TY - JOUR
T1 - MyD88 mediates instructive signaling in dendritic cells and protective inflammatory response during rickettsial infection
AU - Bechelli, Jeremy
AU - Smalley, Claire
AU - Zhao, Xuemei
AU - Judy, Barbara
AU - Valdes, Patricia
AU - Walker, David H.
AU - Fang, Rong
N1 - Funding Information:
We thank Kerry Graves, UTMB, for professional assistance with the immunohistochemical staining. This study was supported by grants AI021242 and AI101413 from the National Institute of Allergy and Infectious Diseases. J.B. is supported at UTMB by Biodefense Training Grant PT32-AI060549. HHS|NIH| National Institute of Allergy and Infectious Diseases (NIAID) provided funding to David H. Walker under grant number AI021242. HHS|NIH| National Institute of Allergy and Infectious Diseases (NIAID) provided funding to Rong Fang under grant number AI101413. Biodefense Training Grant at the University of Texas Medical Branch provided funding to Jeremy Bechelli under grant number PT32-AI060549.
Publisher Copyright:
© 2016, American Society for Microbiology. All Rights Reserved.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - Spotted fever group rickettsiae cause potentially life-threatening infections throughout the world. Several members of the Tolllike receptor (TLR) family are involved in host response to rickettsiae, and yet the mechanisms by which these TLRs mediate host immunity remain incompletely understood. In the present study, we found that host susceptibility of MyD88-/- mice to infection with Rickettsia conorii or Rickettsia australis was significantly greater than in wild-type (WT) mice, in association with severely impaired bacterial clearance in vivo. R. australis-infected MyD88-/- mice showed significantly lower expression levels of gamma interferon (IFN-γ), interleukin-6 (IL-6), and IL-1β, accompanied by significantly fewer inflammatory infiltrates of macrophages and neutrophils in infected tissues, than WT mice. The serum levels of IFN-γ, IL-12, IL-6, and granulocyte colonystimulating factor were significantly reduced, while monocyte chemoattractant protein 1, macrophage inflammatory protein 1α, and RANTES were significantly increased in infected MyD88-/- mice compared to WT mice. Strikingly, R. australis infection was incapable of promoting increased expression of MHC-IIhigh and production of IL-12p40 in MyD88-/- bone marrow-derived dendritic cells (BMDCs) compared to WT BMDCs, although costimulatory molecules were upregulated in both types of BMDCs. Furthermore, the secretion levels of IL-1β by Rickettsia-infected BMDCs and in the sera of infected mice were significantly reduced in MyD88-/- mice compared to WT controls, suggesting that in vitro and in vivo production of IL-1β is MyD88 dependent. Taken together, our results suggest that MyD88 signaling mediates instructive signals in DCs and secretion of IL-1β and type 1 immune cytokines, which may account for the protective inflammatory response during rickettsial infection.
AB - Spotted fever group rickettsiae cause potentially life-threatening infections throughout the world. Several members of the Tolllike receptor (TLR) family are involved in host response to rickettsiae, and yet the mechanisms by which these TLRs mediate host immunity remain incompletely understood. In the present study, we found that host susceptibility of MyD88-/- mice to infection with Rickettsia conorii or Rickettsia australis was significantly greater than in wild-type (WT) mice, in association with severely impaired bacterial clearance in vivo. R. australis-infected MyD88-/- mice showed significantly lower expression levels of gamma interferon (IFN-γ), interleukin-6 (IL-6), and IL-1β, accompanied by significantly fewer inflammatory infiltrates of macrophages and neutrophils in infected tissues, than WT mice. The serum levels of IFN-γ, IL-12, IL-6, and granulocyte colonystimulating factor were significantly reduced, while monocyte chemoattractant protein 1, macrophage inflammatory protein 1α, and RANTES were significantly increased in infected MyD88-/- mice compared to WT mice. Strikingly, R. australis infection was incapable of promoting increased expression of MHC-IIhigh and production of IL-12p40 in MyD88-/- bone marrow-derived dendritic cells (BMDCs) compared to WT BMDCs, although costimulatory molecules were upregulated in both types of BMDCs. Furthermore, the secretion levels of IL-1β by Rickettsia-infected BMDCs and in the sera of infected mice were significantly reduced in MyD88-/- mice compared to WT controls, suggesting that in vitro and in vivo production of IL-1β is MyD88 dependent. Taken together, our results suggest that MyD88 signaling mediates instructive signals in DCs and secretion of IL-1β and type 1 immune cytokines, which may account for the protective inflammatory response during rickettsial infection.
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U2 - 10.1128/IAI.01361-15
DO - 10.1128/IAI.01361-15
M3 - Article
C2 - 26755162
AN - SCOPUS:84962896242
SN - 0019-9567
VL - 84
SP - 883
EP - 893
JO - Infection and immunity
JF - Infection and immunity
IS - 4
ER -