METHOD FOR DIAGNOSING AND STAGING HERPESVIRUS-MEDIATED NEURODEGENERATION

Abstract

The invention describes a method to identify and stage human herpesvirus-mediated neurodegenerations by measuring secreted herpesvirus protein and RNA levels in a blood sample and comparing that level to an individual's baseline or reference level. Combining herpesvirus secretome levels with other neurodegeneration biomarkers, such as coagulation factors and cell adhesion molecules, can aid in diagnosis and staging of neuropathology. Sensitive and economical ELISA diagnostic kits can detect and quantify the herpesvirus secretome and neurodegeneration biomarkers to diagnose herpesvirus-mediated neurodegeneration, stage disease, and predict disease progression. Finally, this method will elucidate herpesvirus-mediated neurodegenerations and aid in developing therapeutics.

Claims

1. A method of diagnosing risk of herpesvirus-mediated Alzheimer's disease in a human subject comprising, (a) isolating exosomes from a serum sample obtained from a subject by contacting exosomes with an isolation reagent, and incubating serum to precipitate the exosomes, and then centrifuging to pellet the exosomes; (b) releasing the proteins from the exosomes by organic extraction and immobilization on a glass fiber filter, (c) detecting herpesvirus-encoded proteins by contacting the exosome proteins with a plurality of detection reagents

2. wherein the plurality of detection reagents comprises at least 50 detection reagents; (d) measuring the amount of the herpesvirus-encoded protein detected in the blood sample by each detection reagent; (e) comparing the amount of herpesvirus-encoded protein detected in the exosome sample by each detection reagent to a predetermined background control amount; wherein the detection over a background control value confers a diagnosis for risk of herpesvirus-mediated Alzheimer's disease.(Currently amended) A method according to claim 1, wherein the human cytomegalovirus encoded protein detected is selected from the group consisting of pp52 (SEQ ID NO 1), IE1 (SEQ ID NO 2), IE2 (SEQ ID NO 3), pp150 (SEQ ID NO 4), UL21.5 (SEQ ID NO 5), UL7 (SEQ ID NO 6), UL128 (SEQ ID NO 7), vCXCL-1 (SEQ ID NO 8), vCXCL-2 (SEQ ID NO 9), early nuclear protein HWLF1 (SEQ ID NO 12), US34 (SEQ ID NO 13), or UL13 (SEQ ID NO 14).

3. A method according to claim 1, wherein the secreted human herpesvirus 6A encoded protein detected is selected from the group consisting of pp100 (SEQ ID NO 15), IE 1 (SEQ ID NO 18), IE2 (SEQ ID NO 19), PPS (SEQ ID NO 20), glycoprotein B (SEQ ID NO 21), or DR1/DR2 (SEQ ID NO 22).

4. A method according to claim 1, wherein the secreted human herpesvirus 7 encoded protein detected is selected from the group consisting of pp100 (SEQ ID NO 16), IE1 (SEQ ID NO 25), IE2 (SEQ ID NO 26), PPS (SEQ ID NO 27), glycoprotein B (SEQ ID NO 28), or DR1/DR2 (SEQ ID NO 29).

5. A method according to claim 1, wherein the secreted Epstein-Barr virus encoded protein detected is selected from the group consisting of, BHRF1-1 (SEQ ID NO 33), BHRF1-2 (SEQ ID NO 34), BHRF1-3 (SEQ ID NO 35), LMP1 (SEQ ID NO 51), LMP2A (SEQ ID NO 52), or ebvIL-10 (SEQ ID NO 53).

6. A method according to claim 1, wherein the secreted human simplex virus type 1 encoded protein detected is selected from the group consisting of VP22 (SEQ ID NO 54), glycoprotein B (SEQ ID NO 55), glycoprotein C (SEQ ID NO 56), or UL56 (SEQ ID NO 57).

7. A method according to claim 1, wherein the secreted varicella-zoster virus encoded protein detected is selected from the group consisting of glycoprotein B (SEQ ID NO 61), glycoprotein E (SEQ ID NO 62), glycoprotein I (SEQ ID NO 63), glycoprotein C (SEQ ID NO 64), glycoprotein H (SEQ ID NO 65), or glycoprotein L (SEQ ID NO 66).

