Biofilm Producing Salmonella Typhi: Chronic Colonization and Development of Gallbladder Cancer

Abstract

Salmonella enterica subspecies enterica serovar Typhi is the aetiological agent of typhoid or enteric fever. In a subset of individuals, S. Typhi colonizes the gallbladder causing an asymptomatic chronic infection. Nonetheless, these asymptomatic carriers provide a reservoir for further spreading of the disease. Epidemiological studies performed in regions where S. Typhi is endemic, revealed that the majority of chronically infected carriers also harbour gallstones, which in turn, have been indicated as a primary predisposing factor for the onset of gallbladder cancer (GC). It is now well recognised, that S. Typhi produces a typhoid toxin with a carcinogenic potential, that induces DNA damage and cell cycle alterations in intoxicated cells. In addition, biofilm production by S. Typhi may represent a key factor for the promotion of a persistent infection in the gallbladder, thus sustaining a chronic local inflammatory response and exposing the epithelium to repeated damage caused by carcinogenic toxins. This review aims to highlight the putative connection between the chronic colonization by highly pathogenic strains of S. Typhi capable of combining biofilm and toxin production and the onset of GC. Considering the high risk of GC associated with the asymptomatic carrier status, the rapid identification and profiling of biofilm production by S. Typhi strains would be key for effective therapeutic management and cancer prevention.

Keywords: DNA Damage Response; Salmonella Typhi; biofilm; gallbladder cancer; gallstone; infection; inflammation; skin manifestations; toxin.

Figure 1

Proposed model for the intracellular trafficking of the typhoid toxin. (A) The PltB subunits bind to the host cell surface receptor; (B) Endocytosis of the typhoid toxin; (C) Endosome-mediated delivery of the typhoid toxin to the Golgi complex; (D) Passage of the typhoid toxin through the Golgi complex; (E) Entry of the typhoid toxin into the endoplasmic reticulum (ER) and release of the CdtB component from the holotoxin (F) Entry of the CdtB subunit into the nucleus and induction of DNA damage [46,47,48].

Figure 2

CdtB induced double strand breaks and activation of the ataxia-teleangiectasia mutated (ATM) signalling network. ATM is recruited and fully activated to the site of double-strand break (DSB) by the Mre11-Rad50-Nbs1 (MRN) complex. Adjacent to the site of damage, ATM phosphorylates the histone H2AX (γH2AX) which in turn promotes chromatin remodeling and ATM retention at the site of damage. ATM phosphorylates and activates the downstream effector checkpoint kinases 1 (CHK1) and 2 (CHK2). CHK1 activation induces the accumulation and stabilization of p53 which transcriptionally activates the target gene p21. CHK2 phosphorylates and inhibits the cell division cycle 25 (CDC25), leading to the downstream hyperphosphorylation and inactivation of the cyclin dependent cell division cycle 2 (CDC2) kinase. The checkpoints modulation, mediated by ATM, induces cell cycle arrest either in the G1 or G2 phases of the cell cycle to allow the DNA damage repair, alternatively, when the damage cannot be repaired, this response drives the cell to apoptosis or cellular senescence. The ATM signaling in the cytosol activates the Ras homolog gene family, member A (RhoA). This process results in the activation of the RhoA/Rho-associated, coiled-coil containing protein kinase 1 (ROCK) axis which modulates the organization of the actin cytoskeleton, and in the activation of the p38-mediated cell survival pathway.

Figure 3

Possible role of biofilm-producing S. Typhi in gallbladder cancer development. (A) Chronic infection with S. Typhi strains and the presence of gallstones strongly correlates with gallbladder cancer (GC) development; The presence of gallstones (B) may provide the ideal substrate for S. Typhi strains with an increased biofilm forming ability; (C) Once the biofilm is established bacterial cells can detach from the gallstones releasing carcinogenic molecules that induce genomic instability and chronic inflammation which represent key prerequisites for the onset of GC.