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W O 2019/079360 a L 25 April 2019 (25.04.2019) W 1P O PCT

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W O 2019/079360 a L 25 April 2019 (25.04.2019) W 1P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date W O 2019/079360 A l 25 April 2019 (25.04.2019) W 1P O PCT (51) International Patent Classification: (72) Inventors; and G01N 33/48 (2006.01) G01N 33/53 (2006.01) (71) Applicants: KEAN, Leslie [US/US]; c/o 818 Stewart St, Suite 603, Seattle, Washington 98101 (US). COLONNA, (21) International Application Number: Lucrezia [US/US]; c/o 818 Stewart St, Suite 603, Seattle, PCT/US2018/056166 Washington 98101 (US). CARROLL, Shaina [US/US]; (22) International Filing Date: c/o 77 Massachusetts Avenue, Cambridge, Massachusetts 16 October 2018 (16. 10.2018) 02139 (US). (25) Filing Language: English (72) Inventors: SHALEK, Alexander K.; c/o 77 Massachu¬ setts Avenue, Cambridge, Massachusetts 02139 (US). ZIE- (26) Publication Language: English GLER, Carly; c/o 77 Massachusetts Avenue, Cambridge, (30) Priority Data: Massachusetts 02139 (US). 62/573,015 16 October 2017 (16. 10.2017) US (74) Agent: SCHER, Michael B. et al.; Johnson, Marcou & (71) Applicants: MASSACHUSETTS INSTITUTE OF Isaacs, LLC, P.O. Bo 691, Hoschton, Georgia 30548 (US). TECHNOLOGY [US/US]; 77 Massachusetts Av¬ (81) Designated States (unless otherwise indicated, for every enue, Cambridge, Massachusetts 02139 (US). SEAT¬ kind of national protection available): AE, AG, AL, AM, TLE CHILDREN'S HOSPITAL DBA SEATTLE AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CHILDREN'S RESEARCH INSTITUTE [US/US]; 818 CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, Stewart St, Suite 603, Seattle, Washington 98101 (US). DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, (54) Title: CELL ATLAS OF HEALTHY AND DISEASED TISSUES o FIG. 11 OS (57) Abstract: Embodiments disclosed herein provide a pan-tissue cell atlas of healthy and diseased subjects obtained by single cell sequencing. The present invention discloses novel markers for cell types. Moreover, genes associated with disease, including HIV © infection and tuberculosis are identified. The invention provides for diagnostic assays based on gene markers and cell composition, as well as therapeutic targets for controlling immune regulations and cell-cell communication of the cell types disclosed herein. In o addition, novel cell types and methods of quantitating, detecting and isolating the cell types are disclosed. o [Continued on nextpage] W O 2019/079360 A l I lllll II lllll lllll lllll llll I II III lllll lllll lllll lllll lllll llll llll llll llll KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY,MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available) : ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3)) — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) — with sequence listing part of description (Rule 5.2(a)) CELL ATLAS OF HEALTHY AND DISEASED TISSUES CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 62/573,015, filed October 16, 2017. The entire contents of the above-identified application are hereby fully incorporated herein by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH [0002] This invention was made with government support under Grant No. HL095791 awarded by the National Institutes of Health. The government has certain rights in the invention. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [0003] The contents of the electronic sequence listing (BROD-2830W.ST25.txt"; Size is 8 Kilobytes and it was created on October 8, 2018) is herein incorporated by reference in its entirety. TECHNICAL FIELD [0004] The subject matter disclosed herein is generally directed to use of tissue, cellular and gene biomarkers to determine the physiological state of a cell or tissue of interest. The subject matter further relates to a cell atlas of healthy tissues and a matched cell atlas of infectious disease and biomarkers thereof cell types in healthy and disease states. The subject matter further relates to novel cell specific and disease specific markers and infectious disease in [0005] This invention relates generally to compositions and methods identifying and exploiting target genes or target gene products that modulate, control or otherwise influence cell- cell communication, differential expression, immune response in a variety of therapeutic and/or diagnostic indications. BACKGROUND [0006] Immune systems play an essential role in ensuring our health. From decades of laboratory and clinical work, there has been a basic understanding of immune balance and its importance for a healthy immune system. For example, hyperactivity can lead to allergy, inflammation, tissue damage, autoimmune disease and excessive cellular death. On the other hand, immunodeficiency can lead to outgrowth of cancers and the inability to kill or suppress external invaders. The immune system has evolved multiple modalities and redundancies that balance the system, including but not limited to memory, exhaustion, anergy, and senescence. Despite this basic understanding, a comprehensive landscape of immune regulations remains missing. Given the importance of the immune system, a systematic understanding of immune regulations on cell, tissue, and organism levels is crucial for clinicians and researchers to efficiently diagnose and develop treatments for immune system related disease. [0007] Different cells and tissues in a diseased organism are often not impacted at the same level. Analyzing immune regulations with a comprehensive approach allows for identification of cells and tissues that are impacted and that are representative of the disease, interaction between cells, as well as pathways that can be specifically targeted to restore diseased cell or tissues to a normal state. In practice, certain tissues or specimens, for example blood or body fluids, are more easily obtainable than others from a patient. A systematic understanding of immune responses allows clinicians to use easily obtainable tissues as a proxy to diagnose disease and monitor disease state through easily obtainable tissues, and may further allow for treatment or amelioration of symptoms by restoring the state of suppressed immune cells or eliminating severely infected cells, for example, cells impacted with a chronic infection such as HIV infected cells / MTB infected cells. [0008] Despite years of clinical work, essential information including location and identity of the pathogen hosting cells or tissues, immunologic response and pathways involved in the infection and response status of such disease causing infections remain unclear. A comprehensive understanding focusing on diseased as well as healthy organisms will be able to locates key cells and tissues that represent the disease, location, identity, and phenotype of the disease harboring cells, pathways and mechanisms involved in disease response and pathogen replication, thus help developing diagnosis as well as treatment methods. [0009] Reliable diagnosing of disease states and evaluation of therapies remains problematic. In human subjects, many cell type and tissues are inaccessible to non-invasive methods and further may be difficult to locate and test even where, for example, biopsy procedures are available. Such difficulties extend to non-human animals, including but not limited to non- human primates. For example, animal tissues may be available from animals that cannot be obtained from living human subjects, but such tissues may be inaccessible for other reasons, frequently expense. SUMMARY [0010] In certain example embodiments, the present invention provides novel markers for cell types and physiological states of tissues of interests. [0011] In one aspect, the present invention provides for a method of determining a physiological state of a first cell or tissue in a subject, the method comprising: measuring a physiological state of a second cell or tissue in the subject that is correlated with the physiological state of the first cell or tissue, wherein the correlation comprises a correlation between tissue types, cell types, or tissue types and cell types. [0012] In another aspect, the present invention provides for a method of determining the effect of a modulating agent on a first cell or tissue in a subject, the method comprising: measuring the effect of the modulating agent on a second cell or tissue in the subject, wherein the physiological state of the second cell or tissue is correlated with the effect of the modulating agent on the first cell or tissue, wherein the correlation comprises a correlation between tissue types, cell types, or tissue types and cell types. [0013] In certain embodiments, the composition and/or quantity of cell types in different tissues is correlated, or the same cell types in different tissues are correlated, or different cell types are correlated. In certain embodiments, the second cell or tissue is correlated with the first cell or tissue in another organism, whereby the correlation is used as a proxy to determine the physiological state of the first cell or tissue in the subject. [0014] In certain embodiments, the organism is a non-human primate.
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