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WO2012142022A1 - Essais, compositions, systèmes, nécessaires et dispositifs pour diagnostiquer la fièvre typhoïde - Google Patents

Essais, compositions, systèmes, nécessaires et dispositifs pour diagnostiquer la fièvre typhoïde Download PDF

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Publication number
WO2012142022A1
WO2012142022A1 PCT/US2012/032874 US2012032874W WO2012142022A1 WO 2012142022 A1 WO2012142022 A1 WO 2012142022A1 US 2012032874 W US2012032874 W US 2012032874W WO 2012142022 A1 WO2012142022 A1 WO 2012142022A1
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seq
typhi
protein
cytokine
cells
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Edward T. Ryan
Richelle C. CHARLES
Firdausi Qadri
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General Hospital Corp
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General Hospital Corp
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    • 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
    • G01N33/56911—Bacteria
    • G01N33/56916—Enterobacteria, e.g. shigella, salmonella, klebsiella, serratia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
    • C07K14/255—Salmonella (G)
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • G01N33/6866—Interferon
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/195—Assays involving biological materials from specific organisms or of a specific nature from bacteria
    • G01N2333/24—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
    • G01N2333/255—Salmonella (G)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/555—Interferons [IFN]
    • G01N2333/57—IFN-gamma
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the patient can be diagnosed as having typhoid fever or acute typhoid fever. If the amount is not increased, the condition in the patient is not typhoid fever or acute typhoid fever.
  • the typhoid fever is acute typhoid fever.
  • the S. Typhi protein responsive cytokine is selected from the group consisting of IFN- ⁇ , IL-1, IP- 10, IL-8, MCP-1, MDC, and MIP-la or any combination thereof. In some embodiments, the S. Typhi protein responsive cytokine is IFN- ⁇ .
  • the biological sample is a blood sample.
  • the blood sample is a fresh blood sample.
  • the biological sample is peripheral blood mononuclear cell sample.
  • the non-human machine comprises a computer implemented software.
  • the invention provides a computer program comprising computer program code means adapted to perform all the steps of any of the assays set forth herein when said program is run on a computer.
  • the invention provides a composition comprising at least one isolated and purified protein selected from the group consisting of STY0202, STY0372, STY1177, STY1179, STY1304, STY1878, STY2195, STY0206, STY0595, STY0909, STY1375, STY1522, STY2167 FliC, STY2381, STY3089, STY3090, and STY3796 or any combination thereof.
  • the composition may be provided in a dry form or in a suitable solution, such as a storage buffer or a buffer suitable for incubating the protein with the biological sample.
  • the kit further comprises laboratory materials and instructions to implement an assay as described in any and all embodiments described above.
  • the kit further comprises a washing buffer.
  • the kit further comprises a solid support comprising an antibody against at least one of S. Typhi protein responsive cytokine against at least wherein the solid support is an ELISA plate and the marker is an enzyme.
  • the S. Typhi protein responsive cytokine in the kit is selected from the group consisting of IFN- ⁇ , IL-1, IP- 10, IL- 8, MCP-1, MDC, and MIP-la.
  • the kit further comprises a secondary antibody directed against at least one S. Typhi protein responsive cytokine.
  • the at least one isolated and purified S is selected from the at least one isolated and purified S.
  • the S. Typhi protein responsive cytokine is selected from the group consisting of IFN- ⁇ , IL-1, IP-10, IL-8, MCP-1, MDC, and MIP-la.
  • Figure 1 shows interferon- ⁇ ELISPOT responses to S. Typhi proteins
  • Typhi proteins including StaF (STY0202), PagC (STY1878), S. Typhi membrane preparation (MP), and PMA and keyhole limpet hemocyanin (KLH) during acute and convalesecent stage illness in S. Typhi bacteremic patients. Mean and standard error of the mean represented.
  • FIG. 3 shows cellular proliferation responses to S. Typhi proteins
  • the '870 patent does not set forth how the method could be used in diagnosis of typhoid fever including acute typhoid fever. Moreover, the '870 patent only describes the method for diagnosing viral diseases and not for bacterial diseases.
