Fcγ receptor I alpha chain (CD64) expression in macrophages is critical for the onset of meningitis by Escherichia coli K1.
Neonatal meningitis due to Escherichia coli K1 is a serious illness with unchanged morbidity and mortality rates for the last few decades. The lack of a comprehensive understanding of the mechanisms involved in the development of meningitis contributes to this poor outcome. Here, we demonstrate that depletion of macrophages in newborn mice renders the animals resistant to E. coli K1 induced meningitis. The entry of E. coli K1 into macrophages requires the interaction of outer membrane protein A (OmpA) of E. coli K1 with the alpha chain of Fcγ receptor I (FcγRIa, CD64) for which IgG opsonization is not necessary. Overexpression of full-length but not C-terminal truncated FcγRIa in COS-1 cells permits E. coli K1 to enter the cells. Moreover, OmpA binding to FcγRIa prevents the recruitment of the γ-chain and induces a different pattern of tyrosine phosphorylation of macrophage proteins compared to IgG2a induced phosphorylation. Of note, FcγRIa(-/-) mice are resistant to E. coli infection due to accelerated clearance of bacteria from circulation, which in turn was the result of increased expression of CR3 on macrophages. Reintroduction of human FcγRIa in mouse FcγRIa(-/-) macrophages in vitro increased bacterial survival by suppressing the expression of CR3. Adoptive transfer of wild type macrophages into FcγRIa(-/-) mice restored susceptibility to E. coli infection. Together, these results show that the interaction of FcγRI alpha chain with OmpA plays a key role in the development of neonatal meningitis by E. coli K1.
The Saban Research Institute, Childrens Hospital, Los Angeles, CA, USA.
Rahul
R
Mittal
Sunil K
SK
Sukumaran
Suresh K
SK
Selvaraj
David G
DG
Wooster
M Madan
MM
Babu
Alan D
AD
Schreiber
J Sjef
JS
Verbeek
Nemani V
NV
Prasadarao
D000818:Animals; D000831:Animals, Newborn; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D001667:Binding, Competitive; D015153:Blotting, Western; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D019556:COS Cells; D002522:Chlorocebus aethiops; D004926:Escherichia coli / Q000254:growth & development / Q000472:pathogenicity*; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D047468:Immunoprecipitation; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D020814:Meningitis, Escherichia coli / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D010587:Phagocytosis; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D017452:Receptors, IgG / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001425:Bacterial Outer Membrane Proteins; D007074:Immunoglobulin G; D016177:Macrophage-1 Antigen; D012333:RNA, Messenger; D017452:Receptors, IgG; C078167:OMPA outer membrane proteins; D009569:Nitric Oxide