8. A method according to claim 1, wherein the secreted Kaposi's sarcoma virus encoded protein detected is selected from the group consisting of vIL-6 (SEQ ID NO 67), ORF 8.1 (SEQ ID NO 68), ORF 4 (SEQ ID NO 69).

9. (canceled)

10. A method according to claim 1, wherein secreted herpesvirus-encoded proteins from the nine human herpesvirus types are screened in a human subject to identify the total number of herpesvirus types infecting a subject, wherein detection of proteins over a background control indicates the presence of infection, and wherein infection with multiple herpesvirus types prescribes monitoring a subject's herpesvirus-encoded protein levels.

11. (canceled)

12. A diagnostic kit for diagnosing the risk of human herpesvirus-mediated Alzheimer's disease by measuring human herpesvirus encoded proteins secreted from cells in a blood sample obtained from a human subject, the kit comprising: (a) an antibody or aptamer which specifically binds to a secreted human herpesvirus-encoded protein, (b) a solid matrix or microplate well to which a capture antibody or aptamer is bound, (c) a secondary antibody or aptamer permitting the selective formation of a complex between a human herpesvirus protein and two antibodies or aptamers, or one antibody and one aptamer, (d) recombinant herpesvirus protein standard(e) reagents for detection.

13. (canceled)

14. A kit according to claim 12, wherein an antibody or aptamer binds to a secreted human cytomegalovirus-encoded protein, the protein selected from the group consisting of pp52 (SEQ ID NO 1), IE1 (SEQ ID NO 2), IE2 (SEQ ID NO 3), pp150 (SEQ ID NO 4), pUL21.5 (SEQ ID NO 5), UL7 (SEQ ID NO 6), UL128 (SEQ ID NO 7), vCXCL-1 (SEQ ID NO 8), vCXCL-2 (SEQ ID NO 9), vIL-10 (SEQ ID NO 10), and protein LAvIL-10 (SEQ ID NO 11), early nuclear protein HWLF1 (SEQ ID NO 12), US34 (SEQ ID NO 13), or UL13 (SEQ ID NO 14)

15. A kit according to claim 12, wherein the antibody or aptamer binds to a secreted human herpesvirus 6A-encodedprotein, the proteins are selected from the group consisting of pp100 (SEQ ID NO 15), IE1 (SEQ ID NO 18), IE2 (SEQ ID NO 19), PPS (SEQ ID NO 20), glycoprotein B (SEQ ID NO 21) or DR1/DR2 (SEQ ID NO 22).

16. A kit according to claim 12, wherein the antibody or aptamer binds to a secreted human herpesvirus 7-encodedprotein, the protein selected from the group consisting of pp100 (SEQ ID NO 16), IE1 (SEQ ID NO 25), IE2 (SEQ ID NO 26), PPS (SEQ ID NO 27), glycoprotein B (SEQ ID NO 28) or DR1/DR2 (SEQ ID NO 29).

17. A kit according to claim 12, wherein the antibody or aptamer binds to a secreted Epstein-Barr virus protein, the protein selected from the group consisting of, LMP1 (SEQ ID NO 51), LMP2A (SEQ ID NO 52), or protein ebvIL-10 (SEQ ID NO 53).

18. A kit according to claim 12, wherein the antibody or aptamer binds to a secreted human simplex virus type 1protein, the protein selected from the group consisting of VP22 protein (SEQ ID NO 54), glycoprotein B (SEQ ID NO 55), glycoprotein C (SEQ ID NO 56), or UL56 (SEQ ID NO 57).

19. A kit according to claim 12, wherein the antibody or aptamer binds to a secreted varicella-zoster virusprotein, the protein selected from the group consisting of glycoprotein B (SEQ ID NO 61), glycoprotein E (SEQ ID NO 62), glycoprotein I (SEQ ID NO 63), glycoprotein C (SEQ ID NO 64), glycoprotein H (SEQ ID NO 65), or glycoprotein L (SEQ ID NO 66).

20. (canceled)

21. A method according to claim 1, wherein the human simplex virus type 2 encoded protein detected selected from the group consisting of glycoprotein B (SEQ ID NO 58), N-terminal glycoprotein G (SEQ ID NO 59), or the peptide gG-2p20 (SEQ ID NO 60).

