The influenza-injured lung microenvironment promotes MRSA virulence, contributing to severe secondary bacterial pneumonia
Influenza infection is substantially worsened by the onset of secondary pneumonia caused by bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). The bidirectional interaction between the influenza-injured lung microenvironment and MRSA is poorly understood. By conditioning MRSA ex v...
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| Published in: | Cell reports (Cambridge) Vol. 41; no. 9; p. 111721 |
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| Main Authors: | , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
Elsevier Inc
29-11-2022
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Influenza infection is substantially worsened by the onset of secondary pneumonia caused by bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). The bidirectional interaction between the influenza-injured lung microenvironment and MRSA is poorly understood. By conditioning MRSA ex vivo in bronchoalveolar lavage fluid collected from mice at various time points of influenza infection, we found that the influenza-injured lung microenvironment dynamically induces MRSA to increase cytotoxin expression while decreasing metabolic pathways. LukAB, a SaeRS two-component system-dependent cytotoxin, is particularly important to the severity of post-influenza MRSA pneumonia. LukAB’s activity is likely shaped by the post-influenza lung microenvironment, as LukAB binds to (and is activated by) heparan sulfate (HS) oligosaccharide sequences shed from the epithelial glycocalyx after influenza. Our findings indicate that post-influenza MRSA pneumonia is shaped by bidirectional host-pathogen interactions: host injury triggers changes in bacterial expression of toxins, the activity of which may be shaped by host-derived HS fragments.
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•The influenza-injured lung microenvironment induces MRSA cytotoxin expression•SaeRS-dependent LukAB is critical to the severity of post-influenza secondary pneumonia•The influenza-injured lung microenvironment is further characterized by HS shedding•LukAB binds to soluble HS, augmenting cytotoxicity both in vitro and in vivo
Langouët-Astrié et al. show that the influenza-injured lung microenvironment induces both airspace shedding of the epithelial glycocalyx and MRSA to express pore-forming cytotoxins at key time points post-infection. LukAB is important to the severity of post-influenza MRSA pneumonia by binding to and is activated by shed heparan sulfate oligosaccharides. |
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| Bibliography: | Lead Contact Author Contributions C.L.A., E.P.S., and A.R.H. conceived the project, designed the experiments, and wrote the manuscript. C.L.A. conducted most of the experiments. K.O., S.M., and Y.Y. helped carry out in vivo experiments. J.M.K. and J.S.K. helped design MRSA in vivo and ex vivo experiments. J.S.K. helped with in silico modeling of Hla, LukAB, and HS disaccharides, and with the construction of reporter strains. W.L. helped with glycosaminoglycan PAGE gel. K.O., I.Z., and K.H. helped with mass spectrometry analysis for MRSA supernatants and glycosaminoglycans. D.S. and F.Z. helped perform surface plasmon resonance experiments for LukAB. G.S. and J.L. helped conduct HS glycoarray and develop HS oligos for in vitro and in vivo studies K.M.B., S.S.P., and V.J.T. helped with the purification of LukAB, anti-LukA antibody, and provided the humanized CD11b mice. All authors discussed the results and contributed to the final manuscript. |
| ISSN: | 2211-1247 2211-1247 |
| DOI: | 10.1016/j.celrep.2022.111721 |