  • the biological sample comprises PMBC or isolated
  • PMBC PMBC.
  • T-cells e.g. CD8+ or CD4+ cells that have been activated or pre-sensitized in vivo to a one or more of the particular S. Typhi peptides described herein.
  • T-cells i.e. cells capable of immediate effector function without the need to effect division/differentiation by in vitro culture.
  • the cells secrete various cytokines, herein referred to as S. Typhi protein specific cytokines, of which any one may be selected for the purposes of this assay.
  • the peptide or peptide fragment typically needs to be of a length, e.g., about 6-15 amino acids, for example, 8-12 or 8-10, amino acid residues long, that is recognised by CD8+ cells. It has been proposed, that the generality of the CD8+ cells (and other PBMC) present the peptide to the small minority of CD8+ cells that may have been pre-sensitised to the S. Typhi peptide. If such activated or pre-sensitized peptide- specific T-cells are present in the test biological fluid, they respond by secreting a cytokine which then becomes bound to the, e.g., immobilized antibody.
  • a cytokine which then becomes bound to the, e.g., immobilized antibody.
  • the entire protein may be used, but it may be digested into smaller fragments.
  • the invention provides compositions comprising fragments of any one or more of the S. Typhi proteins described herein. Such fragments may also be past of a kit or a device or an assay. The fragments typically comprise one or more epitopes.
  • Incubation should be continued for a time sufficient to permit CD8+ cells that have been pre- sensitized in vivo to the particular peptide chosen to secrete the cytokine. The incubation should not continue for so long that quiescent CD8+ cells have time to
  • the incubation in some embodiments is performed within in a single working day or overnight, and without the use of sterile conditions required for cell culture in vitro.
  • the assay may be conveniently carried out, for example, in a multiwell plate or on a microfluidic device.
  • each well of the plate has a surface carrying a bound first antibody.
  • a fluid containing an appropriate number e.g. 10 3 -10 6 of cells.
  • Different peptides and/or controls can be added to individual wells of the plate or channels of the microfluidic device. Cells that secrete a cytokine during incubation show up as spots (spot forming cells or SFCs) and the number or density of these in each well can readily be determined.
  • the assay can further comprise a step of diagnosing the patient as having typhoid fever if the amount of the cytokine is increased to at least about 1.5 fold or more compared to a reference amount.
  • the typhoid fever is acute tyhoid fever.
  • the step of diagnosing can be performed automatically, by a machine or a computer implemented software.
  • the amount of cytokines can be determined, measured or detected by well known methods to one skilled in the art. For example, one can measure the cytokines using antibodies that form immunocomplexes with the cytokines.
  • the appropriate mediums, appropriate conditions, and protocols for the formation of the immunocomplexes are known for one skilled in the art working in the field of immunology. By way of example, various methods and protocols which can be used are described in "Current Protocols in
  • the assay can also be a FluoroSpot assay, which is a modification of the
  • a Fluorescence lifetime (FLT) assay can be used to detect and measure the cytokine response in the assays of the present invention.
  • the biological fluid can be peripheral blood mononuclear cells (PMBC). They may suitably isolated, e.g., from a patient's blood. In some embodiments, fresh cells are used, because cells cultured in vitro may develop altered characteristics thus reducing the diagnostic value of the assay.
  • the purpose of the assay is to identify or quantitate peptide- specific T-cells e.g. CD8+ or CD4+ cells that have been activated or pre- sensitized in vivo to a particular peptide. These are unrestimulated T-cells, i.e. cells capable of immediate effector function without the need to effect division/differentiation by in vitro culture. When the peptide in question is presented to such cells, the cells secrete various cytokines, of which any one may be selected for the purposes of this assay.
  • the method comprises use of coated 96-well nitrocellulose plates (Multiscreen HTS, Millipore). Plates can be coated, e.g., with e.g., about 100 ⁇ of 15 ⁇ g/ml human monoclonal anti-interferon- ⁇ antibody (1-DlK), e.g., about 8-24 hours, e.g., overnight at or at about 4°C. The plates can be washed and subsequently blocked with, e.g., about 10% FBS for about 2 h at room temperature.
