Destroying NETs That Hide Bacteria as a Way to Treat Acute Bacterial Meningitis

Acute bacterial meningitis (ABM) is an extremely serious neurological infection that can be fatal if patients are not quickly correctly diagnosed and treated. One of the most common bacterial strains that causes ABM is Streptococcus pneunomiae (pneumococcus). In spite of medical advances to treat pneumococcal ABM, mortality rates remain high. Even if patients recover from ABM, many suffer from long term disabilities like brain damage, hearing loss, and seizures. The development of antibiotic resistance in pneumococcal strains further highlights the urgency to develop alternative, effective therapies to treat ABM.

In a recent study, Mohanty et al. identified neutrophil extracellular traps (NETs) in human cerebrospinal fluid (CSF) as a potential target for ABM treatment. NETs are secreted by neutrophils as part of the innate immune response to destroy foreign pathogens, and are composed of a dense network of extracellular DNA and antimicrobial proteins like histones and neutrophil elastase. NETs normally prevent the spread of bacterial infection by physically capturing and destroying microbial pathogens that invade the body. However, in the case of ABM, researchers observed that an overload of NETs in the CSF was actually detrimental to the host. Pneumococci have unfortunately developed evasion mechanisms to help them escape killing by NETs. As a result, instead of killing the bacteria, NETs actually spread infection by binding and transporting viable pneumococci throughout the host. To make matters worse, an excess of NETs increases CSF viscosity, exacerbating the severity of the disease by hampering the clearance of bacteria and waste. To combat the problem of excessive NET formation and the inadvertent masking of harmful pneumococcal bacteria, researchers devised a way to degrade NETs. Using a rat model of ABM, researchers found that degrading NET-associated DNA via intravenous administration of DNase I resulted in the clearance of pneumococcal bacteria in the CSF. They attributed this bacterial clearance to the fact that degrading NET-associated extracellular DNA exposed the bacteria to neutrophils in the CSF which eradicated them via phagocytosis and degranulation.

This study demonstrates that DNase can potentially be used to reduce bacterial load in the CSF of patients with ABM. Given that DNase is already used in the clinic to treat cystic fibrosis, there is a possibility that it can also be developed as a new therapeutic to treat ABM.

• Mohanty, T. et al. Neutrophil extracellular traps in the central nervous system hinder bacterial clearance during pneumococcal meningitis. Nat. Commun. 10, 1667 (2019).

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