NLRP3 inflammasome pathway has a critical role in the host immunity against clinically relevant Acinetobacter baumannii pulmonary infection

Abstract

The opportunistic Gram-negative bacterium Acinetobacter baumannii (AB) is a leading cause of life-threatening nosocomial pneumonia. Outbreaks of multidrug resistant (MDR)-AB belonging to international clones (ICs) I and II with limited treatment options are major global health threats. However, the pathogenesis mechanisms of various AB clonal groups are understudied. Although inflammation-associated interleukin-1β (IL-1β) levels and IL-1 receptor antagonist polymorphisms were previously implicated in MDR-AB-related pneumonia in patients, whether inflammasomes has any role in the host defense and/or pathogenesis of clinically relevant A. baumannii infection is unknown. Using a sublethal mouse pneumonia model, we demonstrate that an extensively drug-resistant clinical isolate (ICII) of A. baumannii exhibits reduced/delayed early pulmonary neutrophil recruitment, higher lung persistence, and, most importantly, elicits enhanced IL-1β/IL-18 production and lung damage through NLRP3 inflammasome, in comparison with A. baumannii-type strain. A. baumannii infection-induced IL-1β/IL-18 production is entirely dependent on NLRP3-ASC-caspase-1/caspase-11 pathway. Using Nlrp3 mice infection models, we further show that while NLRP3 inflammasome pathway contributes to host defense against A. baumannii clinical isolate, it is dispensable for protection against A. baumannii-type strain. Our study reveals a novel differential role for NLRP3 inflammasome pathway in the immunity against clinically relevant A. baumannii infections, and highlights inflammasome pathway as a potential immunomodulatory target.

Biological sex influences susceptibility to Acinetobacter baumannii pneumonia in mice

“…Studies on the innate immune response to A. baumannii-induced pneumonia can display conflicting results based on the virulence of the strain utilized (17,18). We repeated our weight-matched studies (Supplemental Figure 3) with a less virulent strain to assess whether the sex difference was strain specific.…”

Transcriptome Profiling of Lung Innate Immune Responses Potentially Associated With the Pathogenesis of Acinetobacter baumannii Acute Lethal Pneumonia

“…These data are consistent with previous study showing that some inflammatory cytokines, such as TNF-α, IL-1β, IL-6, IL-10, IL-17 and chemokines including CXCL1, CXCL2, CCL2, are significantly elevated in LAC-4-infected mice at 24 h post infection (9). It has been recognized that NLRP3 inflammasome/IL-1β signaling mediate lung pathology in A. baumannii pneumonia model, since NLRP3 and IL-1 receptordeficient mice showed reduced pathology (14,25,26). Consistent with these results, our RNA-seq data also suggest the critical role of inflammasome pathway, including IL-1β, NLRP3, NLRC4, ASC, caspase-1, and caspase-8 ( Table S1).…”

Cytosolic Recognition of Microbes and Pathogens: Inflammasomes in Action

“…Acholeplasma laidlawii NLRP3 (unknown activator) (119), NLRP7 (acylated lipopeptide) (119), NLRP12 (unknown activator) (119) Acinetobacter baumannii NLRP3 (ROS, cathepsin release, K ϩ efflux, P2X7R) (114,347), caspase-11 (LPS) (112,114) Aeromonas hydrophila NLRP3 (aerolysin, hemolysin, multifunctional repeat-in-toxin) (348) Aeromonas trota NLRP3 (aerolysin) (52), NLRC4 (unknown activator) (52) Aeromonas veronii NLRC4 (T3SS) (349), NLRP3 (aerolysin, T3SS) (349) Aggregatibacter actinomycetemcomitans NLRP3 (cytolethal distending toxin) (350) Bordetella pertussis NLRP3 (adenylate cyclase toxin, CyaA) (351), Pyrin (pertussis toxin) (74) Brucella abortus NLRP3 (mitochondrial ROS) (352,353), AIM2 (dsDNA) (352)(353)(354) Burkholderia cenocepacia NLRP3 (T2SS, T4SS, T6SS) (355), mouse Pyrin (T6SS dependent) (72), human Pyrin (T6SS effector TecA) (73,76) Burkholderia pseudomallei NLRC4 (T3SS rod BsaK, flagellin) (123,356), NLRP3 (unknown activator) (356), caspase-11 (LPS) (42) Burkholderia thailandensis NAIP2-NLRC4 (T3SS rod BsaK) (35), human NAIP-NLRC4 (T3SS needle BsaL and rod BsaK) (35,133), caspase-11 (LPS) (42) Campylobacter jejuni NLRP3 (unknown activator) (155) Chlamydia pneumoniae NLRP3 (mitochondrial dysfunction) (357,358) Chlamydia trachomatis NLRP3 (LPS, mitochondrial ROS) (103,359), AIM2 (dsDNA) (103,359) Chlamydia muridarum Caspase-11 (LPS) (103), AIM2 (dsDNA) (103)…”

“…In this case, caspase-11-and gasdermin D-mediated tissue damage and pyroptosis of endothelial cells in response to LPS have been proposed to be responsible for driving the lethality of endotoxemia (18,40,44,95,111). In contrast, caspase-11 provides host protection in vivo in response to infection by Gram-negative bacterial pathogens, including S. Typhimurium, enteropathogenic E. coli, B. thailandensis, B. pseudomallei, Legionella pneumophila, Acinetobacter baumannii, and Klebsiella pneumoniae (42,85,89,(112)(113)(114). The increased susceptibility of mice lacking caspase-11 or gasdermin D to these bacteria can likely be attributed to defective activation of pyroptosis and an increased bacterial burden.…”