Abstract
Bacterial infection remains one of the leading causes of death worldwide due to the continuous rise of multiple antibiotic-resistant bacteria. Focusing solely on bacteria as the drug targets is a major limitation inherent in the conventional antibiotic therapy. Recently, host-directed therapies have become such an innovative approach to modulate the host defense system and the interplay of innate and adaptive immunity. Our previous studies showed that memantine (MEM), an α7 nAChR antagonist, could efficiently block multi-drug resistant Escherichia coli-caused bacteremia and meningitis in a mouse model. However, the underlying mechanisms that govern the antibacterial effects of MEM are still unknown. In this study, we demonstrated that MEM is able to significantly suppress E. coli infection by enhancing E. coli-induced formation and release of NETs in vitro and in vivo. MEM could promote the trapping and bactericidal activities of the polymorphonuclear neutrophils (PMNs) in a manner dependent on α7 nAChR, since knockdown of this receptor noticeably reduces the survival ability of bacteria in PMNs while MEM no longer affects the survival of bacteria in PMNs. Our results also showed that when the expression of S100A9, an antiseptic protein, is inhibited, pathogen survival rates in PMNs increase significantly. MEM reverses this effect in a concentration-dependent manner. MEM stimulates the production of MPO, S100A9, and DNA in PMNs and accelerates the release of depolymerized chromatin fibers into the extracellular space, suggesting the formation of NETs. Taken together, our data suggest that MEM effectively blocks bacterial infection through the promotion of the antibacterial function of NETs induced by E. coli.
Highlights
The emergence of antibiotic resistance has become a severe public health problem
Using α7 nAChR (α7R) KO in vitro and in vivo model systems, we have demonstrated that α7R plays a detrimental role in the genesis of bacteremia and the penetration of E. coli and neutrophils across the blood-brain barrier (BBB)
We measured the formation of neutrophil elastase (NE) using the NETosis assay kit
Summary
Bacteria resistant to multiple antibacterial agents such as carbapenem-resistant enterobacteriaceae (CRE), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), extensively drugresistant tuberculosis (XDR-TB), and extensively drug-resistant Acinetobacter baumannii (XDRAB) are often referred to as “superbugs.” These bacteria infect at least 2 million people per year in the USA alone, with 23,000 dying as a direct result of these infections (Khan and Siddiqui, 2014). It suggests that there is an emergent need to develop new antibacterial drugs with novel strategies (Yu et al, 2015). Targeting powerful immune cell killing and boosting the host defense system against pathogens could be an important way to treat infections, and would reduce frequencies in inducing drug resistance (Yu et al, 2015; Munguia and Nizet, 2017; Chiang et al, 2018)
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