Innate immune response to bacterial flagellans

Project: Research project

Description

Bacterial flagellins are unusual microbial products that can be directly recognized by
receptors of both the innate and adaptive immune system. Since flagellins initiate an innate
immune response, they have the potential to function as molecularly defined adjuvants, and
are being studied in preclinical vaccine studies. Expanding our knowledge about the innate
immune response to bacterial flagellins is important for understanding immunity to
flagellated pathogens and has the additional potential to influence future vaccine and
adjuvant development.
Mucosal dendritic cells (DC) are the only hematopoietic population known to
constitutively express the flagellin receptor, TLR5. The effect of bacterial flagellins on
intestinal DC antigen presentation and migration have not previously been examined but
have the potential to influence bacterial pathogenesis and host immunity. Our overall
hypothesis is that Salmonella flagellin recognition by intestinal DCs enhances the
presentation of flagellin epitopes and initiates rapid intestinal DC migration. We expect the
rapid response of TLR5'DCs is beneficial to host immunity but is also beneficial to the
bacteria since it enables efficient pathogen dissemination.
It is not known if TLR5 ligation on intestinal DCs can influence the presentation of
flagellin peptides on surface MHC molecules. Our working hypothesis in Specific Aim 1
is that activation of intestinal DCs via TLR5 preferentially enhances the display of
flagellin peptides on surface MHC molecules. This hypothesis predicts a direct link
between surface TLR ligation and subsequent antigen presentation, and could explain the
notable dominance of flagellin-specific T cell responses in infectious and inflammatory
diseases of the intestine. We propose to examine this hypothesis using new reagents that
we have developed to directly track presentation of flagellin epitopes on antigen presenting
cells in vitro and in vivo.
Reports suggest that Salmonella provoke rapid migration of an unusual DC
population in the intestinal lamina propria to enter the host. However, the bacterial stimulus
provoking these early DC migration events are undefined. Our hypothesis in Specific Aim
2 is that recognition of bacterial flagellins causes rapid DC migration in the intestine.
We propose to examine this hypothesis using reagents that will allow us to physically track
DC migration from the lamina propria.
StatusFinished
Effective start/end date12/1/077/31/16

Funding

  • National Institutes of Health: $381,621.00
  • National Institutes of Health: $358,906.00
  • National Institutes of Health: $377,492.00
  • National Institutes of Health: $381,719.00
  • National Institutes of Health: $381,907.00
  • National Institutes of Health: $377,492.00

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Flagellin
Innate Immunity
T-Lymphocytes
Dendritic Cells
Toll-Like Receptor 5
Adaptive Immunity
Immunity
Vaccines
Cell Movement
Scavenger Receptors
Translational Medical Research
Inflammatory Bowel Diseases
Cholera
Typhoid Fever
Histocompatibility Antigens Class II
Antigen Presentation
Bacterial Infections

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)