Abstract
In vivo whole-animal optical (bioluminescence and fluorescence) imaging of Staphylococcus aureus infections has provided the opportunity to noninvasively and longitudinally monitor the dynamics of the bacterial burden and ensuing host immune responses in live anesthetized animals. Herein, we describe several different mouse models of S. aureus skin infection, skin inflammation, incisional/excisional wound infections, as well as mouse and rabbit models of orthopedic implant infection, which utilized this imaging technology. These animal models and imaging methodologies provide insights into the pathogenesis of these infections and innate and adaptive immune responses, as well as the preclinical evaluation of diagnostic and treatment modalities. Noninvasive approaches to investigate host-pathogen interactions are extremely important as virulent community-acquired methicillin-resistant S. aureus strains (CA-MRSA) are spreading through the normal human population, becoming more antibiotic resistant and creating a serious threat to public health.
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References
Andreu N, Zelmer A, Wiles S (2011) Noninvasive biophotonic imaging for studies of infectious disease. FEMS Microbiol Rev 35(2):360–394
Hutchens M, Luker GD (2007) Applications of bioluminescence imaging to the study of infectious diseases. Cell Microbiol 9(10):2315–2322
Ohlsen K, Hertlein T (2018) Towards clinical application of non-invasive imaging to detect bacterial infections. Virulence 9(1):943–945. https://doi.org/10.1080/21505594.2018.1425072
van Oosten M, Hahn M, Crane LM, Pleijhuis RG, Francis KP, van Dijl JM et al (2015) Targeted imaging of bacterial infections: advances, hurdles and hopes. FEMS Microbiol Rev 39(6):892–916. https://doi.org/10.1093/femsre/fuv029
Badr CE, Tannous BA (2011) Bioluminescence imaging: progress and applications. Trends Biotechnol 29(12):624–633
Sjollema J, Sharma PK, Dijkstra RJ, van Dam GM, van der Mei HC, Engelsman AF et al (2010) The potential for bio-optical imaging of biomaterial-associated infection in vivo. Biomaterials 31(8):1984–1995
Francis KP, Joh D, Bellinger-Kawahara C, Hawkinson MJ, Purchio TF, Contag PR (2000) Monitoring bioluminescent Staphylococcus aureus infections in living mice using a novel luxABCDE construct. Infect Immun 68(6):3594–3600
Miller LS, O'Connell RM, Gutierrez MA, Pietras EM, Shahangian A, Gross CE et al (2006) MyD88 mediates neutrophil recruitment initiated by IL-1R but not TLR2 activation in immunity against Staphylococcus aureus. Immunity 24(1):79–91. https://doi.org/10.1016/j.immuni.2005.11.011
Plaut RD, Mocca CP, Prabhakara R, Merkel TJ, Stibitz S (2013) Stably luminescent Staphylococcus aureus clinical strains for use in bioluminescent imaging. PLoS One 8(3):e59232. https://doi.org/10.1371/journal.pone.0059232
Shimomura O (2005) The discovery of aequorin and green fluorescent protein. J Microsc 217(Pt 1):1–15. https://doi.org/10.1111/j.0022-2720.2005.01441.x
Shaner NC, Campbell RE, Steinbach PA, Giepmans BN, Palmer AE, Tsien RY (2004) Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein. Nat Biotechnol 22(12):1567–1572. https://doi.org/10.1038/nbt1037
Cho JS, Guo Y, Ramos RI, Hebroni F, Plaisier SB, Xuan C et al (2012) Neutrophil-derived IL-1β is sufficient for abscess formation in immunity against Staphylococcus aureus in mice. PLoS Pathog 8(11):e1003047. https://doi.org/10.1371/journal.ppat.1003047
Matsushima H, Ogawa Y, Miyazaki T, Tanaka H, Nishibu A, Takashima A (2010) Intravital imaging of IL-1beta production in skin. J Invest Dermatol 130(6):1571–1580
Bernthal NM, Stavrakis AI, Billi F, Cho JS, Kremen TJ, Simon SI et al (2010) A mouse model of post-arthroplasty Staphylococcus aureus joint infection to evaluate in vivo the efficacy of antimicrobial implant coatings. PLoS One 5(9):e12580. https://doi.org/10.1371/journal.pone.0012580
Falahee PC, Anderson LS, Reynolds MB, Pirir M, McLaughlin BE, Dillen CA et al (2017) Alpha-toxin regulates local granulocyte expansion from hematopoietic stem and progenitor cells in Staphylococcus aureus-infected wounds. J Immunol 199(5):1772–1782. https://doi.org/10.4049/jimmunol.1700649
