title: Transcriptional reprogramming in nonhuman primate (rhesus macaque) tuberculosis granulomas.
abstract: BACKGROUND
  In response to Mtb infection, the host remodels the infection foci into a dense mass of cells known as the granuloma. The key objective of the granuloma is to contain the spread of Mtb into uninfected regions of the lung. However, it appears that Mtb has evolved mechanisms to resist killing in the granuloma. Profiling granuloma transcriptome will identify key immune signaling pathways active during TB infection. Such studies are not possible in human granulomas, due to various confounding factors. Nonhuman Primates (NHPs) infected with Mtb accurately reflect human TB in clinical and pathological contexts.
  
  
  RESULTS
  We studied transcriptomics of granuloma lesions in the lungs of NHPs exhibiting active TB, during early and late stages of infection. Early TB lesions were characterized by a highly pro-inflammatory environment, expressing high levels of immune signaling pathways involving IFNgamma, TNFalpha, JAK, STAT and C-C/C-X-C chemokines. Late TB lesions, while morphologically similar to the early ones, exhibited an overwhelming silencing of the inflammatory response. Reprogramming of the granuloma transcriptome was highly significant. The expression of approximately two-thirds of all genes induced in early lesions was later repressed.
  
  
  CONCLUSIONS
  The transcriptional characteristics of TB granulomas undergo drastic changes during the course of infection. The overwhelming reprogramming of the initial pro-inflammatory surge in late lesions may be a host strategy to limit immunopathology. We propose that these host profiles can predict changes in bacterial replication and physiology, perhaps serving as markers for latency and reactivation.
authors.affiliation: Divisions of Bacteriology and Parasitology, Tulane National Primate Research Center, Covington, Louisiana, United States of America.
authors.forename: Smriti
authors.initials: S
authors.lastname: Mehra
authors.forename: Bapi
authors.initials: B
authors.lastname: Pahar
authors.forename: Noton K
authors.initials: NK
authors.lastname: Dutta
authors.forename: Cecily N
authors.initials: CN
authors.lastname: Conerly
authors.forename: Kathrine
authors.initials: K
authors.lastname: Philippi-Falkenstein
authors.forename: Xavier
authors.initials: X
authors.lastname: Alvarez
authors.forename: Deepak
authors.initials: D
authors.lastname: Kaushal
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008171:Lung Diseases / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D008253:Macaca mulatta; D009169:Mycobacterium tuberculosis / Q000502:physiology; D013997:Time Factors; D014375:Tuberculoma / Q000235:genetics* / Q000276:immunology
references.citation: Lancet. 2006 Nov 4;368(9547):1575-80
references.pmid: 17084757
references.citation: Vaccine. 2009 Jul 23;27(34):4709-17
references.pmid: 19500524
references.citation: Mol Microbiol. 2010 Jan;75(1):92-106
references.pmid: 19906174
references.citation: PLoS One. 2008 Aug 06;3(8):e2869
references.pmid: 18682728
references.citation: Science. 2005 Aug 19;309(5738):1251-3
references.pmid: 16020694
references.citation: Infect Immun. 2003 Oct;71(10):5831-44
references.pmid: 14500505
references.citation: Tuberculosis (Edinb). 2003;83(1-3):112-5
references.pmid: 12758199
references.citation: Tuberculosis (Edinb). 2008 Aug;88 Suppl 1:S35-47
references.pmid: 18762152
references.citation: J Immunol. 2004 Sep 1;173(5):3287-96
references.pmid: 15322191
references.citation: PLoS Pathog. 2009 Apr;5(4):e1000392
references.pmid: 19381260
references.citation: PLoS One. 2008 Jan 30;3(1):e1502
references.pmid: 18231589
references.citation: Inflammation. 1991 Feb;15(1):61-70
references.pmid: 1711512
references.citation: Nat Rev Microbiol. 2007 Jan;5(1):39-47
references.pmid: 17160001
references.citation: Lancet. 2006 Mar 18;367(9514):938-40
references.pmid: 16546542
references.citation: Infect Immun. 2009 Feb;77(2):598-603
references.pmid: 19064634
references.citation: Tuberculosis (Edinb). 2003;83(1-3):131-4
references.pmid: 12758202
references.citation: J Immunol. 2006 Mar 15;176(6):3642-51
references.pmid: 16517733
references.citation: PLoS Pathog. 2009 May;5(5):e1000430
references.pmid: 19436699
references.citation: Infect Immun. 2002 Apr;70(4):1684-93
references.pmid: 11895930
references.citation: Cell Microbiol. 2010 Mar;12(3):301-9
references.pmid: 20039878
references.citation: J Exp Med. 2005 Jun 6;201(11):1693-7
references.pmid: 15939785
references.citation: Infect Immun. 2009 Oct;77(10):4631-42
references.pmid: 19620341
references.citation: Science. 2010 Jan 22;327(5964):466-9
references.pmid: 20007864
references.citation: Curr Protoc Bioinformatics. 2004 Oct;Chapter 7:Unit 7.9
references.pmid: 18428735
references.citation: J Pathol. 2007 Jul;212(3):295-305
references.pmid: 17534845
references.citation: PLoS One. 2009;4(4):e5264
references.pmid: 19367339
references.citation: Virology. 2007 Jun 20;363(1):36-47
references.pmid: 17307212
references.citation: J Immunol. 1999 Mar 15;162(6):3549-58
references.pmid: 10092813
references.citation: Infect Immun. 2008 Jun;76(6):2333-40
references.pmid: 18347040
references.citation: Tuberculosis (Edinb). 2003;83(5):299-309
references.pmid: 12972343
references.citation: J Infect Dis. 2001 Jun 15;183(12):1801-4
references.pmid: 11372034
references.citation: Arch Intern Med. 2003 May 12;163(9):1009-21
references.pmid: 12742798
references.citation: J Pathol. 2006 Nov;210(3):298-305
references.pmid: 17001607
references.citation: Ann Rheum Dis. 2002 Nov;61 Suppl 2:ii54-8
references.pmid: 12379623
references.citation: Eur J Immunol. 2003 Oct;33(10):2676-86
references.pmid: 14515251
references.citation: J Infect Dis. 2010 Jun 1;201(11):1743-52
references.pmid: 20394526
references.citation: Infect Immun. 2003 Dec;71(12):7023-34
references.pmid: 14638792
references.citation: Nat Immunol. 2007 Apr;8(4):369-77
references.pmid: 17351619
references.citation: Am J Respir Cell Mol Biol. 1998 Sep;19(3):513-21
references.pmid: 9730880
references.citation: Trends Microbiol. 1995 Oct;3(10):401-4
references.pmid: 8564360
references.citation: Scand J Immunol. 2008 Dec;68(6):668-74
references.pmid: 18959625
references.citation: Microbes Infect. 2006 Apr;8(4):1179-88
references.pmid: 16513383