EP3465211A1 - Method for determining the number of sites of infection of a cell culture - Google Patents
Method for determining the number of sites of infection of a cell cultureInfo
- Publication number
- EP3465211A1 EP3465211A1 EP17727839.7A EP17727839A EP3465211A1 EP 3465211 A1 EP3465211 A1 EP 3465211A1 EP 17727839 A EP17727839 A EP 17727839A EP 3465211 A1 EP3465211 A1 EP 3465211A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- areas
- cell culture
- infection
- transmitted light
- fluorescence analysis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 95
- 208000015181 infectious disease Diseases 0.000 title claims abstract description 47
- 238000004113 cell culture Methods 0.000 title claims abstract description 44
- 238000012921 fluorescence analysis Methods 0.000 claims abstract description 20
- 241000700605 Viruses Species 0.000 claims abstract description 19
- 230000007547 defect Effects 0.000 claims description 14
- 230000003612 virological effect Effects 0.000 claims description 14
- 238000010790 dilution Methods 0.000 claims description 4
- 239000012895 dilution Substances 0.000 claims description 4
- 238000011156 evaluation Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 238000003908 quality control method Methods 0.000 claims description 4
- 238000005259 measurement Methods 0.000 claims description 3
- 238000009792 diffusion process Methods 0.000 claims description 2
- 238000003384 imaging method Methods 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 238000011534 incubation Methods 0.000 claims 1
- 239000012530 fluid Substances 0.000 description 10
- 239000000975 dye Substances 0.000 description 7
- 238000002795 fluorescence method Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 229960000907 methylthioninium chloride Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56983—Viruses
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
- C12Q1/04—Determining presence or kind of microorganism; Use of selective media for testing antibiotics or bacteriocides; Compositions containing a chemical indicator therefor
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/59—Transmissivity
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
- G01N2021/6439—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks
Definitions
- the invention relates to a method for determining the number of foci of infection of a cell culture.
- a cell culture is grown on a sample carrier.
- Titer plates and Mitkotiterplatten are particularly suitable as a sample carrier, cell cultures are grown in the individual wells, so that the cells grow on the well bottom.
- the cells are infected with a viral fluid.
- This is usually diluted, with different wells in particular viral liquids added in different dilutions.
- a removal, in particular a pumping out of the viral fluid After a predetermined, in particular dependent on the type of virus period, there is a removal, in particular a pumping out of the viral fluid.
- the viral fluid usually affects the cell culture for several minutes to several hours. After removal of the viral fluid is usually carried out a supply of a medium which is intended to prevent diffusion of virus particles released later.
- the destroyed areas or areas in which there are no living cells can be counted.
- Such counting is usually done after taking a corresponding image by persons, photographing or microscopy.
- the sample can be dyed with a dye.
- the determination of the number of foci of infection of a cell culture with the aid of the transmitted light method has the particular disadvantage that, for example, later infected cells or cells which react differently to the virus have not yet died and insofar as a corresponding hole can not be seen in the transmitted light method. This also applies, for example, to cells that react more slowly, so that the corresponding holes are still very small and therefore not or hardly visible.
- Another disadvantage of the transmitted light method is that other defects that were not caused by the viruses are recognized as such defects and incorrectly counted. Such imperfections may, for example, be areas in which the cells have been washed away or impurities are present. The Wegschwemmen can occur, for example, in the addition of the viral fluids or even with the addition of the gel.
- the length of the period of time that must be waited before a corresponding implementation of the transmitted light method is difficult to determine and depends in particular on the type of virus. If the period is too short, the corresponding infected areas have only one small number of dead cells, so that the corresponding holes or defects are difficult to detect. If the period chosen is too long, individual areas grow together, making it difficult to determine whether it is originally a source of infection or multiple sites of infection with a common infected area of cell culture.
- the object of the invention is to provide a method for determining the number of foci of infection of a cell culture with which the number of foci of infection can be determined more accurately and reliably.
