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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., Author Summary 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.

Approximately one-third of the world's population suffers from chronic helminth infections with no effective vaccines currently available. Antibodies and alternatively activated macrophages (AAM) form crucial components of protective immunity against challenge infections with intestinal helminths. However, the mechanisms by which antibodies target these large multi-cellular parasites remain obscure. Alternative activation of macrophages during helminth infection has been linked to signaling through the IL-4 receptor alpha chain (IL-4Rα), but the potential effects of antibodies on macrophage differentiation have not been explored. We demonstrate that helminth-specific antibodies induce the rapid trapping of tissue migrating helminth larvae and prevent tissue necrosis following challenge infection with the natural murine parasite Heligmosomoides polygyrus bakeri (Hp). Mice lacking antibodies (JH −/−) or activating Fc receptors (FcRγ−/−) harbored highly motile larvae, developed extensive tissue damage and accumulated less Arginase-1 expressing macrophages around the larvae. Moreover, Hp-specific antibodies induced FcRγ- and complement-dependent adherence of macrophages to larvae in vitro, resulting in complete larval immobilization. Antibodies together with helminth larvae reprogrammed macrophages to express wound-healing associated genes, including Arginase-1, and the Arginase-1 product L-ornithine directly impaired larval motility. Antibody-induced expression of Arginase-1 in vitro and in vivo occurred independently of IL-4Rα signaling. In summary, we present a novel IL-4Rα-independent mechanism of alternative macrophage activation that is antibody-dependent and which both mediates anti-helminth immunity and prevents tissue disruption caused by migrating larvae., Author Summary Intestinal helminths present a pressing problem in developing countries with approximately 2 billion people suffering from chronic infection. To date no successful vaccines are available and a detailed mechanistic understanding of anti-helminth immunity is urgently needed to improve strategies for prevention and therapy. Antibodies form a crucial component of protective immunity against challenge infections with intestinal helminths. However, the exact mechanisms by which antibodies target these large multi-cellular parasites have remained obscure. We now demonstrate that helminth-specific antibodies induce the rapid trapping of tissue migrating helminth larvae by activating phagocytes. In the absence of antibodies or their receptors, helminth-infected mice developed extensive tissue damage, revealing a novel role for antibodies in limiting parasite-caused tissue disruption. Furthermore, helminth-specific antibodies reprogrammed macrophages to express wound-healing factors such as the arginine-metabolizing enzyme Arginase-1. Interestingly, the Arginase-1 product L-ornithine directly impaired the motility of helminth larvae. In summary, our study provides detailed mechanistic insights into how antibodies can modulate phagocyte function to provide protection against a large multi-cellular parasite. Our findings suggest that novel anti-helminth vaccines should target the larval surface and activate wound-healing macrophages to provide rapid protection against tissue-disruptive larvae.