Noninvasive biophotonic imaging for studies of infectious disease

According to World Health Organization estimates, infectious organisms are responsible for approximately one in four deaths worldwide. Animal models play an essential role in the development of vaccines and therapeutic agents but large numbers of animals are required to obtain quantitative microbiological data by tissue sampling. Biophotonic imaging (BPI) is a highly sensitive, nontoxic technique based on the detection of visible light, produced by luciferase-catalysed reactions (bioluminescence) or by excitation of fluorescent molecules, using sensitive photon detectors. The development of bioluminescent/fluorescent microorganisms therefore allows the real-time noninvasive detection of microorganisms within intact living animals. Multiple imaging of the same animal throughout an experiment allows disease progression to be followed with extreme accuracy, reducing the number of animals required to yield statistically meaningful data. In the study of infectious disease, the use of BPI is becoming widespread due to the novel insights it can provide into established models, as well as the impact of the technique on two of the guiding principles of using animals in research, namely reduction and refinement. Here, we review the technology of BPI, from the instrumentation through to the generation of a photonic signal, and illustrate how the technique is shedding light on infection dynamics in vivo.

[1]  M. Nicola,et al.  Bioluminescent Aspergillus fumigatus, a New Tool for Drug Efficiency Testing and In Vivo Monitoring of Invasive Aspergillosis , 2008, Applied and Environmental Microbiology.

[2]  S. Molliex,et al.  Halogenated Anesthetics Inhibit Pseudomonas aeruginosa Growth in Culture Conditions Reproducing the Alveolar Environment , 1998, Anesthesia and analgesia.

[3]  S. Mordon,et al.  In Vivo Imaging of Bioluminescent Escherichia coli in a Cutaneous Wound Infection Model for Evaluation of an Antibiotic Therapy , 2004, Antimicrobial Agents and Chemotherapy.

[4]  Paul S. Cohen,et al.  Respiration of Escherichia coli in the Mouse Intestine , 2007, Infection and Immunity.

[5]  C. Rosenberger,et al.  Toll‐like receptor 2 plays a critical role in maintaining mucosal integrity during Citrobacter rodentium‐induced colitis , 2007, Cellular microbiology.

[6]  C. Hill,et al.  Improved Luciferase Tagging System for Listeria monocytogenes Allows Real-Time Monitoring In Vivo and In Vitro , 2007, Applied and Environmental Microbiology.

[7]  Stephen T. C. Wong,et al.  A quantitative study of factors affecting in vivo bioluminescence imaging. , 2008, Luminescence : the journal of biological and chemical luminescence.

[8]  Selvakumar Subbian,et al.  Application of optical imaging to study of extrapulmonary spread by tuberculosis. , 2009, Tuberculosis.

[9]  Pamela J. Glass,et al.  Eastern and Venezuelan Equine Encephalitis Viruses Differ in Their Ability To Infect Dendritic Cells and Macrophages: Impact of Altered Cell Tropism on Pathogenesis , 2008, Journal of Virology.

[10]  Meng Yang,et al.  Monotherapy with a tumor-targeting mutant of Salmonella typhimurium cures orthotopic metastatic mouse models of human prostate cancer , 2007, Proceedings of the National Academy of Sciences.

[11]  J. Mullins,et al.  Photonic detection of bacterial pathogens in living hosts , 1995, Molecular microbiology.

[12]  Sanjiv Sam Gambhir,et al.  Consensus guided mutagenesis of Renilla luciferase yields enhanced stability and light output. , 2006, Protein engineering, design & selection : PEDS.

[13]  G. Ulrich Nienhaus,et al.  mRuby, a Bright Monomeric Red Fluorescent Protein for Labeling of Subcellular Structures , 2009, PloS one.

[14]  M. Woodward,et al.  Role of NleH, a Type III Secreted Effector from Attaching and Effacing Pathogens, in Colonization of the Bovine, Ovine, and Murine Gut , 2008, Infection and Immunity.

[15]  R. Sun,et al.  Induction of Protective Immunity against Murine Gammaherpesvirus 68 Infection in the Absence of Viral Latency , 2009, Journal of Virology.

[16]  W. Matthew Leevy,et al.  Optical imaging of bacterial infection in living mice using a fluorescent near-infrared molecular probe. , 2006, Journal of the American Chemical Society.

[17]  G Ulrich Nienhaus,et al.  Optimized and far-red-emitting variants of fluorescent protein eqFP611. , 2008, Chemistry & biology.

[18]  Ryan M. O’Connell,et al.  Conserved herpesviral kinase promotes viral persistence by inhibiting the IRF-3-mediated type I interferon response. , 2009, Cell host & microbe.

[19]  Diane E. Griffin,et al.  Luciferase Imaging of a Neurotropic Viral Infection in Intact Animals , 2003, Journal of Virology.

[20]  K. Vasquez,et al.  Imaging schistosomes in vivo , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[21]  J. W. Hastings,et al.  [54] Bacterial luciferase: FMNH2-aldehyde oxidase , 1978 .

[22]  O. Shimomura,et al.  Light-emitters involved in the luminescence of coelenterazine. , 2000, Luminescence : the journal of biological and chemical luminescence.

[23]  J. Davies,et al.  Improved lux reporters for use in Staphylococcus aureus. , 2009, Plasmid.

[24]  E. Tuomanen,et al.  Tissue-specific contributions of pneumococcal virulence factors to pathogenesis. , 2004, The Journal of infectious diseases.

[25]  R. Ramphal,et al.  Control of Pseudomonas aeruginosa in the Lung Requires the Recognition of Either Lipopolysaccharide or Flagellin1 , 2008, The Journal of Immunology.

[26]  M. Karp,et al.  Generation and Comparison of Bioluminescent and Fluorescent Bacillus licheniformis , 2008, Current Microbiology.