  • PBMCs from individual patients, and optionally controls can be added at a concentration of 2xl0 5 per well.
  • the plates can be developed with aminoethylcarbazol plus H 2 0 2 , and the amount of interferon- ⁇ secreted by the cells or the number of interferon- ⁇ secreting cells can be counted. In some embodiments, the counting is performed using a stereomicro scope .
  • the enzyme and corresponding soluble substrate can be selected from the following combinations comprising: the alkaline phosphatase and the soluble substrate 4- nitrophenyl phosphate (PNPP); the peroxidase and the soluble substrate orthophenylene diamine (OPD); the .beta.-galactosidase and the soluble substrate 2-nitrophenyl .beta.- galactoside (ONPG); or the glucose-6-phosphate dehydrogenase and the soluble substrate glucose-6-phosphate (G6P).
  • PNPP 4- nitrophenyl phosphate
  • OPD peroxidase and the soluble substrate orthophenylene diamine
  • ONPG 2-nitrophenyl .beta.- galactoside
  • G6P glucose-6-phosphate dehydrogenase and the soluble substrate glucose-6-phosphate
  • DNase mix (10 mg/ml DNase; Sigma Aldrich in 900 mM MgCl 2 , 100 mM MnCl 2 ) to the lysate and agitated the preparation at 900 rpm for 10 min.
  • lysis buffer II 100 mM NaH 2 P0 4 , 10 mM Tris, 6 M guanidine hydrochloride, 10 mM, 2-mercaptoethanol, pH 8.0
  • the LabChip90 analyzed 96 proteins at a time with analysis time of 40 seconds per sample. We parsed the output results and imported them into the Harvard Institute of Proteomics protein database. We assessed for presence of contaminating E. coli LPS using a HEK-Blue LPS Detection kit (InvivoGen, San Diego, CA).
  • compositions comprising the novel isolated and purified or recombinantly or synthetically produced proteins, selected from the group consisting of STY0202, STY0372, STY1177, STY1179, STY1304, STY1878, STY2195, STY0206, STY0595, STY0909, STY1375, STY1522, STY2167 FliC, STY2381, STY3089, STY3090, STY3796.
  • the compositions can be used in assays guiding diagnosis for typhoid fever, including acute typhoid fever.
  • the invention further provides kits for determining level of cytokines in a blood sample.
  • the kit comprises (a) a composition consisting of at least one of the following isolated S. Typhi proteins: recombinant or synthesized or isolated STY0202, recombinant or synthesized or isolated STY0372, recombinant or synthesized or isolated STY1177, recombinant or synthesized or isolated STY1179, recombinant or synthesized or isolated STY 1304, recombinant or synthesized or isolated STY 1878, recombinant or synthesized or isolated STY2195, recombinant or synthesized or isolated STY0206, recombinant or synthesized or isolated STY0595, recombinant or synthesized or isolated STY0909, recombinant or synthesized or isolated STY1375, recombinant or synthesized or isolated STY1522, recombinant or synthesized or isolated STY2167 Fl
  • the kit may further comprise buffers and washing solutions for facilitating incubation of the proteins with the blood sample and detection of the cytokines from the sample after incubation.
  • the kit can include a solid support.
  • the solid support has bound to it an antibody that can bind one or more of the S. Typhi responsive cytokines.
  • the soli support is an ELISA plate.
  • the kit comprises a microfluidic device.
  • Antibodies both monoclonal and polyclonal, against the human cytokines useful according to the present invention are readily available to one skilled in the art from commercial sources. They can be readily picked according to the application, and can be purchased with or without specific labels already attached to them.
  • cytokines useful according to the present invention are also readily available to one of ordinary skill in the art, e.g., in publicly available databases.
  • Antibodies can be optionally produced by a cell line, a mixed cell line, an immortalized cell or clonal population of immortalized cells, as well known in the art. See, e.g., Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, N.Y.
