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Microbially cleaved immunoglobulins are sensed by the innate immune receptor LILRA2

Abstract

Microbial proteases degrade a variety of host proteins13. However, it has remained largely unknown why microorganisms have evolved to acquire such proteases and how the host responds to microbially degraded products. Here, we have found that immunoglobulins disrupted by microbial pathogens are specifically detected by leukocyte immunoglobulin-like receptor A2 (LILRA2), an orphan activating receptor expressed on human myeloid cells. Proteases from Mycoplasma hyorhinis, Legionella pneumophila, Streptococcus pneumonia and Candida albicans cleaved the N-terminus of immunoglobulins. Identification of the immunoglobulin-cleaving protease from L. pneumophila revealed that the protease is conserved across some bacteria including Vibrio spp. and Pseudomonas aeruginosa. These microbially cleaved immunoglobulins but not normal immunoglobulins stimulated human neutrophils via LILRA2. In addition, stimulation of primary monocytes via LILRA2 inhibited the growth of L. pneumophila. When mice were infected with L. pneumophila, immunoglobulins were cleaved and recognized by LILRA2. More importantly, cleaved immunoglobulins were detected in patients with bacterial infections and stimulated LILRA2-expressing cells. Our findings demonstrate that LILRA2 is a type of innate immune receptor in the host immune system that detects immunoglobulin abnormalities caused by microbial pathogens.

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Figure 1: Recognition of cleaved Ig by LILRA2.
Figure 2: Activation of LILRA2-expressing neutrophils by truncated Ig.
Figure 3: Cleavage of Ig by various pathogens in vitro and in vivo.
Figure 4: Activation of LILRA2-expressing cells by pus fluids from patients with a bacterial infection.

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Acknowledgements

The authors thank K. Saito of the DNA-chip Development Center for Infectious Diseases (RIMD, Osaka University) for technical assistance, Y. Horiguchi (Department of Molecular Bacteriology, RIMD, Osaka University) for discussions, J. Matsuyama (Pathogenic Microbes Repository Unit, RIMD, Osaka University) for preparing various bacteria and J. Coers (Department of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center) for providing a plasmid for the P. luminescens luxCDABE operon. This work was partially supported by JSPS KAKENHI (grant nos. 15K15131, 15H02545, 24115005, 26117714 and 26870334), the Practical Research Project for Allergic Diseases and Immunology from the Japan Agency for Medical Research and development, AMED, The Mochida Memorial Foundation for Medical and Pharmaceutical Research (to K.H.), The Uehara Memorial Foundation, the Terumo Life Science Foundation and the Tokyo Biochemical Research Foundation (to H.A.).

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Contributions

K.H. performed experiments, analysed and discussed the data and wrote the manuscript. F.S. assisted with experiments, discussed the data and edited the manuscript. T.S. assisted with experimental design, discussed the data and edited the manuscript. K.S. assisted with experiments and discussed the data. N.A., K.O., T.Y., H.M., I.N., Y.N. and I.K. collected and analysed clinical samples and discussed the data. H.C. assisted with fungal experiments and discussed the data. T.K. and H.N. assisted with bacterial experiments and discussed the data. M.C. assisted with experiments and discussed the data. H.A. designed the study, analysed the data and wrote the manuscript.

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Correspondence to Hisashi Arase.

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Hirayasu, K., Saito, F., Suenaga, T. et al. Microbially cleaved immunoglobulins are sensed by the innate immune receptor LILRA2. Nat Microbiol 1, 16054 (2016). https://doi.org/10.1038/nmicrobiol.2016.54

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