[27]  P. Gorce,et al.  Effects of isoflurane on bacterial growth. , 2000, European journal of anaesthesiology.

[28]  K. Frei,et al.  Toll-like receptor 2-deficient mice are highly susceptible to Streptococcus pneumoniae meningitis because of reduced bacterial clearing and enhanced inflammation. , 2002, The Journal of infectious diseases.

[29]  R. Munson,et al.  Identification and Characterization of a Mucosal Antimicrobial Peptide Expressed by the Chinchilla (Chinchilla lanigera) Airway* , 2004, Journal of Biological Chemistry.

[30]  B. Michel,et al.  The Major Portal of Entry of Koi Herpesvirus in Cyprinus carpio Is the Skin , 2009, Journal of Virology.

[31]  Sanjiv S Gambhir,et al.  Creating self-illuminating quantum dot conjugates , 2006, Nature Protocols.

[32]  G. Zonios,et al.  Skin melanin, hemoglobin, and light scattering properties can be quantitatively assessed in vivo using diffuse reflectance spectroscopy. , 2001, The Journal of investigative dermatology.

[33]  J. Jansson,et al.  Simultaneous Monitoring of Cell Number and Metabolic Activity of Specific Bacterial Populations with a Dualgfp-luxAB Marker System , 1999, Applied and Environmental Microbiology.

[34]  R. Munson,et al.  A Mutation in the sap Operon Attenuates Survival of Nontypeable Haemophilus influenzae in a Chinchilla Model of Otitis Media , 2005, Infection and Immunity.

[35]  S. Clare,et al.  Organ specificity, colonization and clearance dynamics in vivo following oral challenges with the murine pathogen Citrobacter rodentium , 2004, Cellular microbiology.

[36]  Marc Lipsitch,et al.  Visualizing Pneumococcal Infections in the Lungs of Live Mice Using Bioluminescent Streptococcus pneumoniaeTransformed with a Novel Gram-Positive luxTransposon , 2001, Infection and Immunity.

[37]  Hui Zhao,et al.  The Potential Salmonella aroA– Vaccine Strain Is Safe and Effective in Young BALB/c Mice , 2006, Neonatology.

[38]  R. Novick,et al.  Transient interference with staphylococcal quorum sensing blocks abscess formation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[39]  O. Shimomura,et al.  Extraction, purification and properties of aequorin, a bioluminescent protein from the luminous hydromedusan, Aequorea. , 1962, Journal of cellular and comparative physiology.

[40]  L. Kruidenier,et al.  The p50 Subunit of NF-κB Is Critical for In Vivo Clearance of the Noninvasive Enteric Pathogen Citrobacter rodentium , 2008, Infection and Immunity.

[41]  S. Gray-Owen,et al.  A Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Homologue Plays a Pivotal Role in Nontypeable Haemophilus influenzae Colonization of the Chinchilla Nasopharynx via the Outer Membrane Protein P5-Homologous Adhesin , 2007, Infection and Immunity.

[42]  S. Akira,et al.  Herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9. , 2004, Blood.

[43]  Michael Z. Lin,et al.  Improving the photostability of bright monomeric orange and red fluorescent proteins , 2008, Nature Methods.

[44]  R. Hoffman,et al.  Whole-body imaging of bacterial infection and antibiotic response , 2006, Nature Protocols.

[45]  S. Molin,et al.  Assessment of GFP fluorescence in cells of Streptococcus gordonii under conditions of low pH and low oxygen concentration. , 2001, Microbiology.

[46]  F. O'Gara,et al.  Construction of p16Slux, a Novel Vector for Improved Bioluminescent Labeling of Gram-Negative Bacteria , 2007, Applied and Environmental Microbiology.

[47]  Vasilis Ntziachristos,et al.  Iterative boundary method for diffuse optical tomography. , 2003, Journal of the Optical Society of America. A, Optics, image science, and vision.

[48]  K. Francis,et al.  Noninvasive Optical Imaging Method To Evaluate Postantibiotic Effects on Biofilm Infection In Vivo , 2004, Antimicrobial Agents and Chemotherapy.

[49]  U. Schaible,et al.  Optimisation of Bioluminescent Reporters for Use with Mycobacteria , 2010, PloS one.

[50]  G. Dougan,et al.  Emergence of a ‘hyperinfectious’ bacterial state after passage of Citrobacter rodentium through the host gastrointestinal tract , 2005, Cellular microbiology.

[51]  Hua-bei Jiang,et al.  Three-dimensional bioluminescence tomography with model-based reconstruction. , 2004, Optics express.

[52]  Ivo Que,et al.  Murine malaria parasite sequestration: CD36 is the major receptor, but cerebral pathology is unlinked to sequestration. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[53]  Sanjiv S. Gambhir,et al.  In Vivo Visualization of Embryonic Stem Cell Survival, Proliferation, and Migration After Cardiac Delivery , 2006, Circulation.

[54]  B. Rice,et al.  Quantitative comparison of the sensitivity of detection of fluorescent and bioluminescent reporters in animal models. , 2004, Molecular imaging.

[55]  F. Baguet,et al.  Kinetics of Light Emission and Oxygen Consumption by Bioluminescent Bacteria , 2001, Journal of bioenergetics and biomembranes.

[56]  Tayyaba Hasan,et al.  Rapid Control of Wound Infections by Targeted Photodynamic Therapy Monitored by In Vivo Bioluminescence Imaging¶ , 2002 .

[57]  R. Munson,et al.  The PilA protein of non‐typeable Haemophilus influenzae plays a role in biofilm formation, adherence to epithelial cells and colonization of the mammalian upper respiratory tract , 2007, Molecular microbiology.

[58]  M. Saraçlı,et al.  Effects of sevoflurane and/or nitrous oxide on bacterial growth in in vitro culture conditions , 2007, Journal of Anesthesia.

