Project Details

Description

In this application we will explore the hypothesis that Toll-like receptor 2 (TLR2) is the master regulator
controlling both protective and pathologic features of the tubercle granuloma. The hypothesis builds on
novel findings made in our laboratory. Previously we had reported that TLR9 and TLR2 induce pro- and
anti-inflammatory cytokines, respectively, in M. tuberculosis (Mtb)-infected dendritic cells (DCs), while
TLR2 induces both pro- and anti-inflammatory cytokines in infected macrophages. A reasonable
prediction, based on these observations, is that during Mtb infection the innate anti-inflammatory response
triggered by TLR2 may control the magnitude of Th1 effector and memory T cell activation. Contrary to
expectation, we found that the absence of TLR2 did not affect the magnitude of the Th1 effector response
generated following aerosol infection with Mtb or the induction of recall Th1 memory immunity in response
to Mtb challenge. However, the consequence of TLR2 absence to host resistance was manifested at the
level of the granuloma. The infected lungs of TLR2KO mice exhibited enhanced inflammation associated
with reduced infiltration of FoxP3+ T regulatory cells (Tregs) into the lung, while lungs from infected WT
animals had resolved their inflammation and had small, compact granulomas. Tregs have been shown to
thwart host antimicrobial responses against persistent pathogens. Surprisingly, despite the absence of
Tregs, lungs from chronically-infected TLR2KO mice exhibited enhanced bacterial burden and loss of
granuloma integrity in comparison with infected WT mice indicating a hitherto under-appreciated role for
TLR2 in controlling antimicrobial responses in vivo in the granuloma. The following specific hypotheses will be tested in the proposal: i)TLR2 is essential for macrophage
control of Mtb replication and containment within the granuloma;ii) TLR2 induces Tregs which operate
primarily as inhibitors of lung immunopathology but not as inhibitors of macrophage antimicrobial
responses;iii) TLR2-triggers two distinct signaling pathways for the induction of pro- and anti-inflammatory
cytokine production within Mtb-infected macrophages, and iv) the signaling pathways cross-regulate each
other and Mtb can maneuver the pathways to its own benefit. The collective findings from the proposed
studies will provide insights into TLR2-triggered signaling pathways in the tubercle granuloma and unique
ways in which they can be manipulated therapeutically.
StatusFinished
Effective start/end date9/1/098/31/17

Funding

  • National Institutes of Health: $390,000.00
  • National Institutes of Health: $397,500.00
  • National Institutes of Health: $390,000.00
  • National Institutes of Health: $190,557.00
  • National Institutes of Health: $397,500.00
  • National Institutes of Health: $195,000.00
  • National Institutes of Health: $179,948.00
  • National Institutes of Health: $384,400.00

ASJC

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

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