- infecting a cell culture arranged in a sample carrier with viruses first takes place. This is done in particular by adding a viral fluid, which may optionally be diluted.
- a viral fluid which may optionally be diluted.
- infection foci are to be understood region on the sample carrier, in which an initial infection of the cells is carried out by the virus, forming infected areas starting from the respective infection, in which the cells are already infected and / or have already been destroyed.
- sample carriers are preferably titer plates, in particular microtiter plates used, wherein the cell cultures are preferably grown on the well bottom.
- an identification of infected cells is carried out using a particular specific fluorescent marker.
- the marking of the infected cells takes place directly on the basis of the virus and / or on the basis of an effect caused directly by the virus.
- the infected areas can thereby be distinguished from the uninfected areas of the cell culture.
- the infected areas of the cell culture are then determined by fluorescence analysis method.
- at least initially, even large fluorescent areas are counted as only one area.
- the combination of the two methods according to the invention is carried out in such a way that an area-wise evaluation of the areas determined in the two methods takes place in order to determine the number of foci of infection.
- all the areas previously determined beforehand either by means of transmitted light method or by means of fluorescence analysis methods are consecutively passed through in succession, and the combination of the two methods reliably determines the respective number of sources of infection of the respective area considered. It would be possible, for example, to sum up the areas determined in the two methods. Since this individual Areas can be counted twice, so far as a balance can be made in particular by superimposing the determined results of the transmitted light method and the fluorescence analysis method of the determined areas that the areas determined in both methods are only counted easily.
- sequence of the steps of the method of using the transmitted light method as described above, labeling the infected cells by a specific marker as described above and applying the fluorescence analysis method as described above are arbitrary, of course, labeling the infected cells always before the fluorescence analysis method got to.
- the evaluation of the areas determined by the two methods takes place in such a way that areas recognized in the transmitted-light method, which, however, were not recognized in the fluorescence analysis method, are not counted as a source of infection.
- the corresponding sample can not be taken into account in the evaluation. This can be done automatically due to the number or size of the corresponding defects in particular.
- the control of the frequency and size of these defects is also important for the quality control of the sample preparation.
- regions are determined which are detected in the fluorescence method but not in the transmitted-light method. These areas are counted as sources of infection of the cell culture. These are areas that have virus-infected cells, but in which no such great damage to the cells has occurred, that a corresponding number of dead cells, which then also decay and would be visible as an empty area with the transmitted light method, is present. In particular, it is also possible to count these areas separately or to weight them. Suitably, this analysis z. B. be to get clues to greatly varying infection rate of the virus. It is also possible to control the quality of certain aspects of sample preparation.
- the areas detected in particular in both methods are analyzed based on their size and / or shape.
- a predetermined limit value that is, when a predetermined extent or a predetermined area of the infected area is exceeded, the corresponding area can be counted several times.
- the assumption is reasons that these are several coalesced original foci of infection.
- a more accurate analysis of such areas takes place.
- a number of foci of infection are determined.
- the number of defects due to fluorescence on dead cells preferably represents the minimum number of sites of infection originally infected in this area. If necessary, this number is increased due to the strong fluorescence, since it is assumed that in this area For example, originally infected cells are present, which have not yet died, so that no defect has arisen.
- the limit size is determined as a function of the samples and / or the measurements. For example, it is possible to determine the limit size based on a size distribution of the corresponding found areas. For example, a comparison with the median value of such found areas would also be possible. In particular, a determination of the limit value can be made on the basis of a size statistic of the different regions.
- the transmitted light method and / or the fluorescence analysis method is carried out as automated methods.
- this is done on the basis of imaging techniques.
- Particularly suitable for this purpose are automated microscopes or plate readers with image processing methods. Suitable for this example, the disk reader EnSight manufacturer PerkinElmer.
- the cell culture can be colored. This can be done with known methods and dyes, especially methylene blue.
- the staining of the cell culture is carried out with a nonspecific dye which dyes all cells of the cell culture equally, so as to clearly highlight defects within the cell culture. If necessary, the spectral properties of the dye used for the fluorescence method must be taken into account.
