Multifaceted effects of Francisella tularensis on human neutrophil function and lifespan

Abstract

Summary Francisella tularensis in an intracellular bacterial pathogen that causes a potentially lethal disease called tularemia. Studies performed nearly 100 years ago revealed that neutrophil accumulation in infected tissues correlates directly with the extent of necrotic damage during F. tularensis infection. However, the dynamics and details of bacteria-neutrophil interactions have only recently been studied in detail. Herein we review current understanding regarding the mechanisms that recruit neutrophils to F. tularensis infected lungs, opsonization and phagocytosis, evasion and inhibition of neutrophil defense mechanisms, as well as the ability of F. tularensis to prolong neutrophil lifespan. In addition, we discuss distinctive features of the bacterium, including its ability to act at a distance to alter overall neutrophil responsiveness to exogenous stimuli, and the evidence which suggests that macrophages and neutrophils play distinct roles in tularemia pathogenesis, such that macrophages are major vehicles for intracellular growth and dissemination whereas neutrophils drive tissue destruction by dysregulation of the inflammatory response.

Bacterial lipoproteins and other factors released byFrancisella tularensismodulate human neutrophil lifespan: Effects of aTLR1SNP on apoptosis inhibition

“…Francisella tularensis is a Gram‐negative, facultative intracellular bacterium and the causative agent of zoonosis tularaemia. Infection can ensue following inhalation of bacteria into the lungs, ingestion of contaminated food or water, direct contact with an infected animal carcass, or inoculation into the skin via the bite of an infected arthropod vector (Kinkead & Allen, ). As few as 10 organisms can result in severe disease with mortality rates up to 60% in untreated infections (Dennis et al, ).…”

“…As few as 10 organisms can result in severe disease with mortality rates up to 60% in untreated infections (Dennis et al, ). F. tularensis subspecies tularensis (Type A) is exclusive to North America, whereas F. tularensis subspecies holarctica (Type B) is found throughout the northern hemisphere (Kinkead & Allen, ). Both Type A and Type B strains of F. tularensis replicate in phagocytes at sites of infection and disseminate to distal organs, including liver, spleen, and lymph nodes, leading to tissue destruction that may progress to sepsis or death, often prior to development of an adaptive immune response (Dennis et al, ; Kinkead & Allen, ).…”

“…F. tularensis utilises a variety of strategies to modulate the innate immune response and its effectors, as exemplified by its ability to elicit severe illness at low inocula. This organism infects several cell types including macrophages and neutrophils, interferes with oxidative host defence mechanisms by disrupting reduced nicotinamide adenine dinucleotide phosphate oxidase assembly and activity, escapes the phagosome to replicate in host cell cytosol, and produces an atypical lipopolysaccharide (LPS) that lacks endotoxic activity yet synergises with capsular polysaccharides for protection against complement‐mediated lysis (J. H. Barker, Weiss, Apicella, & Nauseef, ; Kinkead & Allen, ; Lindemann et al, ; McCaffrey & Allen, ; McLendon, Apicella, & Allen, ; Schulert et al, ). Moreover, we discovered that both Type A and Type B F. tularensis strains modulate the major apoptotic pathways of human neutrophils and significantly extend cell lifespan (McCracken, Kinkead, McCaffrey, & Allen, ; Schwartz et al, , ).…”

Importance of Metabolic Adaptations in Francisella Pathogenesis

“…After engulfment by phagocytic cells, Francisella transiently resides in a phagosomal compartment (Figure 1) that sequentially displays membrane markers of early (EEA1) and late endosomes/lysosomes (LAMP-1 and -2) but does not acquire the hydrolase cathepsin D or lysosomal tracers (Celli and Zahrt, 2013). Within the phagosome, Francisella must fight against several host antimicrobial defenses, including notably reactive oxygen species (ROS) produced by the NADPH oxidase (Kinkead and Allen, 2016). For this, Francisella is equipped with a series of enzymes that include superoxide dismutase, catalase and acid phosphatases (Jones et al, 2012).…”

Neutrophils, from cradle to grave and beyond

“…Kinkead and Allen review studies from the Allen lab that have identified several maneuvers which Francisella employs to thwart neutrophil‐mediated killing and disturb neutrophil cell death pathways. Francisella not only survives within neutrophils but also globally interferes with oxidase activation .…”