  • IL-8 also referred to as CXCL8; GCP-1 ; GCP1 ; LECT; LUCT; LYNAP; MDNCF; MONAP; NAF; NAP-1; NAP1; C-X-C motif chemokine 8;
  • the methods according to the present invention can be automated using robotics and computer directed systems.
  • the entire assay can be automated from the point of introducing the biological fluid sample comprising T cells to an protein or a mixture thereof, incubating the reaction mixture, washing the reaction mixture, exposing the reaction mixture to a secondary antibody and detecting the amount of cytokine secreted by the cells.
  • the step of comparing and displaying the results can also be automated and connected to the same system or in a remote system.
  • the analysis, comparison and the result is performed in one location.
  • the invention further provides a system to facilitate the diagnosis of typhoid fever in a human subject, comprising: a determination module configured to receive and output the amount of cytokines produced by the T-cells in the biological sample taken from a human and contacted with at least one S. Typhi protein or fragment thereof; a storage module configured to store output information from the determination module; a comparison module adapted to compare the data stored on the storage module with reference data and/or control data, and to provide a comparison content, and an output module for displaying the comparison content for the user, wherein if the cytokine amount is about 1.5 fold or more compared to the reference value, in the sample, then the subject will be indicated as having typhoid fever.
  • the invention provides a computer readable storage medium comprising: a storing data module containing data from a sample obtained from a subject that represents a signal level from the cytokine assay after exposure of the human biological sample comprising T cells to at least one of the S.
  • the cut off value is about 1.5 fold the reference value, which is or has been typically obtained from normal cytokine amount in a control human or a pool of control humans or an average of a set of control humans who is/are known not to be affected with typhoid fever.
  • the fever is still very high and oscillates very little over 24 hours. Dehydration ensues and the patient is delirious (typhoid state). By the end of third week the fever has started reducing this (defervescence). This carries on into the fourth and final week.
  • a person may become an asymptomatic carrier of typhoid fever, suffering no symptoms, but capable of infecting others. According to the CDC approximately 5% of people who contract typhoid continue to carry the disease after they recover.
  • S. Typhi contains approximately 4,400 open reading frames, and although protein microarrays can be used to screen for humoral responses across the immunoproteome, no comparable system has yet been developed to assess cellular immune responses in a high throughput manner, despite the critical role that cellular immune responses play against intracellular pathogens.
  • CD4 and CD8 cells are critical to the development of protective immunity, and control of Salmonella infection involves prominent expression of interferon- ⁇ by both CD4 and CD8 cells [24,25,26].
  • CD4 and CD8 cells are critical to the development of protective immunity, and control of Salmonella infection involves prominent expression of interferon- ⁇ by both CD4 and CD8 cells [24,25,26].
  • CD4 and CD8 cells are critical to the development of protective immunity, and control of Salmonella infection involves prominent expression of interferon- ⁇ by both CD4 and CD8 cells [24,25,26].
  • CD4 and CD8 cells are critical to the development of protective immunity, and control of Salmonella infection involves prominent expression of interferon- ⁇ by both CD4 and CD8 cells [24,25,26].
  • CD4 and CD8 cells include epitopes in FliC and SipC for CD4 cells, and OmpC and GroEL for CD8 cells [24,40,45,46,47,48].
  • Salmonella proteins are also able to induce partially protective immunity when included in subunit-based vaccines in mice, including flagellin, MIG-14 and SseB (Salmonella proteins expressed in vivo), suggesting that immune responses against a number of Salmonella proteins could contribute to protective immunity [49,50,51].
  • Typhi develop a serum antibody response to PagC and that this response increases at convalescence [28].
  • detection of a parallel cellular response against PagC during human infection including both interferon- ⁇ and proliferative responses, and show that responses in convalesence were higher than during acute stage illness although both were significantly increased compared to a control.
  • the role of PagC during human infection is not fully understood, its expression is known to be controlled by the PhoP- regulon involved in intra-macrophage survival [19,54].
