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(12) Patent Application Publication (10) Pub. No.: US 2011/0196614 A1 Banchereau Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/0196614 A1 Banchereau Et Al US 2011 0196614A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0196614 A1 Banchereau et al. (43) Pub. Date: Aug. 11, 2011 (54) BLOODTRANSCRIPTIONAL SIGNATURE OF Related U.S. Application Data MYCOBACTERIUMITUBERCULOSS INFECTION (60) Provisional application No. 61/075,728, filed on Jun. 25, 2008. (75) Inventors: Jacques F. Banchereau, Dallas, TX Publication Classification (US); Damien Chaussabel, Bainbridge Island, WA (US); Anne (51) Int. Cl. O'Garra, London (GB); Matthew G06F 9/00 (2011.01) Berry, London (GB); Onn Min GOIN 33/48 (2006.01) Kon, London (GB) (52) U.S. Cl. .......................................................... 702/19 (57) ABSTRACT (73) Assignees: BAYLOR RESEARCH INSTITUTE, Dallas, TX (US); The present invention includes methods, systems and kits for NATIONAL INSTITUTE FOR distinguishing between active and latent mycobacterium MEDICAL RESEARCH, London tuberculosis infection in a patient Suspected of being infected (GB); IMPERIAL COLLEGE with mycobacterium tuberculosis, and distinguishing Such HEALTHCARE NHS TRUST, patients from uninfected individuals, the method including London (GB) the steps of obtaining a gene expression dataset from a whole blood obtained sample from the patient and determining the (21) Appl. No.: 12/602,488 differential expression of one or more transcriptional gene expression modules that distinguish between infected and (22) PCT Fled: Jun. 25, 2009 non-infected patients, wherein the dataset demonstrates an aggregate change in the levels of polynucleotides in the one or (86) PCT NO.: PCT/USO9A48698 more transcriptional gene expression modules as compared to matched non-infected patients, thereby distinguishing S371 (c)(1), between active and latent mycobacterium tuberculosis infec (2), (4) Date: Apr. 25, 2011 tion. Patent Application Publication Aug. 11, 2011 Sheet 2 of 19 US 2011/O196614 A1 igure 2 Active PTB Latent TB Healthy Controls Patent Application Publication Aug. 11, 2011 Sheet 3 of 19 US 2011/O196614 A1 Active PTB Figure 3A 8. Latent TB Healthy BCG non-vaccinated i Patent Application Publication Aug. 11, 2011 Sheet 4 of 19 US 2011/O196614 A1 Active PTB Figure 3B is Latent TB 88. Healthy BCG non-vaccinated Healthy BCG vaccinated Re&bsis Patent Application Publication Aug. 11, 2011 Sheet 5 of 19 US 2011/O196614 A1 Figure 3C E. g. its east Pala 2 DAL felloteh sculius III:4:53. FR33 cs: IF-38s Active PTB iii. Latent TB . s: Healthy BCG ics Cefa-Intersson L-3UDALF-001BH sci-m-ins non-vaccinate Healthy BCG vaccinated Patent Application Publication Aug. 11, 2011 Sheet 6 of 19 US 2011/O196614 A1 Active PTB Figure 3D Latent TB S Healthy BCG non-vaccinated Healthy BCG I vaccinated (3.3 TF10 8 &ST:LE TIFRSFSR, i: colored by P38 8&": is: Ps: 282 Patent Application Publication Aug. 11, 2011 Sheet 8 of 19 US 2011/O196614 A1 Active PTB Figure 5A Latent TB 8 Healthy Controls CD273/PDL2 & & Active PTB Patent Application Publication Aug. 11, 2011 Sheet 9 of 19 US 2011/O196614 A1 Figure 5B Control Control BCG BCG Patent Application Publication Aug. 11, 2011 Sheet 12 of 19 US 2011/O196614 A1 Figure 8A : P&S 3 8 Normalised Expression 8. Healthy Controls Latent TB Selected & Trek: P22431838 T-Rat P&L 2.2xl.a.LStatsberged Colored by: F23. 38'ay8TB-Referen: Default interpretation Selected Condition Tres: P22428 May8TERef P&L 22x DAL Statsberged 3 sns List: Merged ListStats.LTE and FTB (118 Branch color parameter: Study group2 Patent Application Publication Aug. 11, 2011 Sheet 18 of 19 US 2011/O196614 A1 Modules must have >25% of the total genes change in the direction represented and the number of genes changing in that UNDER-XP. direction must be > 10. is 38 8 is 3: Functionai interpretation % pixie sets x.S. issi: ::is Erysidey8s ississis isis SS 8-celis interists &isis; iii.3883& S iia:gto: isitos(xis:’atiss irreissertities {yiotixi &isis Patent Application Publication Aug. 11, 2011 Sheet 19 of 19 US 2011/O196614 A1 Figure 10 Modules must have >25% of the total genes change in the direction represented and the number of genes changing in that direction must be >10. S3 c Functional interpretation Pisia (sis Erissyfes seis Š: i: sists 8&isis iis&g: S. iii.338gsix isix-sopsis proteis facieges risis: {yin: xis: sis is sis: is irogiris US 2011/0196614 A1 Aug. 11, 2011 BLOODTRANSCRIPTIONAL SIGNATURE OF demonstrating immunoreactivity to specific M. tuberculosis MYCOBACTERIUMITUBERCULOSS antigens, which are absent in BCG. Reactivity to these M. INFECTION tuberculosis antigens, as measured by production of IFN-Y by blood cells in Interferon Gamma Release Assays (IGRA), TECHNICAL FIELD OF THE INVENTION however, does not differentiate latent from active disease. Latent TB is defined in the clinic by a delayed type hypersen 0001. The present invention relates in general to the field sitivity reaction when the patient is intradermally challenged of Mycobacterium tuberculosis infection, and more particu with PPD, together with an IGRA positive