Regulation of Innate Immune Responses

  • Barber, Glen N (PI)
  • Harhaj, Edward (PI)
  • Rosenblatt, Joseph David (PI)
  • Ruiz, Phillip (PI)
  • Guettouche, Toumy (PI)

Project: Research project

Description

Our objectives here are to further understand mechanisms of innate immune signaling and clarify
mechanisms by which select oncogenic viruses such as HTLV-1 and HHV8 may subvert these important
signaling pathways. We believe that elucidafing these processes will have significant impact on
understanding pathogenesis and on the development of novel therapeutics and vaccines to combat
oncoviral-related malignant disease. While the cellular signaling molecules required for recognizing virus
infection remain to be fully defined, it has recently been reported that the DExD/H box RNA helicases, RIG-I
(Refinoic acid inducible gene-1) and MDA5 (melanoma differentiation antigen 5) are key players in
recognizing viral dsRNA species to trigger innate immune responses. Importanfiy, ours and others data
confirm that the molecule RIP1 is also required to facilitate DExD/H box-mediated signaling. Of note is that
we have observed that HTLV-1 and HHV-8 encoded Tax and vIRFI, respecfively, may inhibit these important
pathways, mechanisms that may explain viral pathogenicity and modes of latency. Given these data, we aim
to do the following:
l.)We have recently identified that a mitochondrial protein GRIM19/B16.6 associates with RIG-I and MDA5.
Given this, we aim to explore the importance of GRIM19/B16.6 in innate signaling processes, including
potential suppression by HHV8 vIRFI and HPV E6.
II.) We have demonstrated that RIP1 is important in facilitafing RIG-I/MDA5 signaling. Our data also
indicates that RIP1 can bind to GRIM19 as well as HTLV-1 Tax. We therefore aim to further study the
importance of RIP1 in innate signaling as well as potential repression by the oncoviral protein Tax.
III.) Given that we have observed that Tax inhibits innate immune signaling, and that innate signaling is
defective in HTLV-1 induced ATL. we aim to evaluate the use of VSV as an oncolytic agent to treat such
diseases. Such therapeutic approaches have been designed based on data obtained from Aims I and II.
We anticipate that these studies will improve our knowledge of oncognesis and provide new concepts for the
rafional design of novel drugs and vaccine strategies.
RELEVANCE (See instructions):
Innate immune responses are essenfial for mounfing an effecfive host response against virus infecfion. This
proposal intends to understand these processes as well as understand how viruses subvert such processes
to cause disease. This project will also utilize information gained through these studies to design new
therapeutics to combat viral-related cancers.
StatusFinished
Effective start/end date7/1/097/31/14

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $1,044,934.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $1,107,550.00
  • National Institutes of Health: $1,103,015.00
  • National Institutes of Health
  • National Institutes of Health: $1,161,984.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $1,166,688.00
  • National Institutes of Health
  • National Institutes of Health

Fingerprint

Human T-lymphotropic virus 1
Melanoma-Specific Antigens
Innate Immunity
Differentiation Antigens
Carcinogenesis
Virus Diseases
Viruses
Human Herpesvirus 8
Neoplasms
Interferons
Adult T Cell Leukemia Lymphoma
Vaccines
tax Gene Products
RNA Helicases
Human Herpesvirus 4
Oncogenic Viruses
Drug Design
Mitochondrial Proteins
Genes
Deltaretrovirus Infections

ASJC

  • Medicine(all)