individuals to Staphylococcus aureus colonization; however, the contribution of S. aureus to insulin resistance remains unclear. Here, we show that S. aureus infection causes impaired glucose tolerance via secretion of an insulin-binding protein extracellular domain of LtaS, eLtaS, which blocks insulin-mediated glucose uptake. Notably, eLtaS transgenic mice (eLtaStrans) exhibited a metabolic syndrome similar to that observed in patients, including increased food and water consumption, impaired glucose tolerance and decreased hepatic glycogen synthesis. Furthermore, transgenic mice showed significant metabolic differences compared to their wild-type counterparts, particularly for the early insulin resistance marker α-hydroxybutyrate. We subsequently developed a full human monoclonal antibody against eLtaS that blocked the interaction between eLtaS and insulin, which effectively restored glucose tolerance in eLtaStrans and S. aureus-challenged mice. Thus, our results reveal a mechanism for S. aureus-induced insulin resistance.

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Fig. 1: Impaired glucose tolerance in S. aureus-challenged mice.
Fig. 2: eLtaS directly binds to insulin.
Fig. 3: eLtaS impairs insulin sensitivity.
Fig. 4: eLtaS impairs insulin sensitivity in vivo.
Fig. 5: eLtaS impairs insulin sensitivity in vivo.

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Acknowledgements

We thank H. Wu, Q. Wu and Y. Wu (Beijing Institute of Basic Medical Sciences) for technical support on preparation of the frozen tissue sections. This work was supported by grants from the National Natural Science Foundation of China (http://www.nsfc.gov.cn) (31370170) and the Natural Science Foundation of Beijing (http://bjnsf.bjkw.gov.cn/) (7142119). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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  1. These authors contributed equally: Yu Liu, Fang-Jie Liu

Authors and Affiliations

  1. Beijing Institute of Basic Medical Sciences, Beijing, China

    Yu Liu, Fang-Jie Liu, Zhang-Chun Guan, Ya-Ping Gao, Di Li, Jun Yan, Cheng-Hua Liu, Dian-Peng Han, Jian-Nan Feng, Bei-Fen Shen & Guang Yang

  2. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China

    Yu Liu, Fang-Jie Liu, Zhang-Chun Guan, Ya-Ping Gao, Di Li, Jun Yan, Cheng-Hua Liu, Dian-Peng Han, Jian-Nan Feng, Bei-Fen Shen & Guang Yang

  3. National Center of Biomedical Analysis, Beijing, China

    Fang-Ting Dong & Jian-Hua Cheng

  4. Health Care Center, Hospital of Chinese People’s Armed Police Force, Beijing, China

    Chun-Mei Ma

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Contributions

Y.L., F.-J.L. and Z.-C.G. acquired, analysed and interpreted the data. F.-T.D., J.-H.C., Y.-P.G., D.L. and D.-P.H. provided administrative, technical and material support. J.Y. and C.-H.L. analysed the data. C.-M.M. provided material support. J.-N.F. and B.-F.S. supervised the study. G.Y. conceived and designed the study, obtained funding and prepared the manuscript.

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Correspondence to Guang Yang.

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Liu, Y., Liu, FJ., Guan, ZC. et al. The extracellular domain of Staphylococcus aureus LtaS binds insulin and induces insulin resistance during infection. Nat Microbiol 3, 622–631 (2018). https://doi.org/10.1038/s41564-018-0146-2

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