[59]  Michelle Cronin,et al.  Development of a luciferase-based reporter system to monitor Bifidobacterium breve UCC2003 persistence in mice , 2008, BMC Microbiology.

[60]  James R. Johnson,et al.  Quantum dot probes for bacteria distinguish Escherichia coli mutants and permit in vivo imaging. , 2008, Chemical communications.

[61]  Kathrin U. Jansen,et al.  Real-Time Monitoring of Bacterial Infection In Vivo: Development of Bioluminescent Staphylococcal Foreign-Body and Deep-Thigh-Wound Mouse Infection Models , 2003, Antimicrobial Agents and Chemotherapy.

[62]  A. Karsi,et al.  Development of bioluminescent Edwardsiella ictaluri for noninvasive disease monitoring. , 2006, FEMS microbiology letters.

[63]  M. Svensson,et al.  Induction of dendritic cell migration upon Toxoplasma gondii infection potentiates parasite dissemination , 2006, Cellular microbiology.

[64]  Jianke Ren,et al.  Functional imaging of interleukin 1 beta expression in inflammatory process using bioluminescence imaging in transgenic mice , 2008, BMC Immunology.

[65]  C. Hill,et al.  Novel Luciferase Reporter System for In Vitro and Organ-Specific Monitoring of Differential Gene Expression in Listeria monocytogenes , 2006, Applied and Environmental Microbiology.

[66]  M. Stefanidou,et al.  Alternative Luciferase for Monitoring Bacterial Cells under Adverse Conditions , 2005, Applied and Environmental Microbiology.

[67]  Meng Yang,et al.  Tumor-targeting bacterial therapy with amino acid auxotrophs of GFP-expressing Salmonella typhimurium. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[68]  Konstantin A Lukyanov,et al.  The first mutant of the Aequorea victoria green fluorescent protein that forms a red chromophore. , 2008, Biochemistry.

[69]  G. Luker,et al.  Bioluminescence imaging of reporter mice for studies of infection and inflammation. , 2010, Antiviral research.

[70]  T. Doyle,et al.  Visualizing fungal infections in living mice using bioluminescent pathogenic Candida albicans strains transformed with the firefly luciferase gene. , 2006, Microbial pathogenesis.

[71]  G. Milon,et al.  Optimization of Topical Therapy for Leishmania major Localized Cutaneous Leishmaniasis Using a Reliable C57BL/6 Model , 2007, PLoS neglected tropical diseases.

[72]  Robin Hull,et al.  A good practice guide to the administration of substances and removal of blood, including routes and volumes , 2001, Journal of applied toxicology : JAT.

[73]  Jen-Chieh Tseng,et al.  Systemic tumor targeting and killing by Sindbis viral vectors , 2004, Nature Biotechnology.

[74]  H. Fraga,et al.  Thermostable red and green light-producing firefly luciferase mutants for bioluminescent reporter applications. , 2007, Analytical biochemistry.

[75]  S. Swift,et al.  Engineering the luxCDABE genes from Photorhabdus luminescens to provide a bioluminescent reporter for constitutive and promoter probe plasmids and mini-Tn5 constructs. , 1998, FEMS microbiology letters.

[76]  James C. Sacchettini,et al.  Imaging tuberculosis with endogenous β-lactamase reporter enzyme fluorescence in live mice , 2010, Proceedings of the National Academy of Sciences.

[77]  Ning Zhang,et al.  Compounds in Transgenic Mice Vivo Testing of Anti-inflammatory Synthase-Luciferase Reporter System for In An Inducible Nitric Oxide , 2003 .

[78]  Robin Patel,et al.  Daptomycin in experimental murine pneumococcal meningitis , 2008, BMC infectious diseases.

[79]  A. Barragan,et al.  Dissemination of Toxoplasma gondii to immunoprivileged organs and role of Toll/interleukin‐1 receptor signalling for host resistance assessed by in vivo bioluminescence imaging , 2005, Cellular microbiology.

[80]  C. Contag,et al.  Induced Biliary Excretion of Listeria monocytogenes , 2006, Infection and Immunity.

[81]  Kathryn E Luker,et al.  Transgenic reporter mouse for bioluminescence imaging of herpes simplex virus 1 infection in living mice. , 2006, Virology.

[82]  M. Lipsitch,et al.  Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[83]  Vladimir I Martynov,et al.  GFP family: structural insights into spectral tuning. , 2008, Chemistry & biology.

[84]  B. Applegate,et al.  Real-time imaging and quantification of bioluminescent bacteria in root canals in vitro. , 2004, Journal of endodontics.

[85]  S. Wiles,et al.  Use of biophotonic imaging as a training aid for administration of substances in laboratory rodents , 2007, Laboratory animals.

[86]  James R. Johnson,et al.  Noninvasive optical imaging of staphylococcus aureus bacterial infection in living mice using a Bis-dipicolylamine-Zinc(II) affinity group conjugated to a near-infrared fluorophore. , 2008, Bioconjugate chemistry.

[87]  M. Giovannini,et al.  Bioluminescence Imaging of Live Infected Salmonids Reveals that the Fin Bases Are the Major Portal of Entry for Novirhabdovirus , 2006, Journal of Virology.

[88]  Yusuke Inoue,et al.  Diet and Abdominal Autofluorescence Detected by in Vivo Fluorescence Imaging of Living Mice , 2008, Molecular imaging.

[89]  Brian D Robertson,et al.  Bioluminescent monitoring of in vivo colonization and clearance dynamics by light-emitting bacteria. , 2009, Methods in molecular biology.

[90]  Daniel E. Hall,et al.  Molecular imaging of gene expression and efficacy following adenoviral-mediated brain tumor gene therapy. , 2002, Molecular imaging.