Faust N, Varas F, Kelly LM, Heck S, Graf T (2000) Insertion of enhanced green fluorescent protein into the lysozyme gene creates mice with green fluorescent granulocytes and macrophages. Blood 96(2):719–726
Granick JL, Falahee PC, Dahmubed D, Borjesson DL, Miller LS, Simon SI (2013) Staphylococcus aureus recognition by hematopoietic stem and progenitor cells via TLR2/MyD88/PGE2 stimulates granulopoiesis in wounds. Blood 122(10):1770–1778. https://doi.org/10.1182/blood-2012-11-466268
Kim MH, Granick JL, Kwok C, Walker NJ, Borjesson DL, Curry FR et al (2011) Neutrophil survival and c-kit(+)-progenitor proliferation in Staphylococcus aureus-infected skin wounds promote resolution. Blood 117(12):3343–3352. https://doi.org/10.1182/blood-2010-07-296970
Kim MH, Liu W, Borjesson DL, Curry FR, Miller LS, Cheung AL et al (2008) Dynamics of neutrophil infiltration during cutaneous wound healing and infection using fluorescence imaging. J Invest Dermatol 128(7):1812–1820. https://doi.org/10.1038/sj.jid.5701223
Miller LS, Pietras EM, Uricchio LH, Hirano K, Rao S, Lin H et al (2007) Inflammasome-mediated production of IL-1beta is required for neutrophil recruitment against Staphylococcus aureus in vivo. J Immunol 179(10):6933–6942
Cho JS, Pietras EM, Garcia NC, Ramos RI, Farzam DM, Monroe HR et al (2010) IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice. J Clin Invest 120(5):1762–1773. https://doi.org/10.1172/JCI40891
Chan LC, Chaili S, Filler SG, Barr K, Wang H, Kupferwasser D et al (2015) Nonredundant roles of interleukin-17A (IL-17A) and IL-22 in murine host defense against cutaneous and Hematogenous infection due to methicillin-resistant Staphylococcus aureus. Infect Immun 83(11):4427–4437. https://doi.org/10.1128/IAI.01061-15
Chan LC, Chaili S, Filler SG, Miller LS, Solis NV, Wang H et al (2017) Innate immune memory contributes to host defense against recurrent skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus. Infect Immun 85(2):e00876-16. https://doi.org/10.1128/IAI.00876-16
Brandt SL, Klopfenstein N, Wang S, Winfree S, McCarthy BP, Territo PR et al (2018) Macrophage-derived LTB4 promotes abscess formation and clearance of Staphylococcus aureus skin infection in mice. PLoS Pathog 14(8):e1007244. https://doi.org/10.1371/journal.ppat.1007244
Chan LC, Rossetti M, Miller LS, Filler SG, Johnson CW, Lee HK et al (2018) Protective immunity in recurrent Staphylococcus aureus infection reflects localized immune signatures and macrophage-conferred memory. Proc Natl Acad Sci U S A 115:E11111. https://doi.org/10.1073/pnas.1808353115
Dillen CA, Pinsker BL, Marusina AI, Merleev AA, Farber ON, Liu H et al (2018) Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection. J Clin Invest 128(3):1026–1042. https://doi.org/10.1172/JCI96481
Liu H, Archer NK, Dillen CA, Wang Y, Ashbaugh AG, Ortines RV et al (2017) Staphylococcus aureus Epicutaneous exposure drives skin inflammation via IL-36-mediated T cell responses. Cell Host Microbe 22(5):653–666.e655. https://doi.org/10.1016/j.chom.2017.10.006
Nakagawa S, Matsumoto M, Katayama Y, Oguma R, Wakabayashi S, Nygaard T et al (2017) Staphylococcus aureus virulent PSMα peptides induce keratinocyte Alarmin release to orchestrate IL-17-dependent skin inflammation. Cell Host Microbe 22(5):667–677.e665. https://doi.org/10.1016/j.chom.2017.10.008
Nakamura Y, Oscherwitz J, Cease KB, Chan SM, Muñoz-Planillo R, Hasegawa M et al (2013) Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nature 503(7476):397–401. https://doi.org/10.1038/nature12655
Cho JS, Zussman J, Donegan NP, Ramos RI, Garcia NC, Uslan DZ et al (2011) Noninvasive in vivo imaging to evaluate immune responses and antimicrobial therapy against Staphylococcus aureus and USA300 MRSA skin infections. J Invest Dermatol 131(4):907–915. https://doi.org/10.1038/jid.2010.417
Guo Y, Ramos RI, Cho JS, Donegan NP, Cheung AL, Miller LS (2013) In vivo bioluminescence imaging to evaluate systemic and topical antibiotics against community-acquired methicillin-resistant Staphylococcus aureus-infected skin wounds in mice. Antimicrob Agents Chemother 57(2):855–863. https://doi.org/10.1128/AAC.01003-12
