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A paradox in bacterial pathogenesis: Activation of the local macrophage inflammasome is required for virulence of streptococcus uberis

Archer, Nathan; Egan, Sharon A.; Coffey, Tracey J.; Emes, Richard D.; Addis, M. Filippa; Ward, Philip N.; Blanchard, Adam M.; Leigh, James A.


Professor of Sustainable Livestock Production

Richard D. Emes

M. Filippa Addis

Philip N. Ward


© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Streptococcus uberis is a common cause of intramammary infection and mastitis in dairy cattle. Unlike other mammary pathogens, S. uberis evades detection by mammary epithelial cells, and the host–pathogen interactions during early colonisation are poorly understood. Intramammary challenge of dairy cows with S. uberis (strain 0140J) or isogenic mutants lacking the surface-anchored serine protease, SUB1154, demonstrated that virulence was dependent on the presence and correct location of this protein. Unlike the wild-type strain, the mutant lacking SUB1154 failed to elicit IL-1β from ex vivo CD14+ cells obtained from milk (bovine mammary macrophages, BMM), but this response was reinstated by complementation with recombinant SUB1154; the protein in isolation elicited no response. Production of IL-1β was ablated in the presence of various inhibitors, indicating dependency on internalisation and activation of NLRP3 and caspase-1, consistent with inflammasome activation. Similar transcriptomic changes were detected in ex vivo BMM in response to the wild-type or the SUB1154 deletion mutant, consistent with S. uberis priming BMM, enabling the SUB1154 protein to activate inflammasome maturation in a transcriptionally independent manner. These data can be reconciled in a novel model of pathogenesis in which, paradoxically, early colonisation is dependent on the innate response to the initial infection.


Archer, N., Egan, S. A., Coffey, T. J., Emes, R. D., Addis, M. F., Ward, P. N., …Leigh, J. A. (2020). A paradox in bacterial pathogenesis: Activation of the local macrophage inflammasome is required for virulence of streptococcus uberis. Pathogens, 9(12), 1-23.

Journal Article Type Article
Acceptance Date Nov 26, 2020
Online Publication Date Nov 28, 2020
Publication Date Dec 1, 2020
Deposit Date Dec 2, 2020
Publicly Available Date Dec 2, 2020
Journal Pathogens
Electronic ISSN 2076-0817
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 9
Issue 12
Article Number 997
Pages 1-23
Keywords Streptococcus uberis; mastitis; inflammasome; NLRP3; macrophage; pathogenesis
Public URL
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