[91]  W. D. Welch Effect of enflurane, isoflurane, and nitrous oxide on the microbicidal activity of human polymorphonuclear leukocytes. , 1984, Anesthesiology.

[92]  J. Boothroyd,et al.  Bioluminescence Imaging of Toxoplasma gondii Infection in Living Mice Reveals Dramatic Differences between Strains , 2005, Infection and Immunity.

[93]  J. Swanson,et al.  Live cell fluorescence microscopy to study microbial pathogenesis , 2009, Cellular microbiology.

[94]  M. Geusz,et al.  Imaging gene expression in live transgenic mice after providing luciferin in drinking water , 2006, Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology.

[95]  C. M. Thomson,et al.  The widespread occurrence and tissue distribution of the imidazolopyrazine luciferins. , 1997, Journal of bioluminescence and chemiluminescence.

[96]  Christopher H Contag,et al.  Foci of Listeria monocytogenes persist in the bone marrow , 2009, Disease Models & Mechanisms.

[97]  Kevin P. Francis,et al.  Rapid Direct Method for Monitoring Antibiotics in a Mouse Model of Bacterial Biofilm Infection , 2003, Antimicrobial Agents and Chemotherapy.

[98]  Vasilis Ntziachristos,et al.  Fluorescent protein tomography scanner for small animal imaging , 2005, IEEE Transactions on Medical Imaging.

[99]  M. Mock,et al.  Noncapsulated Toxinogenic Bacillus anthracis Presents a Specific Growth and Dissemination Pattern in Naive and Protective Antigen-Immune Mice , 2007, Infection and Immunity.

[100]  Vasilis Ntziachristos,et al.  Volumetric tomography of fluorescent proteins through small animals in vivo. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[101]  Robert W. Sauerwein,et al.  Visualisation and Quantitative Analysis of the Rodent Malaria Liver Stage by Real Time Imaging , 2009, PloS one.

[102]  Sanjiv S Gambhir,et al.  Self-illuminating quantum dot conjugates for in vivo imaging , 2006, Nature Biotechnology.

[103]  G Ulrich Nienhaus,et al.  A far-red fluorescent protein with fast maturation and reduced oligomerization tendency from Entacmaea quadricolor (Anthozoa, Actinaria) , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[104]  Xiaoen Wang,et al.  Spatial–temporal imaging of bacterial infection and antibiotic response in intact animals , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[105]  Shimon Weiss,et al.  Quantum Dots for In Vivo Small-Animal Imaging , 2009, Journal of Nuclear Medicine.

[106]  Kshitij D Modi,et al.  Noninvasive Monitoring of Pneumococcal Meningitis and Evaluation of Treatment Efficacy in an Experimental Mouse Model* , 2005, Molecular imaging.

[107]  P. Iversen,et al.  Validation of a Noninvasive, Real-Time Imaging Technology Using Bioluminescent Escherichia coli in the Neutropenic Mouse Thigh Model of Infection , 2001, Antimicrobial Agents and Chemotherapy.

[108]  M. Pavelka,et al.  Genetic analysis of the beta-lactamases of Mycobacterium tuberculosis and Mycobacterium smegmatis and susceptibility to beta-lactam antibiotics. , 2005, Microbiology.

[109]  G. Luker,et al.  Luciferase real-time bioluminescence imaging for the study of viral pathogenesis. , 2005, Methods in molecular biology.

[110]  K. Kristensson,et al.  Preclinical Assessment of the Treatment of Second-Stage African Trypanosomiasis with Cordycepin and Deoxycoformycin , 2009, PLoS neglected tropical diseases.

[111]  K. Francis,et al.  Membranous Cells in Nasal-Associated Lymphoid Tissue: A Portal of Entry for the Respiratory Mucosal Pathogen Group A Streptococcus 1 , 2003, The Journal of Immunology.

[112]  Kshitij D Modi,et al.  Reduction of Astrogliosis by Early Treatment of Pneumococcal Meningitis Measured by Simultaneous Imaging, In Vivo, of the Pathogen and Host Response , 2005, Infection and Immunity.

[113]  Katherine W Ferrara,et al.  Enhanced in vivo bioluminescence imaging using liposomal luciferin delivery system. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[114]  Rick Lyons,et al.  The temporal expression profile of Mycobacterium tuberculosis infection in mice. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[115]  J. Curtis,et al.  Murine alveolar macrophages limit replication of vaccinia virus , 2007, Virology.

[116]  Yingfu Li,et al.  A synthetic luxCDABE gene cluster optimized for expression in high-GC bacteria , 2007, Nucleic acids research.

[117]  Vasilis Ntziachristos,et al.  Looking and listening to light: the evolution of whole-body photonic imaging , 2005, Nature Biotechnology.

[118]  B. Branchini,et al.  In Vivo Bioluminescence Imaging for the Study of Intestinal Colonization by Escherichia coli in Mice , 2009, Applied and Environmental Microbiology.

[119]  G. Luker,et al.  Bioluminescence Imaging Reveals Systemic Dissemination of Herpes Simplex Virus Type 1 in the Absence of Interferon Receptors , 2003, Journal of Virology.

[120]  P. Cossart,et al.  Modeling human listeriosis in natural and genetically engineered animals , 2009, Nature Protocols.

[121]  F. Alem,et al.  Detection of Bacillus anthracis Spore Germination In Vivo by Bioluminescence Imaging , 2008, Infection and Immunity.

[122]  J. Boothroyd,et al.  Behavioral changes induced by Toxoplasma infection of rodents are highly specific to aversion of cat odors , 2007, Proceedings of the National Academy of Sciences.

[123]  T. Merkel,et al.  Role of Anthrax Toxins in Dissemination, Disease Progression, and Induction of Protective Adaptive Immunity in the Mouse Aerosol Challenge Model , 2008, Infection and Immunity.