Ortines RV, Liu H, Cheng LI, Cohen TS, Lawlor H, Gami A et al (2018) Neutralizing alpha-toxin accelerates healing of Staphylococcus aureus-infected wounds in nondiabetic and diabetic mice. Antimicrob Agents Chemother 62(3):e02288-17. https://doi.org/10.1128/AAC.02288-17
Niska JA, Meganck JA, Pribaz JR, Shahbazian JH, Lim E, Zhang N et al (2012) Monitoring bacterial burden, inflammation and bone damage longitudinally using optical and muCT imaging in an orthopaedic implant infection in mice. PLoS One 7(10):e47397. https://doi.org/10.1371/journal.pone.0047397
Niska JA, Shahbazian JH, Ramos RI, Pribaz JR, Billi F, Francis KP et al (2012) Daptomycin and tigecycline have broader effective dose ranges than vancomycin as prophylaxis against a Staphylococcus aureus surgical implant infection in mice. Antimicrob Agents Chemother 56(5):2590–2597. https://doi.org/10.1128/AAC.06291-11
Pribaz JR, Bernthal NM, Billi F, Cho JS, Ramos RI, Guo Y et al (2012) Mouse model of chronic post-arthroplasty infection: noninvasive in vivo bioluminescence imaging to monitor bacterial burden for long-term study. J Orthop Res 30(3):335–340. https://doi.org/10.1002/jor.21519
Niska JA, Shahbazian JH, Ramos RI, Francis KP, Bernthal NM, Miller LS (2013) Vancomycin-rifampin combination therapy has enhanced efficacy against an experimental Staphylococcus aureus prosthetic joint infection. Antimicrob Agents Chemother 57(10):5080–5086. https://doi.org/10.1128/AAC.00702-13
Bernthal NM, Taylor BN, Meganck JA, Wang Y, Shahbazian JH, Niska JA et al (2014) Combined in vivo optical and microCT imaging to monitor infection, inflammation, and bone anatomy in an orthopaedic implant infection in mice. J Vis Exp 92:e51612. https://doi.org/10.3791/51612
Ashbaugh AG, Jiang X, Zheng J, Tsai AS, Kim WS, Thompson JM et al (2016) Polymeric nanofiber coating with tunable combinatorial antibiotic delivery prevents biofilm-associated infection in vivo. Proc Natl Acad Sci U S A 113(45):E6919–E6928. https://doi.org/10.1073/pnas.1613722113
Stavrakis AI, Zhu S, Hegde V, Loftin AH, Ashbaugh AG, Niska JA et al (2016) In vivo efficacy of a “smart” antimicrobial implant coating. J Bone Joint Surg Am 98(14):1183–1189. https://doi.org/10.2106/JBJS.15.01273
Thompson JM, Saini V, Ashbaugh AG, Miller RJ, Ordonez AA, Ortines RV et al (2017) Oral-only linezolid-rifampin is highly effective compared with other antibiotics for Periprosthetic joint infection: study of a mouse model. J Bone Joint Surg Am 99(8):656–665. https://doi.org/10.2106/JBJS.16.01002
Wang Y, Thompson JM, Ashbaugh AG, Khodakivskyi P, Budin G, Sinisi R et al (2017) Preclinical evaluation of photoacoustic imaging as a novel noninvasive approach to detect an orthopaedic implant infection. J Am Acad Orthop Surg 25(Suppl 1):S7–S12. https://doi.org/10.5435/JAAOS-D-16-00630
Wang Y, Cheng LI, Helfer DR, Ashbaugh AG, Miller RJ, Tzomides AJ et al (2017) Mouse model of hematogenous implant-related Staphylococcus aureus biofilm infection reveals therapeutic targets. Proc Natl Acad Sci U S A 114(26):E5094–E5102. https://doi.org/10.1073/pnas.1703427114
Miller RJ, Thompson JM, Zheng J, Marchitto MC, Archer NK, Pinsker BL et al (2019) In vivo bioluminescence imaging in a rabbit model of orthopedic implant-associated infection to monitor efficacy of an antibiotic-releasing coating. J Bone Joint Surg Am 101(4):e12
Thurlow LR, Hanke ML, Fritz T, Angle A, Aldrich A, Williams SH et al (2011) Staphylococcus aureus biofilms prevent macrophage phagocytosis and attenuate inflammation in vivo. J Immunol 186(11):6585–6596. https://doi.org/10.4049/jimmunol.1002794
Romero Pastrana F, Thompson JM, Heuker M, Hoekstra H, Dillen CA, Ortines RV et al (2018) Noninvasive optical and nuclear imaging of Staphylococcus-specific infection with a human monoclonal antibody-based probe. Virulence 9(1):262–272. https://doi.org/10.1080/21505594.2017.1403004
DeLeo FR, Otto M, Kreiswirth BN, Chambers HF (2010) Community-associated meticillin-resistant Staphylococcus aureus. Lancet 375(9725):1557–1568. https://doi.org/10.1016/S0140-6736(09)61999-1
