Diagnostic and therapeutic applications for biomarkers of infection
First Claim
Patent Images
1. A method of identifying infection by a pathogen comprising the steps of:
- a) isolating mRNA from a whole blood sample; and
b) determining gene expression of at least one stimulus-specific gene, wherein expression of a stimulus-specific gene is indicative of infection by a pathogen to which the stimulus-specific gene is specific.
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Abstract
Distinct gene expression programs activated in response to different pathogens in macrophages are disclosed. Methods of diagnosis and treatment are also disclosed.
61 Citations
71 Claims
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1. A method of identifying infection by a pathogen comprising the steps of:
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a) isolating mRNA from a whole blood sample; and
b) determining gene expression of at least one stimulus-specific gene, wherein expression of a stimulus-specific gene is indicative of infection by a pathogen to which the stimulus-specific gene is specific. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10)
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11. A method of classifying a pathogen comprising the steps of:
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a) exposing macrophages with a pathogen or immunogenic components thereof;
b) isolating and labeling mRNA from said macrophages;
c) detecting labeled mRNA from said macrophages such that a gene expression profile is produced; and
d) analyzing the gene expression profile relative to one or more reference gene expression profile(s), such that similarities between the gene expression profile of the pathogen-exposed macrophage and at least one reference gene expression profile classify the pathogen as belonging to the class corresponding to the reference gene expression profile.
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12. A method of diagnosing infection in a mammal comprising the steps of:
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a) isolating mRNA from a whole blood sample obtained from the mammal; and
b) contacting the mRNA with at least one stimulus-responsive gene probe wherein hybridization of a stimulus-responsive probe to the mRNA is indicative of infection in said mammal. - View Dependent Claims (13, 14, 15)
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16. A method of diagnosing infection by a pathogen in a mammal comprising the steps of:
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a) isolating mRNA from a whole blood sample obtained from the mammal; and
b) determining gene expression of at least one stimulus-specific gene, wherein expression of the stimulus-specific gene is indicative of infection by a pathogen to which the stimulus-specific gene is specific. - View Dependent Claims (17, 18, 19, 20, 21)
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22. A method of formulating a therapeutic regimen for treating a pathogenic infection comprising the steps of:
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a) identifying a pathogen that causes the infection from a diagnostic assay performed on a whole blood sample; and
b) formulating the therapeutic regimen according to the pathogen identified. - View Dependent Claims (23)
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24. A method of optimizing a vaccine comprising the steps of:
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a) contacting one or more macrophages with at least one test vaccine;
b) isolating mRNA from said macrophages;
c) determining gene expression profiles in said macrophages; and
e) comparing the macrophage gene expression profile to a reference gene expression profile, wherein a similarity to a pathogen-specific or pathogen-responsive gene expression profile is indicative of an optimized vaccine.
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25. An ex vivo therapeutic treatment for a disorder selected from the group consisting of pathogenic infection, sepsis and autoimmunity comprising the steps of:
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a) contacting a patient'"'"'s macrophages with a pathogen or components thereof, such that the macrophages would normally signal an immune response, thereby producing activated macrophages;
b) returning the activated macrophages to the patient such that the activated macrophages trigger an immune response against the pathogen.
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26. A method of measuring the immune response to a stimulus comprising the steps of:
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a) contacting a whole blood sample with a stimulus;
b) isolating mRNA from the sample; and
c) determining a gene expression profile such that the expression of at least one stimulus-responsive gene measured, thereby indicating the level of the immune response.
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27. A method of measuring the immune response to a stimulus comprising the steps of:
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a) contacting macrophages with a stimulus;
b) isolating and labeling mRNA from the macrophages;
c) contacting a DNA microarray with labeled mRNA from the macrophages; and
d) measuring and analyzing the gene expression profile relative to control stimulus such that at least one stimulus-responsive gene is identified which is indicative of an immune response. - View Dependent Claims (28, 29, 30, 31, 32, 33, 34)
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35. A method of measuring the gene expression profile in macrophages in response to a stimulus comprising the steps of:
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a) contacting immature macrophages with a stimulus;
b) isolating and labeling mRNA from the macrophages;
c) contacting a DNA microarray with labeled mRNA from the macrophages; and
d) measuring and analyzing the gene expression profile relative to control stimulus such that at least one stimulus-responsive gene is identified. - View Dependent Claims (36, 37, 38, 39, 40, 41, 42)
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43. A method for generating a database of stimulus-responsive genes comprising the steps of:
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a) contacting macrophages with a stimulus;
b) isolating and labeling mRNA from the macrophages;
c) contacting a DNA microarray with labeled mRNA from the macrophages; and
d) measuring and analyzing the gene expression profile relative to a control stimulus such that a database comprising at least one stimulus-responsive gene is generated.
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44. A method of generating a database of stimulus-specific genes comprising the steps of:
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a) contacting immature macrophages with a stimulus;
b) isolating and labeling mRNA from the macrophages;
c) contacting a DNA microarray with labeled mRNA from the macrophages; and
d) measuring and analyzing the gene expression profile relative to control stimulus such that a database of stimulus-specific genes comprising at least one stimulus-specific gene is generated.
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45. A method of generating a database of common stimulus-responsive genes comprising the steps of:
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a) contacting macrophages with a stimulus;
b) isolating and labeling mRNA from the macrophages;
c) contacting a DNA microarray with labeled mRNA from the macrophages; and
d) measuring and analyzing the gene expression profile relative to control stimulus such that a database of common stimulus-responsive genes comprising at least one common stimulus-responsive gene is generated
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- 46. A database of stimulus-responsive genes.