result, in the larly, to a system, method and apparatus for the diagnosis, absence of clinical symptoms or signs, or radiology Sugges prognosis and monitoring of latent and active Mycobacterium tive of active disease. The reactivation of latent/dormant tuberculosis infection and disease progression before, during tuberculosis (TB) presents a major health hazard with the risk and after treatment. of transmission to other individuals, and thus biomarkers reflecting differences in latent and active TB patients would LENGTHY TABLE be of use in disease management, particularly since anti 0002 The patent application contains a lengthy table sec mycobacterial drug treatment is arduous and can result in tion. A copy of the table is available in electronic form from serious side-effects. the USPTO web site (http://seqdata.uspto.gov/). An elec tronic copy of the table will also be available from the USPTO SUMMARY OF THE INVENTION upon request and payment of the fee set forth in 37 CFR 0006. The present invention includes methods and kits for 1.19(b)(3). the identification of latent versus active tuberculosis (TB) patients, as compared to healthy controls. In one embodi BACKGROUND OF THE INVENTION ment, microarray analysis of blood of a distinct and reciprocal 0003. Without limiting the scope of the invention, its back immune signature is used to determine, diagnose, track and ground is described in connection with the identification and treat latent versus active tuberculosis (TB) patients. treatment of Mycobacterium tuberculosis infection. 0007. In one embodiment, the present invention includes 0004 Pulmonary tuberculosis (PTB) is a major and methods, systems and kits for distinguishing between active increasing cause of morbidity and mortality worldwide and latent Mycobacterium tuberculosis infection in a patient caused by Mycobacterium tuberculosis (M. tuberculosis). suspected of being infected with Mycobacterium tuberculo However, the majority of individuals infected with M. tuber sis, the method including the steps of obtaining a gene culosis remain asymptomatic, retaining the infection in a expression dataset from a whole blood sample from the latent form and it is thought that this latent state is maintained patient; determining the differential expression of one or by an active immune response (WHO; Kaufmann, SH & more transcriptional gene expression modules that distin McMichael, A. J., Nat Med, 2005). This is supported by guish between infected patients and non-infected individuals, reports showing that treatment of patients with Crohn's Dis wherein the dataset demonstrates an aggregate change in the ease or Rheumatoid Arthritis with anti-TNF antibodies, levels of polynucleotides in the one or more transcriptional results in improvement of autoimmune symptoms, but on the gene expression modules as compared to matched non-in other hand causes reactivation of TB in patients previously in fected individuals, and distinguishing between active and contact with M. tuberculosis (Keane). The immune response latent Mycobacterium tuberculosis (TB) infection based on to M. tuberculosis is multifactorial and includes genetically the one or more transcriptional gene expression modules that determined host factors, such as TNF, and IFN-Y and IL-12, of differentiate between active and latent infection. In one the Th1 axis (Reviewed in Casanova, Ann Rev. Newport). aspect, the invention may also include the step of using the However, immune cells from adult pulmonary TB patients determined comparative gene product information to formu can produce IFN-y, IL-12 and TNF, and IFN-y therapy does late a diagnosis. not help to ameliorate disease (Reviewed in Reljic, 2007, J 0008. In another aspect, the method may also include the Interferon & Cyt Res., 27, 353-63), suggesting that a broader step of using the determined comparative gene product infor number of host immune factors are involved in protection mation to formulate a prognosis or the step of using the against M. tuberculosis and the maintenance of latency. Thus, determined comparative gene product information to formu a knowledge of host factors induced in latent versus active TB late a treatment plan. In one alternative aspect, the method may provide information with respect to the immune may include the step of distinguishing patients with latent TB response which can control infection with M. tuberculosis. from active TB patients. In one aspect, the module may 0005. The diagnosis of PTB can be difficult and problem include a dataset of the genes in modules M1.2, M1.3, M1.4. atic for a number of reasons. Firstly demonstrating the pres M1.5, M1.8, M2.1, M2.4, M2.8, M3.1, M3.2, M3.3, M3.4, ence of typical M. tuberculosis bacilli in the sputum by M3.6, M3.7, M3.8 or M3.9 to detect active pulmonary infec microscopy examination (Smear positive) has a sensitivity of tion. In another aspect, the module may include a dataset of only 50-70%, and positive diagnosis requires isolation of M. the genes in modules M1.5, M2.1, M2.6, M2.10, M3.2 or tuberculosis by culture, which can take up to 8 weeks.
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