[124]  G. Splitter,et al.  Temporal analysis of pathogenic events in virulent and avirulent Brucella melitensis infections , 2005, Cellular microbiology.

[125]  M. Griffiths,et al.  In vivo assessment of effect of fermented milk diet on course of infection in mice with bioluminescent Salmonella. , 2003, Journal of food protection.

[126]  Kristin L. Hazelwood,et al.  Far-red fluorescent tags for protein imaging in living tissues. , 2009, The Biochemical journal.

[127]  J. W. Hastings,et al.  Chemistries and colors of bioluminescent reactions: a review. , 1996, Gene.

[128]  P. Cossart,et al.  Conjugated action of two species-specific invasion proteins for fetoplacental listeriosis , 2008, Nature.

[129]  Kevin P. Francis,et al.  Monitoring Bioluminescent Staphylococcus aureusInfections in Living Mice Using a Novel luxABCDEConstruct , 2000, Infection and Immunity.

[130]  S. Cherry,et al.  Fetal gene transfer using lentiviral vectors: in vivo detection of gene expression by microPET and optical imaging in fetal and infant monkeys. , 2006, Human gene therapy.

[131]  S. Wiles,et al.  In Vivo Bioluminescence Imaging of the Murine Pathogen Citrobacter rodentium , 2006, Infection and Immunity.

[132]  A. Haque,et al.  A role for natural regulatory T cells in the pathogenesis of experimental cerebral malaria. , 2007, The American journal of pathology.

[133]  C. Gilchrist,et al.  Resistance to Intestinal Entamoeba histolytica Infection Is Conferred by Innate Immunity and Gr-1+ Cells , 2005, Infection and Immunity.

[134]  A. Welch,et al.  A review of the optical properties of biological tissues , 1990 .

[135]  Touqir Zahra,et al.  Optical monitoring and treatment of potentially lethal wound infections in vivo. , 2003, Journal of Infectious Diseases.

[136]  B. Rice,et al.  Three-dimensional reconstruction of in vivo bioluminescent sources based on multispectral imaging. , 2007, Journal of biomedical optics.

[137]  E. B. Smith,et al.  Effects of Anaesthetics on Luminous Bacteria , 1970, Nature.

[138]  I. Weissman,et al.  Myeloid progenitors protect against invasive aspergillosis and Pseudomonas aeruginosa infection following hematopoietic stem cell transplantation. , 2002, Blood.

[139]  N. P. Franks,et al.  Do general anaesthetics act by competitive binding to specific receptors? , 1984, Nature.

[140]  D. White,et al.  Effect of Anaesthetics on Emission of Light by Luminous Bacteria , 1970, Nature.

[141]  R. Schooley,et al.  Real-Time In Vivo Green Fluorescent Protein Imaging of a Murine Leishmaniasis Model as a New Tool for Leishmania Vaccine and Drug Discovery , 2008, Clinical and Vaccine Immunology.

[142]  Gary D. Luker,et al.  Noninvasive Bioluminescence Imaging of Herpes Simplex Virus Type 1 Infection and Therapy in Living Mice , 2002, Journal of Virology.

[143]  J. Dame,et al.  Plasmepsin 4-deficient Plasmodium berghei are virulence attenuated and induce protective immunity against experimental malaria. , 2010, The American journal of pathology.

[144]  Michael Z. Lin,et al.  Mammalian Expression of Infrared Fluorescent Proteins Engineered from a Bacterial Phytochrome , 2009, Science.

[145]  V. Ntziachristos Fluorescence molecular imaging. , 2006, Annual review of biomedical engineering.

[146]  Hidefumi Akiyama,et al.  Firefly bioluminescence quantum yield and colour change by pH-sensitive green emission , 2008 .

[147]  M. Levine,et al.  Precise estimation of the numbers of chronic carriers of Salmonella typhi in Santiago, Chile, an endemic area. , 1982, The Journal of infectious diseases.

[148]  R. Munson,et al.  Nontypeable Haemophilus influenzae Gene Expression Induced In Vivo in a Chinchilla Model of Otitis Media , 2003, Infection and Immunity.

[149]  C. Olson,et al.  Bioluminescent imaging of Trypanosoma cruzi infection. , 2008, International journal for parasitology.

[150]  Philip J. Hill,et al.  agr Expression Precedes Escape of InternalizedStaphylococcus aureus from the Host Endosome , 2001, Infection and Immunity.

[151]  Nathan C Shaner,et al.  A guide to choosing fluorescent proteins , 2005, Nature Methods.

[152]  David J. Miller,et al.  Diversity and Evolution of Coral Fluorescent Proteins , 2008, PloS one.

[153]  K. Francis,et al.  Real-Time In Vivo Bioluminescent Imaging for Evaluating the Efficacy of Antibiotics in a Rat Staphylococcus aureus Endocarditis Model , 2005, Antimicrobial Agents and Chemotherapy.

[154]  Development of real-time in vivo imaging of device-related Staphylococcus epidermidis infection in mice and influence of animal immune status on susceptibility to infection. , 2008, The Journal of infectious diseases.

[155]  R. Tsien,et al.  Evolution of new nonantibody proteins via iterative somatic hypermutation. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[156]  H. Carlsen,et al.  In Vivo Imaging of NF-κB Activity1 , 2002, The Journal of Immunology.

[157]  Michael R Hamblin,et al.  Use of chitosan bandage to prevent fatal infections developing from highly contaminated wounds in mice. , 2006, Biomaterials.

[158]  C. Wolz,et al.  Bioluminescence imaging to study the promoter activity of hla of Staphylococcus aureus in vitro and in vivo. , 2008, International journal of medical microbiology : IJMM.

[159]  D. Shcherbo,et al.  Bright far-red fluorescent protein for whole-body imaging , 2007, Nature Methods.