  • coli YadK contains a Pfam motif thought to be involved in cellular adhesion.
  • PagC is expressed in vivo under the control of the virulence- associated PhoP-regulon required for intra-macrophage survival of Salmonella.
  • STY2195 is a conserved hypothetical protein of unknown function.
  • DNase mix (10 mg/ml DNase; Sigma Aldrich in 900 mM MgCl 2 , 100 mM MnCl 2 ) to the lysate and agitated the preparation at 900 rpm for 10 min.
  • lysis buffer II 100 mM NaH 2 P0 4 , 10 mM Tris, 6 M guanidine hydrochloride, 10 mM, 2-mercaptoethanol, pH 8.0
  • Typhi bacteremia were continued on amoxicillin if they showed signs of improvement and their blood isolates showed sensitivity to first line treatment; or were switched to parenteral ceftriaxone or oral ciprofloxacin, if their isolates were not sensitive and/or they failed to improve by 72 hours; therapy was continued for up to 14 days, or up to 7 days beyond defervescence, whichever occurred first. All patients recovered.
  • PBMC isolation We diluted heparinized blood in phosphate buffered saline (PBS; 10 mM, pH 7.2) and isolated peripheral blood mononuclear cell (PBMC) by gradient centrifugation on Ficoll-Isopaque (Pharmacia, Uppsala, Sweden). We re-suspended isolated PBMCs to a concentration of lxl06cells/ml in RPMI complete medium RPMI-1640 (Gibco, Gaithersburg, Md) with 10% heat-inactivated fetal bovine serum (Hyclone-Thermo
  • S. Typhi membrane preparation Mass spectrometric analysis of the S. Typhi membrane preparation.
  • Our mass spectrometric analysis of S. Typhi membrane preparation identified 934 S. Typhi proteins (636 with three or more spectral counts), including many involved in energy metabolism, protein synthesis and fate, cell envelope or peptidoglycan synthesis or maintenance, cellular processes, proteins involved in transport, proteins involved in regulatory functions, and proteins involved in virulence and pathogenesis (Table 2 and 3 and Supplemental Table 1).
  • IFN- ⁇ ELISPOT responses and T cell characterization We found that patients with S. Typhi bacteremia had elevated interferon- ⁇ ELISPOT responses at both acute and convalescent stages of infection compared to healthy controls for all seven of the purified S. Typhi proteins, as well as against S. Typhi crude membrane preparation (P ⁇ 0.05) ( Figure 1). In contrast, responses to PHA did not differ significantly between patients and healthy controls, and minimal responses were detected against control protein and KLH in both patients and healthy controls.
  • Table 2 sets forth the S. Typhi protein sequences useful in the methods of the present invention.

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Abstract

La présente invention porte sur des procédés qui permettent de diagnostiquer la fièvre typhoïde et la fièvre typhoïde aiguë, chez un patient, à l'aide d'antigènes ou de protéines Typhi du type sérologique de la Salmonella enterica. L'induction d'une réponse des lymphocytes T lors d'un contact avec un ou plusieurs des antigènes ou des protéines isolés indique que le patient souffre de la fièvre typhoïde.
PCT/US2012/032874 2011-04-11 2012-04-10 Essais, compositions, systèmes, nécessaires et dispositifs pour diagnostiquer la fièvre typhoïde Ceased WO2012142022A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2018130855A1 (fr) * 2017-01-16 2018-07-19 Oxford University Innovation Limited Biomarqueurs typhoïdes
WO2022067076A1 (fr) * 2020-09-25 2022-03-31 Epivax, Inc. Épitopes de lymphocytes t régulateurs retro-inverso

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Cited By (2)

* Cited by examiner, † Cited by third party
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WO2018130855A1 (fr) * 2017-01-16 2018-07-19 Oxford University Innovation Limited Biomarqueurs typhoïdes
WO2022067076A1 (fr) * 2020-09-25 2022-03-31 Epivax, Inc. Épitopes de lymphocytes t régulateurs retro-inverso

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