22. A method of detecting diagnosing risk of herpesvirus-mediated Alzheimer's disease neurodegeneration in a human subject comprising, (a) isolating exosomes from a serum sample obtained from a subject by contacting exosomes with an isolation reagent, and incubating serum to precipitate the exosomes, and then centrifuging to pellet the exosomes; (b) releasing the proteins from the exosomes by organic extraction and immobilization on a glass fiber filter, (c) detecting herpesvirus-encoded proteins by cleaning with trypsin digestion and isoelectric fractionation and processing by liquid chromatography and mass spectrometry and analyzing the data (e) comparing the amount of herpesvirus-encoded protein detected in the exosome sample by each detection reagent to a predetermined background control amount; wherein the detection over a background control value confers a diagnosis for risk of herpesvirus-mediated Alzheimer's disease.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0068] FIG. 1 shows the wide range of HCMV vIL-10 protein levels among individuals. Shown with permission from the author and copyright owner Vivian Young (Vivian P. Young, Master's Thesis: Detection of HCMV viral IL-10 (vIL-10) in healthy blood donors, The University of San Francisco, published May 17, 2015).

[0069] FIG. 2 depicts the annual levels of HCMV, VZV, and EBV secreted proteins in blood samples from a hypothetical individual along with annual Mini-Mental State Exam scores.

[0070] FIG. 3 depicts the annual herpesvirus levels of a hypothetical individual along with AD biomarkers, γ-fibrinogen, and noradrenaline, wherein the biomarkers levels aid in disease staging and progression.

[0071] FIG. 4 depicts the annual herpesvirus levels of a hypothetical individual along with AD biomarkers, γ-fibrinogen, and noradrenaline, wherein the individual is positive for HCMV and VZV, but shows no disease progression, stage 0.

SEQUENCE DISCLOSURE

[0072] The sequences are disclosed in a 339 kB text file named, “10005B—US—NP_Sequences-as-filed”, created on 2021/01/10.

Definitions

[0073] As used herein, the term “AD patient”, and refer to an individual who has been diagnosed with Alzheimer's Disease or has been given a probable diagnosis of Alzheimer's Disease.

[0074] As used herein, the phrase “AD biomarker” refers to a biomarker that is associated with an AD diagnosis.

[0075] The term “aptamer”, as used herein, refers to an oligonucleotide or peptide molecule that binds to a specific target molecule.

[0076] The term norepinephrine and noradrenaline refer to the same chemical.

[0077] The term RNA herein refers to non-coding RNA and includes long non-coding RNA and miRNA.

[0078] The term “secreted factor” or “secreted protein” includes herpesvirus RNA or proteins secreted in capsid types A and B, dense bodies, RNA and proteins secreted in a complex with other proteins, and RNA and proteins secreted in exosomes.

[0079] As used herein, methods for “aiding diagnosis” refer to methods that assist in making a clinical determination regarding a contributing cause of AD or mild cognitive impairment. Accordingly, for example, a method of aiding diagnosis of AD can comprise measuring the amount of one or more AD biomarkers in a blood sample from an individual.

[0080] As used herein, the term “staging” refers to sorting individuals into different classes or strata based on the level of herpesvirus secreted proteins and neurodegeneration-related biomarkers. Staging individuals based on blood biomarkers can correlate with cognitive impairment and aids in disease staging (e.g., mild, moderate, advanced, etc.).

[0081] As used herein, the term “predicting” means determining the probability that an individual will develop symptoms of neurodegeneration.

[0082] As used herein, the phrase “neurodegeneration” refers to a disease or disorder of the central nervous system. Neurodegeneration includes multiple sclerosis, neuropathies, AD, Parkinson's disease, amyotrophic lateral sclerosis (ALS), mild cognitive impairment (MCI), retinitis, herpes zoster ophthalmicus, and frontotemporal dementia.

[0083] As used herein, the phrase “neuropathology” refers to the presence of physical or physiological abnormality.

[0084] A “blood sample” is a biological sample that is derived from peripheral blood. A blood sample may be, for example, whole blood, plasma, or serum. The definition also includes samples that have been manipulated in any way after their procurement, such as by treatment with reagents, solubilization, or enrichment for certain components, such as proteins or polynucleotides.

[0085] An “individual” is a mammal, more preferably a human. Mammals include, but are not limited to, humans, primates, farm animals, sport animals, rodents, and pets.

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