Hijacking of the Host's Immune Surveillance Radars by Burkholderia pseudomallei

Abstract

Burkholderia pseudomallei (B. pseudomallei) causes melioidosis, a potentially fatal disease for which no licensed vaccine is available thus far. The host-pathogen interactions in B. pseudomallei infection largely remain the tip of the iceberg. The pathological manifestations are protean ranging from acute to chronic involving one or more visceral organs leading to septic shock, especially in individuals with underlying conditions similar to COVID-19. Pathogenesis is attributed to the intracellular ability of the bacterium to 'step into' the host cell's cytoplasm from the endocytotic vacuole, where it appears to polymerize actin filaments to spread across cells in the closer vicinity. B. pseudomallei effectively evades the host's surveillance armory to remain latent for prolonged duration also causing relapses despite antimicrobial therapy. Therefore, eradication of intracellular B. pseudomallei is highly dependent on robust cellular immune responses. However, it remains ambiguous why certain individuals in endemic areas experience asymptomatic seroconversion, whereas others succumb to sepsis-associated sequelae. Here, we propose key insights on how the host's surveillance radars get commandeered by B. pseudomallei.

Keywords: Burkholderia pseudomallei; immunology; melioidosis; pathogenesis; virulence.

Figure 1

B. pseudomallei is diffused from the external reservoir to respiratory epithelial cells where the initial attachment initiates possibly through capsule and type IV pili. Upon invasion of epithelial cells, the T3SS-3 effectors promote in vacuolar evade and intracellular motility via BimA-mediated actin polymerization. Subsequent to phagocytosis, B. pseudomallei exits the phagosome and enters the host cytoplasm to replicates. This eventually causes the host cell death through initiation of apoptosis. The B. pseudomallei LPS regulates IFN secretion, which down-regulates iNOS expression and NO production. Also, B. pseudomallei influence the regulation of suppressor of cytokine signalling and cytokine-inducible Src homology 2-containing proteins that obstruct the JAK–STAT signalling pathway and iNOS activation.

Figure 2

B. pseudomallei secretes N-acyl-homoserine lactone (AHL) signalling molecules that are implicated in coordinating attacks in contradiction of the host environment and biofilm formation. The T3SS effector proteins are vital for invasion and escape from host endosomal vesicle. Host cell entry is assisted by flagella, lipopolysaccharide (LPS), type IV pili and adhesion molecules. B. pseudomallei evades the vesicle and lyses the endosomal membrane using T3SS, T6SS and T2SS. Production of cationic peptides and ecotins facilitate B. pseudomallei to survive within an acidic endosomal environment. BopA (an effector protein) and BipD (translocator protein) obstruct sequestration in endosomal vesicles and avert microtubule-associated protein mediated autophagy. Upon entry into the cytoplasm compartment, B. pseudomallei replicates, and initiates the development of actin-based membrane protrusions and can pass through constant polymerization of host cell actin, thus accelerating dissemination to neighboring cells causing cell fusion and multinuclear giant cell (MNGC) formation. TLRs positioned on cell surfaces engage with the PAMPs and mediate NF-κB-induced initiation of immune responses, releasing pro-inflammatory cytokines IL-1β and IL-18 and facilitate caspase-1-mediated pyroptosis. Additionally, IL-18 warrants defensive IFNγ production, which allows recruitment of neutrophils, dendritic cells, B cells and T cells to the infection site, eventually activating the complement and coagulation cascades.