M. tuberculosis has infected 1.8 billion humans and accounts for 2 to 3 million deaths annually based on its ability to persist as an intracellular pathogen in human tissues. The host response to mycobacterial infection depends crucially on T cells, which until recently, were thought to be activated solely by peptide antigens bound to MHC class I and II proteins. The discovery of CD1 antigen presenting molecules shows how Langerhans cells and dendritic cells can activate T cells by presenting lipid antigens, including glucose monomycolate (Science 278, p. 283), mannosyl phosphomycoketides (Nature 404, p.884) and mycobactin like lipopeptides (Science 303, p. 527). This proposal aims to use high performance liquid chromatography to isolate immunodominant antigens from the M. tuberculosis and M. leprae cell walls and then determine their structures using collision induced dissociation mass spectrometry, nuclear magnetic resonance and Xray crystallography. Because mycobacteria remodel their cell walls and alter their antigen profiles during adaptation to intracellular growth, antigen discovery efforts will focus on pathogenic mycobacteria isolated directly from mammalian tissues and genetically modified M. tuberculosis that are deficient in the enzymes necessary for iron-scavenging from host tissues. The immunogenicity of each lipid antigen will be investigated by ex vivo analysis of T cell precursor frequencies in tuberculosis patients as measured by cytokine-capture ELISA, cell surface cytokine-capture immunofluorescence and staining with lipid-loaded CD1 tetramers. By measuring memory responses and the complexity of lipid antigen specificities in the CD 1-restricted T cell repertoire, these studies will provide insight into the basic question of whether CD1 functions in the innate or acquired immune responses in humans. In addition, identification of the precise molecular structures of antigenic lipids offers the prospect of fundamentally novel, MHC-unrestricted immunodulatory drugs and vaccines against leprosy, tuberculosis and multi-drug resistant tuberculosis. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI049313-06
Application #
6965263
Study Section
Special Emphasis Panel (ZRG1-IHD (01))
Program Officer
Sizemore, Christine F
Project Start
2001-03-01
Project End
2011-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
6
Fiscal Year
2006
Total Cost
$437,500
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Lehmann, Johannes; Cheng, Tan-Yun; Aggarwal, Anup et al. (2018) An Antibacterial ?-Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis. Angew Chem Int Ed Engl 57:348-353
Wun, Kwok S; Reijneveld, Josephine F; Cheng, Tan-Yun et al. (2018) T cell autoreactivity directed toward CD1c itself rather than toward carried self lipids. Nat Immunol 19:397-406
Madigan, Cressida A; Cambier, C J; Kelly-Scumpia, Kindra M et al. (2017) A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy. Cell 170:973-985.e10
Moody, D Branch (2017) How T cells grasp mycobacterial lipid antigens. Proc Natl Acad Sci U S A 114:13312-13314
Cheng, Janice M H; Liu, Ligong; Pellicci, Daniel G et al. (2017) Total Synthesis of Mycobacterium tuberculosis Dideoxymycobactin-838 and Stereoisomers: Diverse CD1a-Restricted T Cells Display a Common Hierarchy of Lipopeptide Recognition. Chemistry 23:1694-1701
Moody, D Branch; Cotton, Rachel N (2017) Four pathways of CD1 antigen presentation to T cells. Curr Opin Immunol 46:127-133
Moody, D Branch; Suliman, Sara (2017) CD1: From Molecules to Diseases. F1000Res 6:1909
Van Rhijn, Ildiko; Iwany, Sarah K; Fodran, Peter et al. (2017) CD1b-mycolic acid tetramers demonstrate T-cell fine specificity for mycobacterial lipid tails. Eur J Immunol 47:1525-1534
Kasprowicz, Victoria O; Cheng, Tan-Yun; Ndung'u, Thumbi et al. (2016) HIV Disrupts Human T Cells That Target Mycobacterial Glycolipids. J Infect Dis 213:628-33
Jarrett, Rachael; Salio, Mariolina; Lloyd-Lavery, Antonia et al. (2016) Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite-derived phospholipase. Sci Transl Med 8:325ra18

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