Tong SY, Davis JS, Eichenberger E, Holland TL, Fowler VG (2015) Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev 28(3):603–661. https://doi.org/10.1128/CMR.00134-14
Byrd AL, Deming C, Cassidy SKB, Harrison OJ, Ng WI, Conlan S et al (2017) Staphylococcus aureus and Staphylococcus epidermidis strain diversity underlying pediatric atopic dermatitis. Sci Transl Med 9(397):eaal4651. https://doi.org/10.1126/scitranslmed.aal4651
Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA et al (2012) Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res 22(5):850–859. https://doi.org/10.1101/gr.131029.111
Eleftheriadou I, Tentolouris N, Argiana V, Jude E, Boulton AJ (2010) Methicillin-resistant Staphylococcus aureus in diabetic foot infections. Drugs 70(14):1785–1797. https://doi.org/10.2165/11538070-000000000-00000
Alavi A, Sibbald RG, Mayer D, Goodman L, Botros M, Armstrong DG et al (2014) Diabetic foot ulcers: part II. Management. J Am Acad Dermatol 70(1):21.e21–21.e24.; ; quiz 45-26. https://doi.org/10.1016/j.jaad.2013.07.048
Alavi A, Sibbald RG, Mayer D, Goodman L, Botros M, Armstrong DG et al (2014) Diabetic foot ulcers: part I. Pathophysiology and prevention. J Am Acad Dermatol 70(1):1.e1–1.18; quiz 19-20. https://doi.org/10.1016/j.jaad.2013.06.055
Decker CG, Wang Y, Paluck SJ, Shen L, Loo JA, Levine AJ et al (2016) Fibroblast growth factor 2 dimer with superagonist in vitro activity improves granulation tissue formation during wound healing. Biomaterials 81:157–168. https://doi.org/10.1016/j.biomaterials.2015.12.003
Schierle CF, De la Garza M, Mustoe TA, Galiano RD (2009) Staphylococcal biofilms impair wound healing by delaying reepithelialization in a murine cutaneous wound model. Wound Repair Regen 17(3):354–359. https://doi.org/10.1111/j.1524-475X.2009.00489.x
Del Pozo JL, Patel R (2009) Clinical practice. Infection associated with prosthetic joints. N Engl J Med 361(8):787–794. https://doi.org/10.1056/NEJMcp0905029
Osmon DR, Berbari EF, Berendt AR, Lew D, Zimmerli W, Steckelberg JM et al (2013) Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 56(1):e1–e25. https://doi.org/10.1093/cid/cis803
Zimmerli W, Trampuz A, Ochsner PE (2004) Prosthetic-joint infections. N Engl J Med 351(16):1645–1654. https://doi.org/10.1056/NEJMra040181
Konigsberg BS, Della Valle CJ, Ting NT, Qiu F, Sporer SM (2014) Acute hematogenous infection following total hip and knee arthroplasty. J Arthroplast 29(3):469–472. https://doi.org/10.1016/j.arth.2013.07.021
Sendi P, Banderet F, Graber P, Zimmerli W (2011) Periprosthetic joint infection following Staphylococcus aureus bacteremia. J Infect 63(1):17–22. https://doi.org/10.1016/j.jinf.2011.05.005
Tande AJ, Patel R (2014) Prosthetic joint infection. Clin Microbiol Rev 27(2):302–345. https://doi.org/10.1128/CMR.00111-13
Lovati AB, Bottagisio M, de Vecchi E, Gallazzi E, Drago L (2017) Animal models of implant-related low-grade infections. A twenty-year review. Adv Exp Med Biol 971:29–50. https://doi.org/10.1007/5584_2016_157
Spaan AN, van Strijp JAG, Torres VJ (2017) Leukocidins: staphylococcal bi-component pore-forming toxins find their receptors. Nat Rev Microbiol 15(7):435–447. https://doi.org/10.1038/nrmicro.2017.27
Acknowledgments
This work was supported by the National Institutes of Arthritis and Musculoskeletal and Skin Diseases (grant numbers: R01AR069502 and R01AR073665 [to L.S.M.]), and the National Institute of Allergy and Infectious Diseases (grant numbers: R21AI126896 [to L.S.M.] and R01 AI047294 [to S.S.] and R56 AI103687 [to S.I.S.]) from the US National Institutes of Health, Department of Health and Human Services. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health.
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Archer, N.K. et al. (2020). Preclinical Models and Methodologies for Monitoring Staphylococcus aureus Infections Using Noninvasive Optical Imaging. In: Ji, Y. (eds) Methicillin-Resistant Staphylococcus Aureus (MRSA) Protocols. Methods in Molecular Biology, vol 2069. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9849-4_15
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