- the growth of the cells, the infecting of the cells with viral fluid, the covering with a gel can be infected by means of an optionally diluted viral fluid. It is preferred here that the dilution factor is taken into account in the determination of the number of foci of infection.
- the same cell culture is present on each well and or the same viral liquid is optionally supplied in different dilutions.
- microtiter plates with a large number of wells it is also possible to use different regions with different cell cultures, different viral fluids or cell cultures treated with different pharmaceutically active substances.
- control values for quality control are determined automatically in particular. This may be a closer look or even just a counting of the imperfections that are flaws, caused for example by swimming away or impurities and not by dead cells.
- Important control values are also the quality of the object recognition, the texture of the cell layers, which in particular are not disturbed by a virus infection, or also the strength of the specific infection marker averaged over a sample.
- details about the size or Morphology of the detected infection areas are used for the interpretation of the measurement.
- nonspecific detection methods can also be used.
- fluorescence methods which mark cells or areas of cells independently of an infection and which are then read microscopically.
- a fluorescent dye with different properties is preferred for this purpose.
- infection-specific detection methods instead of a fluorescence analysis method.
- non-fluorescent infection-specific markers may, for example, be dyes for colorimetric processes.
- a well of a titer plate is shown as a schematic example.
- a cell culture is arranged, which was infected with viruses as described above.
- different areas are formed.
- the area shown in white is an area in which cells have been washed away, for example, in the addition of the viral fluid or the like, and thus an area without cells is formed.
- the dark shaded areas are fluorescent areas, that is, areas where infected cells are present.
- different areas can form. In the example shown, it is an area without a free center. This is an area in which cells are infected, but still no free center of dead cells has emerged.
- infected area which has a free or empty center.
- the empty center is the area where dead cells are present. These are surrounded by infected and therefore fluorescent cells.
- the large area shown in the left part of the well represents a coalesced focus of infection. It has four empty centers surrounded by fluorescent and therefore infected cells.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Virology (AREA)
- Organic Chemistry (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Cell Biology (AREA)
- Genetics & Genomics (AREA)
- General Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- Toxicology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Optics & Photonics (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP16171730.1A EP3249406A1 (en) | 2016-05-27 | 2016-05-27 | Method for determining the number of infection focuses of a cell culture |
PCT/EP2017/062617 WO2017202956A1 (en) | 2016-05-27 | 2017-05-24 | Method for determining the number of sites of infection of a cell culture |
Publications (1)
Publication Number | Publication Date |
---|---|
EP3465211A1 true EP3465211A1 (en) | 2019-04-10 |
Family
ID=56112830
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP16171730.1A Withdrawn EP3249406A1 (en) | 2016-05-27 | 2016-05-27 | Method for determining the number of infection focuses of a cell culture |
EP17727839.7A Pending EP3465211A1 (en) | 2016-05-27 | 2017-05-24 | Method for determining the number of sites of infection of a cell culture |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP16171730.1A Withdrawn EP3249406A1 (en) | 2016-05-27 | 2016-05-27 | Method for determining the number of infection focuses of a cell culture |
