Bacteria-induced phagocyte secondary necrosis as a pathogenicity mechanism

Abstract

Triggering of phagocyte apoptosis is a major virulence mechanism used by some successful bacterial pathogens. A central issue in the apoptotic death context is that fully developed apoptosis results in necrotic cell autolysis (secondary necrosis) with release of harmful cell components. In multicellular animals, this occurs when apoptosing cells are not removed by scavengers, mainly macrophages. Secondary necrotic lysis of neutrophils and macrophages may occur in infection when extensive phagocyte apoptosis is induced by bacterial cytotoxins and removal of apoptosing phagocytes is defective because the apoptotic process exceeds the available scavenging capacity or targets macrophages directly. Induction of phagocyte secondary necrosis is an important pathogenic mechanism, as it combines the pathogen evasion from phagocyte antimicrobial activities and the release of highly cytotoxic molecules, particularly of neutrophil origin, such as neutrophil elastase. This pathogenicity mechanism therefore promotes the unrestricted multiplication of the pathogen and contributes directly to the pathology of several necrotizing infections, where extensive apoptosis and necrosis of macrophages and neutrophils are present. Here, examples of necrotizing infectious diseases, where phagocyte secondary necrosis is implicated, are reviewed.

Host Responses to Group A Streptococcus: Cell Death and Inflammation

“…Macrophages are principally responsible for the clearance of apoptotic PMNs, and either apoptotic or necrotic depletion of macrophages may exacerbate damage resulting from GAS-induced PMN cell death [52]. Apoptotic PMNs not phagocytosed by macrophages proceed to secondary necrosis and elicitation of inflammatory responses [53]. These data support an emerging theme in bacterial pathogenesis [43], and we propose manipulation of phagocyte cell death responses has inflammatory implications for GAS disease.…”

Francisella tularensis Inhibits the Intrinsic and Extrinsic Pathways To Delay Constitutive Apoptosis and Prolong Human Neutrophil Lifespan

“…As PMN apoptosis is essential to limit tissue injury, particularly in the lung (61), and we demonstrate here that F. tularensis profoundly inhibits this process, our findings support a model in which neutrophils play a prominent role in dysregulation of the inflammatory response during tularemia. The effects of delayed PMN apoptosis can be exacerbated by defects in corpse removal by macrophages, which increases the probability that dying neutrophils will progress to secondary necrosis with spilling of toxic cell contents and alarmins that amplify inflammation and tissue damage (6–8, 60, 62). During tularemia, efferocytosis is directly undermined by intramacrophage bacteria (63), and may be compromised further by local macrophage depletion (64).…”

Neutrophil migration in infection and wound repair: going forward in reverse

“…Neutrophil swarms have been observed after infection with multiple types of pathogen, including bacteria 64 and protozoa 65 . Neutrophil infiltration in response to early recruited neutrophil cell death 54 is likely to be even more pronounced in infections, as many pathogens can cause necrosis of host cells 66 . Neutrophil recruitment can also be altered by pathogens that carry virulence factors that directly interfere with or promote neutrophil recruitment 67–69 .…”