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Inability to sustain intraphagolysosomal killing of Staphylococcus aureus predisposes to bacterial persistence in macrophages

Inability to sustain intraphagolysosomal killing of Staphylococcus aureus predisposes to bacterial persistence in macrophages
Inability to sustain intraphagolysosomal killing of Staphylococcus aureus predisposes to bacterial persistence in macrophages

Macrophages are critical effectors of the early innate response to bacteria in tissues. Phagocytosis and killing of bacteria are interrelated functions essential for bacterial clearance but the rate-limiting step when macrophages are challenged with large numbers of the major medical pathogen Staphylococcus aureus is unknown. We show that macrophages have a finite capacity for intracellular killing and fail to match sustained phagocytosis with sustained microbial killing when exposed to large inocula of S. aureus (Newman, SH1000 and USA300 strains). S. aureus ingestion by macrophages is associated with a rapid decline in bacterial viability immediately after phagocytosis. However, not all bacteria are killed in the phagolysosome, and we demonstrate reduced acidification of the phagolysosome, associated with failure of phagolysosomal maturation and reduced activation of cathepsin D. This results in accumulation of viable intracellular bacteria in macrophages. We show macrophages fail to engage apoptosis-associated bacterial killing. Ultittop mately macrophages with viable bacteria undergo cell lysis, and viable bacteria are released and can be internalized by other macrophages. We show that cycles of lysis and reuptake maintain a pool of viable intracellular bacteria over time when killing is overwhelmed and demonstrate intracellular persistence in alveolar macrophages in the lungs in a murine model.

Animals, Cell Survival, Disease Models, Animal, Macrophages, Mice, Microbial Viability, Phagocytosis, Pneumonia, Staphylococcal, Staphylococcus aureus, Journal Article
1462-5814
80-96
Jubrail, Jamil
a90012af-fe69-40cd-8adb-a342a194d7b4
Morris, Paul
f59943a2-9989-448f-94a3-b6d80790b7b6
Bewley, Martin A.
1412f184-67e0-4fe7-8692-db253d411471
Stoneham, Simon
26cdbbfb-7487-4757-a388-6418e4f10b40
Johnston, Simon A.
95451ad6-c8fa-4fa6-a502-f925e34f0de7
Foster, Simon J.
6266b6db-9700-49c0-bee5-da9f52ca243a
Peden, Andrew A.
84ac3fef-b97a-45fa-999e-0dd2e253ff4d
Read, Robert C.
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Marriott, Helen M.
34ca8904-d637-4081-b34c-12be45ecef9f
Dockrell, David H.
a068c9bf-35b8-4c10-8f91-58639cfeca0b
Jubrail, Jamil
a90012af-fe69-40cd-8adb-a342a194d7b4
Morris, Paul
f59943a2-9989-448f-94a3-b6d80790b7b6
Bewley, Martin A.
1412f184-67e0-4fe7-8692-db253d411471
Stoneham, Simon
26cdbbfb-7487-4757-a388-6418e4f10b40
Johnston, Simon A.
95451ad6-c8fa-4fa6-a502-f925e34f0de7
Foster, Simon J.
6266b6db-9700-49c0-bee5-da9f52ca243a
Peden, Andrew A.
84ac3fef-b97a-45fa-999e-0dd2e253ff4d
Read, Robert C.
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Marriott, Helen M.
34ca8904-d637-4081-b34c-12be45ecef9f
Dockrell, David H.
a068c9bf-35b8-4c10-8f91-58639cfeca0b

Jubrail, Jamil, Morris, Paul, Bewley, Martin A., Stoneham, Simon, Johnston, Simon A., Foster, Simon J., Peden, Andrew A., Read, Robert C., Marriott, Helen M. and Dockrell, David H. (2016) Inability to sustain intraphagolysosomal killing of Staphylococcus aureus predisposes to bacterial persistence in macrophages. Cellular Microbiology, 18 (1), 80-96. (doi:10.1111/cmi.12485).

Record type: Article

Abstract

Macrophages are critical effectors of the early innate response to bacteria in tissues. Phagocytosis and killing of bacteria are interrelated functions essential for bacterial clearance but the rate-limiting step when macrophages are challenged with large numbers of the major medical pathogen Staphylococcus aureus is unknown. We show that macrophages have a finite capacity for intracellular killing and fail to match sustained phagocytosis with sustained microbial killing when exposed to large inocula of S. aureus (Newman, SH1000 and USA300 strains). S. aureus ingestion by macrophages is associated with a rapid decline in bacterial viability immediately after phagocytosis. However, not all bacteria are killed in the phagolysosome, and we demonstrate reduced acidification of the phagolysosome, associated with failure of phagolysosomal maturation and reduced activation of cathepsin D. This results in accumulation of viable intracellular bacteria in macrophages. We show macrophages fail to engage apoptosis-associated bacterial killing. Ultittop mately macrophages with viable bacteria undergo cell lysis, and viable bacteria are released and can be internalized by other macrophages. We show that cycles of lysis and reuptake maintain a pool of viable intracellular bacteria over time when killing is overwhelmed and demonstrate intracellular persistence in alveolar macrophages in the lungs in a murine model.

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More information

Accepted/In Press date: 7 July 2015
e-pub ahead of print date: 2 September 2015
Published date: January 2016
Additional Information: © 2015 The Authors. Cellular Microbiology Published by John Wiley & Sons Ltd.
Keywords: Animals, Cell Survival, Disease Models, Animal, Macrophages, Mice, Microbial Viability, Phagocytosis, Pneumonia, Staphylococcal, Staphylococcus aureus, Journal Article

Identifiers

Local EPrints ID: 417196
URI: https://eprints.soton.ac.uk/id/eprint/417196
ISSN: 1462-5814
PURE UUID: 07ed8d1f-2989-43fa-8816-de481d51e7b8
ORCID for Robert C. Read: ORCID iD orcid.org/0000-0002-4297-6728

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Date deposited: 24 Jan 2018 17:30
Last modified: 10 Dec 2019 01:37

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