- 48. A database of stimulus-specific genes.
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54. A database of common stimulus-responsive genes.
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55. The database of claim 55 comprising one or more genes selected from the group consisting of:
- GCSF, GMCSF, IL12B, IL1RN, IL6, IL6, PBEP, ProIL1B, TNFA, IL8, IL8, IP10, MCP1, MGSA, MIP1A, MIPIB, MIP2A, MIP2B, RANTES, CD44, CD44, ICAM1, IFITM1, LAMB3, NINJ1, TNFA1P6, ADORA2A, CCR6, CCR7, CCRL2, DTR, EBI3, HM74, ILI5RA, IL7R, LDLR, P2RX7, P2XR, PLAUR, PVR, SLAM, TNFRSF5, TXN, CNK, DUSP1, DUSP2, DUSP5, EBI2, GBP1, HCK, INHBA, JAG1, KYNU, LIMK2, MAP2K3, MAP3K4, MINOR, NAF1, NFKB1, PDE4B, PPP3CC, PTPN1, TRAF1, TRIP10, DSCR1, ELF4, ETS2, IRF1, IRLB, JUNB, MRF-1, NFKBIA, NFKBIE, NFKBp50, STAT4, STAT5A, TSC22, XBP1, ZFP36, COX2, COX2, COX2, GCH1, PTX3, BIRC2, BIRC3, BIRC3, CFLAR, IER3, TNFAIP3, BTG1, BTG3, TNFRSF9, TNFSF9, DAP, MMP1, MMP10, MMP14, SERPINB2, SERPINB8, GADD45A, HSPA1A, SOD2, SOD2, ATP2B1, NRAMP2, SLC7A5, ADA, AMPD3, beta-1,4-galatosyl transferase, BF, CKB, GJB2, GLCLR, HSD11B1, INDO, MTF1, ADM, ARHH, B4-2, BRCA2, CD83, GEM, GOS, GYPC, H2AFO, HIVEP2, ISG15, ISG20, MACMARKS, MIG2, MXJ, RCN1, SDC4, SNL, TNFAIP2, TSSC3, K1AA0105, KIAA0172, GCHFR, CAT, LTA4H, CD14, ALOX5, MCP1, PECAM1, SPARC, RARA, TNFRSF1A, ENG, L77730, CD36L1, CD163, TGFBR2, GSF1R, MRC1, CD32, P2RX1, SRPK2, SLA, MERTK, DAB2, SF3A3, EGR2, NFATC3, MX11, FOS, Hbrm, SLC29A1, UPA, FGL2, TBXAS1, SGSH, PPP2R5C, IDH2, LPL, MPI, PYGL, HSD17B4, RNASE6, GALC, GLCLC, RNASE1, ME1, PURA, MYO1E, VCL, IV12B, ADFP, MNDA, STAB1, TGFBI, KIAA0022, AD000092, D87075, U79288, P311, HG2090-HT2090, HG2090-HT2090 and HG2090-HT2090.
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56. A method of identifying a pathogen comprising the steps of:
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a) contacting one or more immature macrophages with a stimulus;
b) isolating and labeling mRNA from said macrophages;
c) contacting a DNA microarray with labeled mRNA from said macrophages; and
d) measuring and analyzing the gene expression profile relative to control stimulus such that at least one stimulus-specific gene is identified thereby identifying a pathogen for which the stimulus-specific gene is specific. - View Dependent Claims (57, 58, 59, 60, 61)
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62. A method of diagnosing infection by a pathogen comprising the steps of:
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a) isolating mRNA from a whole blood sample; and
b) determining a gene expression profile such that at least one stimulus-specific gene is identified, thereby identifying the pathogen.
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63. A method of diagnosing infection by a pathogen comprising the steps of:
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a) isolating and labeling mRNA from at least one whole blood sample from a mammal;
b) contacting a DNA microarray with labeled mRNA from the sample; and
c) measuring and analyzing the gene expression profile relative to control stimulus such that at least one stimulus-specific gene is identified thereby identifying the pathogen for which the stimulus-specific gene is specific.
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64. A method of diagnosing infection in a mammal comprising the steps of:
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a) isolating proteins from one or more samples from the mammal;
b) contacting the proteins with at least one stimulus-specific antibody, wherein binding of the stimulus-specific antibody to one or more proteins is indicative of infection in the mammal.
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- 65. A gene expression profile comprising Gram-negative-specific genes.
- 67. A gene expression profile comprising Gram-positive-specific genes.
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69. A method for screening for an agent that induces a pathogen-specific immune response comprising the steps of:
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a) contacting at least one macrophage with a test agent;
b) isolating mRNA from the macrophage(s);
c) determining a gene expression profile from the isolate mRNA; and
d) comparing the gene expression profile obtained from the macrophages contacted by the test agent with a reference gene expression profile of an activated macrophage, wherein a similarity in gene expression profiles indicates the test agent induces a pathogen-specific immune response.
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70. A method of identifying a genus-specific response comprising the steps of:
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a) isolating mRNA from a whole blood sample obtained from a mammal;
b) contacting a DNA microarray with labeled mRNA from said macrophages; and
c) comparing the gene expression profile to a reference genus-specific-induced gene expression profile, wherein a similarity indicates a genus-specific response. - View Dependent Claims (71)
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Specification