[160]  J. Boothroyd,et al.  Toxoplasma gondii: inconsistent dissemination patterns following oral infection in mice. , 2007, Experimental parasitology.

[161]  F. Johnson,et al.  The inhibition of bacterial luminescence by a homologous series of carbamates. , 1951, Journal of cellular and comparative physiology.

[162]  G. Rakhorst,et al.  Spatiotemporal progression of localized bacterial peritonitis before and after open abdomen lavage monitored by in vivo bioluminescent imaging. , 2010, Surgery.

[163]  J. Zweier,et al.  Noninvasive measurement of anatomic structure and intraluminal oxygenation in the gastrointestinal tract of living mice with spatial and spectral EPR imaging. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[164]  T. Doyle,et al.  Expression of firefly luciferase in Candida albicans and its use in the selection of stable transformants. , 2006, Microbial pathogenesis.

[165]  G. Dougan,et al.  Cell attachment properties and infectivity of host-adapted and environmentally adapted Citrobacter rodentium. , 2007, Microbes and infection.

[166]  Andrew Pekosz,et al.  Bioluminescence imaging of vaccinia virus: effects of interferon on viral replication and spread. , 2005, Virology.

[167]  K. Mason,et al.  Development of a Chinchilla Model To Allow Direct, Continuous, Biophotonic Imaging of Bioluminescent Nontypeable Haemophilus influenzae during Experimental Otitis Media , 2005, Infection and Immunity.

[168]  Nathalie Boucher,et al.  Bioluminescent Imaging of Trypanosoma brucei Shows Preferential Testis Dissemination Which May Hamper Drug Efficacy in Sleeping Sickness , 2009, PLoS neglected tropical diseases.

[169]  M. Davidson,et al.  Advances in fluorescent protein technology , 2011, Journal of Cell Science.

[170]  E. Tuomanen,et al.  Organ-specific models of Streptococcus pneumoniae Disease , 2003, Scandinavian journal of infectious diseases.

[171]  R. Cubeddu,et al.  In vivo absorption and scattering spectroscopy of biological tissues , 2003, Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology.

[172]  C. Hill,et al.  AgrD‐dependent quorum sensing affects biofilm formation, invasion, virulence and global gene expression profiles in Listeria monocytogenes , 2009, Molecular microbiology.

[173]  S. Wong,et al.  Luciferin detection after intranasal vector delivery is improved by intranasal rather than intraperitoneal luciferin administration. , 2008, Human gene therapy.

[174]  Meng Yang,et al.  Whole-body imaging with fluorescent proteins , 2006, Nature Protocols.

[175]  G. Coukos,et al.  Vaccinia virus preferentially infects and controls human and murine ovarian tumors in mice , 2007, Gene Therapy.

[176]  F. Shanahan,et al.  Involvement of T helper type 17 and regulatory T cell activity in Citrobacter rodentium invasion and inflammatory damage , 2009, Clinical and experimental immunology.

[177]  P. Kaye,et al.  SIGNR1-negative red pulp macrophages protect against acute streptococcal sepsis after Leishmania donovani-induced loss of marginal zone macrophages. , 2009, The American journal of pathology.

[178]  S. Brooks The discovery of aequorin and green fluorescent protein , 2005 .

[179]  T. Holzman,et al.  Cloning of the luciferase structural genes from Vibrio harveyi and expression of bioluminescence in Escherichia coli. , 1984, Biochemistry.

[180]  R. Weissleder,et al.  Codon-optimized Gaussia luciferase cDNA for mammalian gene expression in culture and in vivo. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[181]  Caixia Ma,et al.  MyD88 signalling plays a critical role in host defence by controlling pathogen burden and promoting epithelial cell homeostasis during Citrobacter rodentium‐induced colitis , 2008, Cellular microbiology.

[182]  Christopher H Contag,et al.  Extracellular Replication of Listeria monocytogenes in the Murine Gall Bladder , 2004, Science.

[183]  M. Bureau,et al.  Optical imaging of luminescence for in vivo quantification of gene electrotransfer in mouse muscle and knee , 2006, BMC biotechnology.

[184]  Frankie L. Trull,et al.  More Regulation of Rodents , 1999, Science.

[185]  S. Remington Fluorescent proteins: maturation, photochemistry and photophysics. , 2006, Current opinion in structural biology.

[186]  Masafumi Oshiro,et al.  Visualizing Gene Expression in Living Mammals Using a Bioluminescent Reporter , 1997, Photochemistry and photobiology.

[187]  M. Malamy,et al.  The strict anaerobe Bacteroides fragilis grows in and benefits from nanomolar concentrations of oxygen , 2004, Nature.

[188]  W. Hanage,et al.  Modelling infectious disease — time to think outside the box? , 2006, Nature Reviews Microbiology.

[189]  M. Burdick,et al.  Antimicrobial Effects of Interferon-Inducible CXC Chemokines against Bacillus anthracis Spores and Bacilli , 2009, Infection and Immunity.

[190]  Statistics of Scientific Procedures on Living Animals 2011: Another Increase in Experimentation, but is there a Shift in Emphasis? , 2012, Alternatives to laboratory animals : ATLA.

[191]  Harry L. T. Mobley,et al.  Expression of flagella is coincident with uropathogenic Escherichia coli ascension to the upper urinary tract , 2007, Proceedings of the National Academy of Sciences.

[192]  E. Hillman,et al.  All-optical anatomical co-registration for molecular imaging of small animals using dynamic contrast. , 2007, Nature photonics.

[193]  J. McCullers,et al.  Treatment with protein synthesis inhibitors improves outcomes of secondary bacterial pneumonia after influenza. , 2009, The Journal of infectious diseases.

[194]  R. Tsien,et al.  Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein , 2004, Nature Biotechnology.

[195]  Kevin Francis,et al.  Direct Continuous Method for Monitoring Biofilm Infection in a Mouse Model , 2003, Infection and Immunity.

