Bacterial Siderophores Hijack Neutrophil Functions

Abstract

Neutrophils are the primary immune cells that respond to inflammation and combat microbial transgression. In order to thrive, the bacteria residing in their mammalian host have to withstand the anti-bactericidal responses of neutrophils. We report that enterobactin (Ent), a catecholate siderophore expressed by E. coli, inhibited PMA-induced generation of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) in both mouse and human neutrophils. Ent also impaired the degranulation of primary granules, inhibited phagocytosis and bactericidal activity of neutrophils, but without affecting their migration and chemotaxis. Molecular analysis revealed that Ent can chelate intracellular labile iron that is required for neutrophil oxidative responses. Other siderophores (pyoverdine, ferrichrome, deferoxamine) likewise inhibited ROS and NETs in neutrophils, thus indicating that the chelation of iron may largely explain their inhibitory effects. To counter iron theft by Ent, neutrophils rely on the siderophore-binding protein lipocalin 2 (Lcn2) in a ‘tug-of-war’ for iron. The inhibition of neutrophil ROS and NETs by Ent was augmented in Lcn2-deficient neutrophils when compared to WT neutrophils, but rescued by the exogenous addition of recombinant Lcn2. Taken together, our findings illustrate the novel concept that microbial siderophore’s iron scavenging property may serve as an anti-radical defense system, that neutralizes immune functions of neutrophils.

Holo-lipocalin-2–derived siderophores increase mitochondrial ROS and impair oxidative phosphorylation in rat cardiomyocytes

“…In addition to producing ROS, a mammalian host fights infection by up-regulating Lcn2, the major function of which is to prevent invading bacteria from acquiring host iron. To thrive after infecting a host, bacteria secrete various siderophores that capture host iron (37). The apo-Lcn2 protein binds to these siderophores with their captured iron, creating the holo-Lcn2 complex that is associated with bacterial demise.…”

Clinical and Microbiological Prognostic Factors of In-Hospital Mortality Caused by Hypervirulent Klebsiella Pneumoniae Infections: A Retrospective Study in a Tertiary Hospital of Southwestern China

“…siderophores as a secondary metabolite of bacteria, breaks the host restriction on the acquisition of free iron by bacteria [9,24]. In addition to this traditional role, siderophores also play an crucial role in promoting the dissemination of bacteria, defensing against the host's immune function of neutrophils and regulating production of virulence genes [25][26][27]. HvKP secrets 4 kinds of siderophores, which are enterobactin, salmochelin, yersiniabactin and aerobactin.…”

Mecanismos de captação de ferro por sideróforos em <i>Chromobacterium violaceum</i>

“…Considerando (i) a hipótese mencionada acima de que o acúmulo de sideróforos na infeção poderia estar favorecendo o hospedeiro, (ii) um estudo recente mostrando que o sideróforo enterobactina inibe as funções dos neutrófilos como a produção de ROS e a formação de NET (SAHA et al, 2017) e (iii) o importante papel dos neutrófilos na defesa do hospedeiro contra a infecção por C. violaceum (MALTEZ et al, 2015), nós decidimos verificar como estaria a atividade dos neutrófilos (produção de NETs) infectados in vitro com diferentes linhagens mutantes de C. violaceum. A infecção por C. violaceum selvagem induziu robusta liberação de NET pelos neutrófilos, liberação esta um pouco aumentada na infecção com mutantes que não produzem sideróforos (ΔCV_1486/2233::pNPT e ΔCV_1485-84-83-82) e diminuída na infecção com o mutante que não capta sideróforos (ΔCV_2230/1491), ou seja, o acúmulo dos sideróforos na infecção levou a diminuição da atividade de NET, como havia sido descrito para o sideróforo enterobactina (SAHA et al, 2017).…”