Tuberculosis is a global health threat, and the emergence of Multiply Drug Resistant (MDR) Mycobacterium tuberculosis (Mtb) strains makes the situation even more alarming. Because of the potential bioterror threat it poses, MDR Mtb is classified as a Class C priority pathogen by NIAID. Means to enhance host response to vaccines and to Mtb infection are central to the control of a catastrophic MDR TB infection. A thorough understanding of the immune response, specifically the role innate and adaptive immunity plays in host protection against Mtb, should facilitate improvement of vaccines for MDR and drug-sensitive Mtb. The focus of this proposal is to study Mtb and determine the roles of TLR and their adaptors, and a new class of genes (CATERPILLER/NOD) that modulates the outcome of TLR activation. The focus on human primary cells is of special relevance to enhancing immunity to Mtb in humans. To understand the interplay between TLR, CATERPILLER and Mtb: 1. We have used, and will continue to use the small interference RNA (siRNA) technology to target human TLR and TLR adaptors for reduced or ablated expression. We will determine if the removal of TLRs and/or their adaptors causes alterations in host responses to Mtb. This will be studied in transformed cell lines and primary macrophage/dendritic cells. Critical data will be reproduced using MDR TB. If a specific adaptor of TLR activation is found to be important, analysis of mice lacking that adaptor will be studied in the future. 2. Preliminary data indicate that Mtb causes the suppression of Monarch-1 gene expression, a negative regulator of NF-KB/AP-1 activation and proinflammatory responses. In reverse, we also found that Monarch-1 inhibits the TLR and NF-kappaB pathways, leading to a reduction of inflammatory cytokines during Mtb infection. We will profile innate and adaptive immune genes in cells containing siRNA targeting Monarch-1 expression to assess if this protein is a negative regulator of host response to Mtb in cell lines and primary cells. In addition, we will use Monarch-1-null mice to assess how the removal of Monarch-1 alters host response. Crucial experiments will be reproduced with MDR TB. 3. Finally, ASC is a modifier of Monarch-1 function. Its removal in monocytic cells resulted in enhanced cytokine response in response to Mtb. It is also thought to control apoptosis in bacteriainfected macrophages.
This Aim will examine the role of ASC in host response by studying cell lines and primary cells during an Mtb infection. Crucial experiments will be reproduced with MDR TB. If ASC alters host response to Mtb, future experiments will be planned to study an ASC-null mouse.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IHD (01))
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Jacobs, Gail G
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Davis, Beckley K; Wen, Haitao; Ting, Jenny P-Y (2011) The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol 29:707-35
Davis, Beckley K; Roberts, Reid A; Huang, Max T et al. (2011) Cutting edge: NLRC5-dependent activation of the inflammasome. J Immunol 186:1333-7
Ting, Jenny P Y; Duncan, Joseph A; Lei, Yu (2010) How the noninflammasome NLRs function in the innate immune system. Science 327:286-90
Taxman, Debra J; Huang, Max T-H; Ting, Jenny P-Y (2010) Inflammasome inhibition as a pathogenic stealth mechanism. Cell Host Microbe 8:7-11
Arthur, Janelle C; Lich, John D; Ye, Zhengmao et al. (2010) Cutting edge: NLRP12 controls dendritic and myeloid cell migration to affect contact hypersensitivity. J Immunol 185:4515-9
McElvania Tekippe, Erin; Allen, Irving C; Hulseberg, Paul D et al. (2010) Granuloma formation and host defense in chronic Mycobacterium tuberculosis infection requires PYCARD/ASC but not NLRP3 or caspase-1. PLoS One 5:e12320
Lord, Christopher A; Savitsky, David; Sitcheran, Raquel et al. (2009) Blimp-1/PRDM1 mediates transcriptional suppression of the NLR gene NLRP12/Monarch-1. J Immunol 182:2948-58
Willingham, Stephen B; Allen, Irving C; Bergstralh, Daniel T et al. (2009) NLRP3 (NALP3, Cryopyrin) facilitates in vivo caspase-1 activation, necrosis, and HMGB1 release via inflammasome-dependent and -independent pathways. J Immunol 183:2008-15
Duncan, Joseph A; Gao, Xi; Huang, Max Tze-Han et al. (2009) Neisseria gonorrhoeae activates the proteinase cathepsin B to mediate the signaling activities of the NLRP3 and ASC-containing inflammasome. J Immunol 182:6460-9
Li, Hanfen; Willingham, Stephen B; Ting, Jenny P-Y et al. (2008) Cutting edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3. J Immunol 181:17-21

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