MyD88-dependent recruitment of monocytes and dendritic cells required for protection from pulmonary Burkholderia mallei infection.
The Gram-negative bacterium Burkholderia mallei causes rapidly fatal illness in equines and humans when contracted by inhalation and also has the potential to be used as a bioweapon. However, little is known regarding the early innate immune responses and signaling mechanisms required to generate protection from pneumonic B. mallei infection. We showed previously that monocyte chemoattractant protein 1 (MCP-1) was a critical chemokine required for protection from pneumonic B. mallei infection. We have now extended those studies to identify key Toll-like receptor (TLR) signaling pathways, effector cells, and cytokines required for protection from respiratory B. mallei infection. We found that MyD88-/- mice were highly susceptible to pulmonary challenge with B. mallei and had significantly short survival times, increased bacterial burdens, and severe organ pathology compared to wild-type mice. Notably, MyD88-/- mice had significantly fewer monocytes and dendritic cells (DCs) in lung tissues and airways than infected wild-type mice despite markedly higher bacterial burdens. The MyD88-/- mice were also completely unable to produce gamma interferon (IFN-γ) at any time points following infection. In wild-type mice, NK cells were the primary cells producing IFN-γ in the lungs following B. mallei infection, while DCs and monocytes were the primary cellular sources of interleukin-12 (IL-12) production. Treatment with recombinant IFN-γ (rIFN-γ) was able to significantly restore protective immunity in MyD88-/- mice. Thus, we conclude that the MyD88-dependent recruitment of inflammatory monocytes and DCs to the lungs and the local production of IL-12, followed by NK cell production of IFN-γ, are the key initial cellular responses required for early protection from B. mallei infection.
Rocky Mountain RCE, CO, USA.
Andrew
A
Goodyear
Ryan
R
Troyer
Helle
H
Bielefeldt-Ohmann
Steven
S
Dow
D000818:Animals; D058491:Bacterial Load; D042726:Burkholderia mallei / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005896:Glanders / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism*; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology; D016019:Survival Analysis
C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D018664:Interleukin-12; D007371:Interferon-gamma