[196]  A. Barragan,et al.  Localized recrudescence of Toxoplasma infections in the central nervous system of immunocompromised mice assessed by in vivo bioluminescence imaging. , 2007 .

[197]  B. Rice,et al.  In vivo imaging of light-emitting probes. , 2001, Journal of biomedical optics.

[198]  R. Szittner,et al.  Nucleotide sequence, expression, and properties of luciferase coded by lux genes from a terrestrial bacterium. , 1990, The Journal of biological chemistry.

[199]  Gooitzen M van Dam,et al.  Real time noninvasive monitoring of contaminating bacteria in a soft tissue implant infection model. , 2009, Journal of biomedical materials research. Part B, Applied biomaterials.

[200]  Vasilis Ntziachristos,et al.  Shedding light onto live molecular targets , 2003, Nature Medicine.

[201]  John Frederick William Herschel,et al.  $\text{'}\text{A}\mu\acute{\text{o}}\rho\Phi\omega\tau\alpha$ No. I. On a Case of Superficial Colour Presented by a Homogeneous Liquid Internally Colourless , 1845 .

[202]  E. Herzog,et al.  Continuous Delivery of D-Luciferin by Implanted Micro-osmotic Pumps Enables True Real-Time Bioluminescence Imaging of Luciferase Activity in Vivo , 2007, Molecular imaging.

[203]  Geneviève Milon,et al.  Bioluminescent Leishmania expressing luciferase for rapid and high throughput screening of drugs acting on amastigote‐harbouring macrophages and for quantitative real‐time monitoring of parasitism features in living mice , 2005, Cellular microbiology.

[204]  C. Janse,et al.  Simple and sensitive antimalarial drug screening in vitro and in vivo using transgenic luciferase expressing Plasmodium berghei parasites. , 2008, International journal for parasitology.

[205]  O. Shimomura,et al.  The discovery of aequorin and green fluorescent protein , 2005, Journal of microscopy.

[206]  Kai Licha,et al.  Optical imaging. , 2013, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[207]  K. Francis,et al.  Monitoring in vivo fitness of rifampicin-resistant Staphylococcus aureus mutants in a mouse biofilm infection model. , 2005, The Journal of antimicrobial chemotherapy.

[208]  R. Tsien,et al.  A monomeric red fluorescent protein , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[209]  Rune Blomhoff,et al.  In vivo imaging of NF-kappa B activity. , 2002, Journal of immunology.

[210]  S. Gambhir,et al.  Optical imaging of Renilla luciferase reporter gene expression in living mice , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[211]  Hong Sjölinder,et al.  Imaging of Disease Dynamics during Meningococcal Sepsis , 2007, PloS one.

[212]  Steven Ripp,et al.  Expression of the Photorhabdus luminescens lux genes (luxA, B, C, D, and E) in Saccharomyces cerevisiae. , 2003, FEMS yeast research.

[213]  M. Chalfie,et al.  Green fluorescent protein as a marker for gene expression. , 1994, Science.

[214]  P. Stevenson,et al.  Murid herpesvirus-4 lacking thymidine kinase reveals route-dependent requirements for host colonization , 2009, The Journal of general virology.

[215]  Weijia Wang,et al.  Genetic Analysis of Varicella-Zoster Virus ORF0 to ORF4 by Use of a Novel Luciferase Bacterial Artificial Chromosome System , 2007, Journal of Virology.

[216]  Touqir Zahra,et al.  Targeted photodynamic therapy of established soft-tissue infections in mice , 2004, SPIE BiOS.

[217]  C. Contag,et al.  In utero delivery of adeno-associated viral vectors: intraperitoneal gene transfer produces long-term expression. , 2001, Molecular therapy : the journal of the American Society of Gene Therapy.

[218]  G. Sayler,et al.  Autonomous Bioluminescent Expression of the Bacterial Luciferase Gene Cassette (lux) in a Mammalian Cell Line , 2010, PloS one.

[219]  A. Campbell Living light: biochemistry, applications. , 1989, Essays in biochemistry.

[220]  Vasilis Ntziachristos,et al.  Complete-angle projection diffuse optical tomography by use of early photons. , 2005, Optics letters.

[221]  H. Hricak,et al.  Escherichia coli Nissle 1917 Facilitates Tumor Detection by Positron Emission Tomography and Optical Imaging , 2008, Clinical Cancer Research.

[222]  G. Splitter,et al.  Brucella TIR Domain-containing Protein Mimics Properties of the Toll-like Receptor Adaptor Protein TIRAP* , 2009, Journal of Biological Chemistry.

[223]  Geneviève Milon,et al.  Intradermal inoculations of low doses of Leishmania major and Leishmania amazonensis metacyclic promastigotes induce different immunoparasitic processes and status of protection in BALB/c mice. , 2003, International journal for parasitology.

[224]  M. Alenquer,et al.  In vivo imaging of murid herpesvirus-4 infection , 2009, The Journal of general virology.

[225]  H. Wigzell,et al.  Use of non-invasive bioluminescent imaging to assess mycobacterial dissemination in mice, treatment with bactericidal drugs and protective immunity. , 2009, Microbes and infection.

[226]  Kshitij D Modi,et al.  Noninvasive Biophotonic Imaging for Monitoring of Catheter-Associated Urinary Tract Infections and Therapy in Mice , 2005, Infection and Immunity.

[227]  S. Mordon,et al.  Monitoring of bactericidal action of laser by in vivo imaging of bioluminescent E. coli in a cutaneous wound infection , 2006, Lasers in Medical Science.

[228]  Michael R Hamblin,et al.  Monitoring photodynamic therapy of localized infections by bioluminescence imaging of genetically engineered bacteria. , 2005, Journal of photochemistry and photobiology. B, Biology.