Country Status (5)
Country | Link |
---|---|
US (1) | US10774360B2 (en) |
EP (2) | EP3249406A1 (en) |
JP (1) | JP6964098B2 (en) |
CN (1) | CN109313191B (en) |
WO (1) | WO2017202956A1 (en) |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL7609183A (en) * | 1975-09-04 | 1977-03-08 | Merck & Co Inc | PROCEDURE FOR DETERMINING THE INFECTIVITY OF VIRUS PREPARATIONS AND PROCEDURE FOR DETERMINING THE ANTIBODY CONTENT OF SERUM. |
CA2075488A1 (en) * | 1990-02-09 | 1991-08-10 | Bruce Wilcox Chesebro | Method for detection of human immunodeficiency virus and cell lines useful therefor |
US6472206B1 (en) * | 2000-04-28 | 2002-10-29 | Interthyr Corporation | In situ growth, freezing and testing of cultured cells |
EP1311254A2 (en) * | 2000-08-15 | 2003-05-21 | Northeastern Ohio Universities | METHODS FOR TREATING SUBJECTS INFECTED WITH A HERPES VIRUS OR i NEISSERIA GONORRHEAE /i |
US7400753B2 (en) * | 2001-07-03 | 2008-07-15 | Hitachi, Ltd. | Biological sample optical measuring method and biological sample optical measuring apparatus |
US6610474B1 (en) * | 2002-04-25 | 2003-08-26 | University Hospitals Of Cleveland | Cells for detection of influenza and parainfluenza viruses |
DE10332117A1 (en) * | 2003-03-04 | 2004-12-02 | NMI Naturwissenschaftliches und Medizinisches Institut an der Universität Tübingen | Process for the preparation of a carrier with immobilized viruses and use of such a carrier |
FR2862069B1 (en) * | 2003-11-07 | 2006-06-23 | Celogos | AUTOMATIC ANALYSIS OF CELLULAR SAMPLES |
CN1314955C (en) * | 2005-01-28 | 2007-05-09 | 晏芸 | Fluorescent in situ hybridization counting slide and counting method thereof |
EP2084234A2 (en) * | 2006-11-08 | 2009-08-05 | Massachusetts Institute of Technology | Polymeric coatings that inactivate viruses and bacteria |
US20100189338A1 (en) * | 2008-04-09 | 2010-07-29 | Nexcelom Bioscience | Systems and methods for counting cells and biomolecules |
JP2010068718A (en) * | 2008-09-16 | 2010-04-02 | Panasonic Corp | Means for specifying cell type using virus |
JP6210685B2 (en) * | 2010-01-27 | 2017-10-11 | マサチューセッツ インスティテュート オブ テクノロジー | Engineered polypeptide agents for targeted broad spectrum influenza neutralization |
WO2012050645A2 (en) * | 2010-06-25 | 2012-04-19 | Purdue Research Foundation | Pathogen detection |
WO2012067495A1 (en) * | 2010-11-17 | 2012-05-24 | Stichting Katholieke Universiteit, More Particularly The Radboud University Nijmegen Medical Centre | New diagnostic assay for determining severity of rsv infection |
US8609363B2 (en) * | 2010-11-18 | 2013-12-17 | Bio-Rad Laboratories, Inc. | Viability cell counting by differential light absorption |
JP2013105245A (en) * | 2011-11-11 | 2013-05-30 | Ikutoku Gakuen | Image processing method, device and program |
US9389229B2 (en) * | 2012-07-18 | 2016-07-12 | Theranos, Inc. | Methods for detecting and measuring aggregation |
JP2016529885A (en) * | 2013-07-12 | 2016-09-29 | イー・エム・デイー・ミリポア・コーポレイシヨン | Method for determining virus removal from a sample containing a target protein using activated carbon |
-
2016
- 2016-05-27 EP EP16171730.1A patent/EP3249406A1/en not_active Withdrawn
-
2017
- 2017-05-24 US US16/304,407 patent/US10774360B2/en active Active
- 2017-05-24 EP EP17727839.7A patent/EP3465211A1/en active Pending
- 2017-05-24 CN CN201780032666.7A patent/CN109313191B/en active Active
- 2017-05-24 WO PCT/EP2017/062617 patent/WO2017202956A1/en unknown
- 2017-05-24 JP JP2018561645A patent/JP6964098B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
US10774360B2 (en) | 2020-09-15 |
US20190292578A1 (en) | 2019-09-26 |
JP6964098B2 (en) | 2021-11-10 |
CN109313191A (en) | 2019-02-05 |
WO2017202956A1 (en) | 2017-11-30 |
JP2019517249A (en) | 2019-06-24 |
CN109313191B (en) | 2022-04-05 |
EP3249406A1 (en) | 2017-11-29 |
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