KSHV is both a commensal and pathogenic microorganism in the oral mucosa. In most healthy individuals with an intact immune system, KSHV is kept in check and does not cause disease. However in conditions of immune suppression like HIV infection or immunosuppressive therapy, KSHV can cause sarcomas and lymphomas in the oral cavity. Thus KSHV is considered to be an opportunistic oral pathogen. The development of Kaposi's sarcoma is much more frequent in older individuals than in young people. Thus there appears to be an age dependency for the onset of Kaposi's sarcoma. It is currently unclear how the immune system keeps KSHV in check in healthy individuals, but allows disease to progress during times of immune suppresion. It is known that the aging process is associated with increased inflammation but decreased anti-viral responses. Additionally, newborns and children have an increased susceptibility to infectious diseases, and this has been linked both to immaturity of the immune system at birth and to the slow development of immune competence in the postnatal years. This susceptibility to infections is even more increased with respect to intracellular pathogens, reflecting the functional immaturity of cell-mediated immunity. Toll-like receptors (TLRs) are a very important means by which the innate immune system recognizes microbial pathogens like KSHV. TLR activation needs a slew of intracellular players that interact with the TLRs, including MyD88, TRAFG, and RIP2. In addition, our collaborator, Dr. Ting, first described the CATERPILLER (CLR) protein family. These proteins play both positive and negative roles in the regulation of innate immunity in response to pathogens. and are considered as intracellular sensors of pathogens. In response to RFA-DE-07-004, we propose to understand how the innate immune system recognizes KSHV and the signaling pathways that are induced by the Toll-like receptors in response to KSHV infection during ontogeny. We hypothesize that activation of TLR signaling pathways by KSHV in cells from neonates and old individuals is blunted as compared to the signaling response in cells from young adults. We also propose to understand the roles of TLRs, their cellular adaptors, and the CLR proteins in KSHV infection durirlg ontogeny. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE018281-01
Application #
7277474
Study Section
Special Emphasis Panel (ZDE1-YL (20))
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2007-06-01
Project End
2012-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$335,090
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Host, Kurtis M; Horner, Marie-Josephe; van der Gronde, Toon et al. (2017) Kaposi's sarcoma in Malawi: a continued problem for HIV-positive and HIV-negative individuals. AIDS 31:318-319
Hsia, Hung-Ching; Stopford, Charles M; Zhang, Zhigang et al. (2017) Signal transducer and activator of transcription 3 (Stat3) regulates host defense and protects mice against herpes simplex virus-1 (HSV-1) infection. J Leukoc Biol 101:1053-1064
Zhang, Zhigang; Chen, Wuguo; Sanders, Marcia K et al. (2016) The K1 Protein of Kaposi's Sarcoma-Associated Herpesvirus Augments Viral Lytic Replication. J Virol 90:7657-66
Ma, Zhe; Damania, Blossom (2016) Editorial: NLRP3: immune activator or modulator? J Leukoc Biol 99:641-3
Bhatt, Aadra Prashant; Wong, Jason P; Weinberg, Marc S et al. (2016) A viral kinase mimics S6 kinase to enhance cell proliferation. Proc Natl Acad Sci U S A 113:7876-81
Damania, Blossom (2016) A Virological Perspective on Cancer. PLoS Pathog 12:e1005326
Speicher, D J; Ramirez-Amador, V; Dittmer, D P et al. (2016) Viral infections associated with oral cancers and diseases in the context of HIV: a workshop report. Oral Dis 22 Suppl 1:181-92
Ma, Zhe; Damania, Blossom (2016) The cGAS-STING Defense Pathway and Its Counteraction by Viruses. Cell Host Microbe 19:150-8
Dittmer, Dirk P; Damania, Blossom (2016) Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy. J Clin Invest 126:3165-75
Giffin, Louise; West, John A; Damania, Blossom (2015) Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Modulates Endothelial Cell Movement by Upregulating Cellular Genes Involved in Migration. MBio 6:e01499-15

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