[229]  B. Applegate,et al.  Influence of irrigant needle depth in removing bioluminescent bacteria inoculated into instrumented root canals using real-time imaging in vitro. , 2005, International endodontic journal.

[230]  L. Mortin,et al.  Rapid Bactericidal Activity of Daptomycin against Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus Peritonitis in Mice as Measured with Bioluminescent Bacteria , 2007, Antimicrobial Agents and Chemotherapy.

[231]  Konstantin A Lukyanov,et al.  Far-red fluorescent proteins evolved from a blue chromoprotein from Actinia equina. , 2005, The Biochemical journal.

[232]  C. Contag,et al.  Emission spectra of bioluminescent reporters and interaction with mammalian tissue determine the sensitivity of detection in vivo. , 2005, Journal of biomedical optics.

[233]  Christopher H Contag,et al.  Monitoring Age-Related Susceptibility of Young Mice To Oral Salmonella enterica Serovar Typhimurium Infection Using an In Vivo Murine Model , 2005, Pediatric Research.

[234]  N. Chaffey Red fluorescent protein , 2001 .

[235]  Julie L Prior,et al.  Imaging reversal of multidrug resistance in living mice with bioluminescence: MDR1 P-glycoprotein transports coelenterazine. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[236]  A. Mackay-Sim,et al.  Nasal-associated lymphoid tissue and olfactory epithelium as portals of entry for Burkholderia pseudomallei in murine melioidosis. , 2009, The Journal of infectious diseases.

[237]  J Davies,et al.  Inactivation of antibiotics and the dissemination of resistance genes. , 1994, Science.

[238]  S. Falkow,et al.  Salmonella typhimurium Persists within Macrophages in the Mesenteric Lymph Nodes of Chronically Infected Nramp1 + / + Mice and Can Be Reactivated by IFNγ Neutralization , 2004, The Journal of experimental medicine.

[239]  W D McElroy,et al.  Complementary DNA coding click beetle luciferases can elicit bioluminescence of different colors. , 1989, Science.

[240]  A. Crisanti,et al.  Temporal and Spatial Distribution of Toxoplasma gondii Differentiation into Bradyzoites and Tissue Cyst Formation In Vivo , 2008, Infection and Immunity.

[241]  J. McCullers,et al.  Role of neuraminidase in lethal synergism between influenza virus and Streptococcus pneumoniae. , 2003, The Journal of infectious diseases.

[242]  Christopher H Contag,et al.  Technoreview: In vivo bioluminescence imaging for integrated studies of infection , 2004, Cellular microbiology.

[243]  M. Jiang,et al.  Uniqueness theorems in bioluminescence tomography. , 2004, Medical physics.

[244]  R. Sun,et al.  TANK-Binding Kinase-1 Plays an Important Role during In Vitro and In Vivo Type I IFN Responses to DNA Virus Infections1 , 2009, The Journal of Immunology.

[245]  M. Mock,et al.  Primary Involvement of Pharynx and Peyer's Patch in Inhalational and Intestinal Anthrax , 2007, PLoS pathogens.

[246]  Anna Moore,et al.  Multiparametric monitoring of tumor response to chemotherapy by noninvasive imaging. , 2009, Cancer research.

[247]  G. Splitter,et al.  Attenuated Bioluminescent Brucella melitensis Mutants GR019 (virB4), GR024 (galE), and GR026 (BMEI1090-BMEI1091) Confer Protection in Mice , 2006, Infection and Immunity.

[248]  J. Ripoll,et al.  Free-space propagation of diffuse light: theory and experiments. , 2003, Physical review letters.

[249]  P. Hwu,et al.  Visualizing fewer than 10 mouse T cells with an enhanced firefly luciferase in immunocompetent mouse models of cancer , 2008, Proceedings of the National Academy of Sciences.

[250]  Thomas L. Chenevert,et al.  Molecular Imaging of Gene Expression and Efficacy following Adenoviral-Mediated Brain Tumor Gene Therapy , 2002 .

[251]  Campbell Ak Living light: biochemistry, applications. , 1989 .

[252]  D. Bumann Examination of Salmonella gene expression in an infected mammalian host using the green fluorescent protein and two‐colour flow cytometry , 2002, Molecular microbiology.

[253]  O. Shimomura,et al.  Properties and reaction mechanism of the bioluminescence system of the deep-sea shrimp Oplophorus gracilorostris. , 1978, Biochemistry.

[254]  J. Burgos,et al.  Non-invasive bioluminescence imaging for monitoring herpes simplex virus type 1 hematogenous infection. , 2006, Microbes and infection.

[255]  G. Milon,et al.  Early Curative Applications of the Aminoglycoside WR279396 on an Experimental Leishmania major-Loaded Cutaneous Site Do Not Impair the Acquisition of Immunity , 2009, Antimicrobial Agents and Chemotherapy.

[256]  H. Mühl,et al.  A brief exposure to isoflurane (50 s) significantly impacts on plasma cytokine levels in endotoxemic rats. , 2005, International immunopharmacology.

[257]  M. Pavelka,et al.  Genetic analysis of the β-lactamases of Mycobacterium tuberculosis and Mycobacterium smegmatis and susceptibility to β-lactam antibiotics , 2005 .

[258]  W. Denk,et al.  Deep tissue two-photon microscopy , 2005, Nature Methods.

[259]  U. Schaible,et al.  Sensitive Detection of Gene Expression in Mycobacteria under Replicating and Non-Replicating Conditions Using Optimized Far-Red Reporters , 2010, PloS one.

[260]  R. Sun,et al.  Persistent Gammaherpesvirus Replication and Dynamic Interaction with the Host In Vivo , 2008, Journal of Virology.

[261]  Joachim Goedhart,et al.  Bright monomeric red fluorescent protein with an extended fluorescence lifetime , 2007, Nature Methods.