Manipulation of autophagy in phagocytes facilitates Staphylococcus aureus bloodstream infection

Kate M. O'Keefe, Miesko M. Wilk, John M. Leech, Alison G. Murphy, Maisem Laabei, Ian R. Monk, Ruth C. Massey, Jodi A. Lindsay, Timothy J. Foster, Joan A. Geoghegan, Rachel M. McLoughlin

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Abstract

The capacity for intracellular survival within phagocytes is likely a critical factor facilitating S. aureus dissemination in the host. To date, the majority of work on S. aureus-phagocyte interactions has focused on neutrophils and to a lesser extent macrophages, yet we understand little about the role played by dendritic cells (DCs) in the direct killing of this bacterium. Using bone-marrow-derived DCs (BMDCs) we demonstrate for the first time that DCs can effectively kill S. aureus, however certain strains of S. aureus have the capacity to evade DC (and macrophage) killing by manipulation of autophagic pathways. Strains with high levels of Agr activity were capable of causing autophagosome accumulation, were not killed by BMDCs and subsequently escaped from the phagocyte, exerting significant cytotoxic effects. Conversely, strains that exhibited low levels of Agr activity failed to accumulate autophagosomes and were killed by BMDCs. Inhibition of the autophagic pathway by treatment with 3-Methyladenine restored the bactericidal effects of BMDCs. Using an in vivo model of systemic infection we demonstrated that the ability of S. aureus strains to evade phagocytic cell killing and to survive temporarily within phagocytes correlated with persistence in the periphery and that this effect is critically Agr dependent. Taken together our data suggests that strains of S. aureus exhibiting high levels of Agr activity are capable of blocking autophagic flux, leading to the accumulation of autophagosomes. Within these autophagosomes the bacteria are protected from phagocytic killing, thus providing an intracellular survival niche within professional phagocytes, which ultimately facilitates dissemination.
Original languageEnglish
Pages (from-to)3445-3457
JournalInfection and immunity
Volume83
Issue number9
Early online date22 Jun 2015
DOIs
Publication statusPublished - Sep 2015

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    O'Keefe, K. M., Wilk, M. M., Leech, J. M., Murphy, A. G., Laabei, M., Monk, I. R., Massey, R. C., Lindsay, J. A., Foster, T. J., Geoghegan, J. A., & McLoughlin, R. M. (2015). Manipulation of autophagy in phagocytes facilitates Staphylococcus aureus bloodstream infection. Infection and immunity, 83(9), 3445-3457. https://doi.org/10.1128/IAI.00358-15