Abstract
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.
Escherichia coli
K1 is the most common cause of meningitis in premature infants; the mortality rate of this disease ranges from 5% to 30%. A better understanding of the pathogenesis of
E
.
coli
K1 meningitis is needed to develop new preventative strategies. We have shown that outer membrane protein A (OmpA) of
E. coli
K1, independent of antibody opsonization, is critical for bacterial entrance and survival within macrophages. Using a newborn mouse model, we found that depletion of macrophages renders the animals resistant to
E. coli
K1 induced meningitis. OmpA binds to α-chain of Fcγ-receptor I (FcγRIa) in macrophages, but does not induce expected gamma chain association and signaling. FcγRIa knockout mice are resistant to
E. coli
K1 infection because their macrophages express more CR3 and are thus able to kill bacteria with greater efficiency, preventing the development of high-grade bacteremia, a pre-requisite for the onset of meningitis. These novel observations demonstrate that inhibiting OmpA binding to FcγRIa is a promising therapeutic target for treatment or prevention of neonatal meningitis.
