Activation of triggering receptor expressed on myeloid cells-1 on human neutrophils by marburg and ebola viruses.
Marburg virus (MARV) and Ebola virus (EBOV), members of the viral family Filoviridae, cause fatal hemorrhagic fevers in humans and nonhuman primates. High viral burden is coincident with inadequate adaptive immune responses and robust inflammatory responses, and virus-mediated dysregulation of early host defenses has been proposed. Recently, a novel class of innate receptors called the triggering receptors expressed in myeloid cells (TREM) has been discovered and shown to play an important role in innate inflammatory responses and sepsis. Here, we report that MARV and EBOV activate TREM-1 on human neutrophils, resulting in DAP12 phosphorylation, TREM-1 shedding, mobilization of intracellular calcium, secretion of proinflammatory cytokines, and phenotypic changes. A peptide specific to TREM-1 diminished the release of tumor necrosis factor alpha by filovirus-activated human neutrophils in vitro, and a soluble recombinant TREM-1 competitively inhibited the loss of cell surface TREM-1 that otherwise occurred on neutrophils exposed to filoviruses. These data imply direct activation of TREM-1 by filoviruses and also indicate that neutrophils may play a prominent role in the immune and inflammatory responses to filovirus infections.
Mohamadzadeh
Mansour
M
U.S. Army Medical Research Institute for Infectious Diseases, 1425 Porter Street, Frederick, MD 21702, USA. Mansour.Mohamadzadeh@amedd.army.mil
Coberley
Sadie S
SS
Olinger
Gene G
GG
Kalina
Warren V
WV
Ruthel
Gordon
G
Fuller
Claudette L
CL
Swenson
Dana L
DL
Pratt
William D
WD
Kuhns
Douglas B
DB
Schmaljohn
Alan L
AL
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002522:Chlorocebus aethiops; D029043:Ebolavirus / Q000276:immunology* / Q000378:metabolism; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D008379:Marburg Virus Disease / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D029024:Marburgvirus / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology*; D008565:Membrane Proteins; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000378:metabolism* / Q000821:virology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000276:immunology; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D018805:Sepsis / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D014709:Vero Cells
D048868:Adaptor Proteins, Signal Transducing; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; C110546:TYROBP protein, human; D000073871:Triggering Receptor Expressed on Myeloid Cells-1