Protective immunity in recurrent Staphylococcus aureus infection reflects localized immune signatures and macrophage-conferred memory

Staphylococcus aureus is the leading cause of skin and skin structure infection (SSSI), a primary portal of entry for invasive infection. Our prior studies discovered a role for protective innate memory against recurrent methicillin-resistant S. aureus (MRSA) SSSI. In the present study, the dynamics...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 115; no. 47; pp. E11111 - E11119
Main Authors Chan, Liana C., Rossetti, Maura, Miller, Lloyd S., Filler, Scott G., Johnson, Colin W., Lee, Hong K., Wang, Huiyuan, Gjertson, David, Fowler, Vance G., Reed, Elaine F., Yeaman, Michael R.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 20.11.2018
SeriesFrom the Cover
Subjects
Abscesses
Adoptive transfer
Bacterial infections
Biological Sciences
Bone marrow
Cytokines
Dendritic cells
Disease prevention
Drug resistance
Helper cells
Immunity
Immunity (Disease)
Immunological memory
Interleukin 17
Interleukin 6
IP-10 protein
Lymph nodes
Lymphocytes T
Macrophages
Methicillin
Phagocytes
PNAS Plus
Priming
RANTES
Recurrent infection
Signatures
Skin diseases
Spleen
Staphylococcus aureus
γ-Interferon
recurrent skin infection
macrophage
adoptive transfer
Staphylococcus aureus
innate immune memory
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Summary:Staphylococcus aureus is the leading cause of skin and skin structure infection (SSSI), a primary portal of entry for invasive infection. Our prior studies discovered a role for protective innate memory against recurrent methicillin-resistant S. aureus (MRSA) SSSI. In the present study, the dynamics and mechanisms of this response were explored in recurrent SSSI in WT mice. Priming by prior infection reduced skin lesion severity and MRSA burden, and protected against dissemination at day 7 but not day 2. Cytokine and cellular signatures in SSSI differed at day 2 versus 7, and were distinct in skin versus blood or spleen. Cytokines associated with protection in skin included increased IL-17, IL-6, monokine inducible by IFN-γ (MIG), and RANTES, while increased IP-10 correlated with protection from dissemination. Cellular signatures of protection included increased Th17, M1 macrophage, and dendritic cell populations in abscesses, and total macrophages in lymph nodes. Priming potentiated S. aureus-specific phagocytic killing by bone marrow-derived macrophages in vitro, and their adoptive transfer into naïve skin afforded protective efficacy in vivo. Present findings indicate that protective immunity in recurrent S. aureus infection is locally targeted, and involves specific memory conferred by macrophages. These insights provide targets for vaccine and immunotherapeutic development against MRSA.
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Author contributions: L.C.C., L.S.M., S.G.F., V.G.F., E.F.R., and M.R.Y. designed research; L.C.C., M.R., C.W.J., H.K.L., and H.W. performed research; L.C.C. and M.R.Y. contributed new reagents/analytic tools; L.C.C., M.R., L.S.M., S.G.F., D.G., E.F.R., M.R.Y., and M.S.I.G. analyzed data; and L.C.C., L.S.M., S.G.F., and M.R.Y. wrote the paper.
Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved September 14, 2018 (received for review May 15, 2018)
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1808353115