Conquering Neutrophils

Neutrophils are the most abundant innate immune cells, making up 50%–70% of all leukocytes. Neutrophils are the “first responders” of host defense, preventing infections by deploying sophisticated antimicrobial strategies acting in concert. As neutrophils are short-living cells, they are continuously produced and released from the bone marrow in abundance (>10 per day). Circulating neutrophils are terminally differentiated, fully equipped with pre-stored antimicrobial molecules [1], and also contribute to shaping adaptive immune responses, as reviewed recently [2]. Neutrophils present challenges and limitations to experimentation, as they are short-lived, non-dividing, and genetically non-modifiable. Furthermore, no adequate cell lines exist that fully recapitulate the cellular and physiological functions of neutrophils, and murine neutrophils differ in number and (re)activity from their human counterparts. On the plus side, neutrophils can be relatively easily and quickly purified in large quantities from the blood of healthy human volunteers. In this article, we discuss the suite of mechanisms employed by neutrophils to clear bacterial infections and the corresponding counterattack mounted by bacterial pathogens. Focusing primarily on the host response, we illustrate how a single human-specific pathogen, Streptococcus pyogenes (group A Streptococcus [GAS]), has developed an impressive range of strategies to thwart neutrophil clearance [3]. This capacity correlates to an estimated 700 million infections and 150,000 deaths annually from GAS disease, a “top 10” cause of infection-related mortality worldwide [4].