Persistent Infection and Long-Term Carriage of Typhoidal and Nontyphoidal Salmonellae

Abstract

The ability of pathogenic bacteria to affect higher organisms and cause disease is one of the most dramatic properties of microorganisms. Some pathogens can establish transient colonization only, but others are capable of infecting their host for many years or even for a lifetime. Long-term infection is called persistence, and this phenotype is fundamental for the biology of important human pathogens, including Helicobacter pylori, Mycobacterium tuberculosis, and Salmonella enterica Both typhoidal and nontyphoidal serovars of the species Salmonella enterica can cause persistent infection in humans; however, as these two Salmonella groups cause clinically distinct diseases, the characteristics of their persistent infections in humans differ significantly. Here, following a general summary of Salmonella pathogenicity, host specificity, epidemiology, and laboratory diagnosis, I review the current knowledge about Salmonella persistence and discuss the relevant epidemiology of persistence (including carrier rate, duration of shedding, and host and pathogen risk factors), the host response to Salmonella persistence, Salmonella genes involved in this lifestyle, as well as genetic and phenotypic changes acquired during prolonged infection within the host. Additionally, I highlight differences between the persistence of typhoidal and nontyphoidal Salmonella strains in humans and summarize the current gaps and limitations in our understanding, diagnosis, and curing of persistent Salmonella infections.

Keywords: Salmonella enterica; bacterial evolution; enteric pathogens; gene regulation; host-pathogen interaction; immunopathogenesis; pathogenicity islands; persistence; virulence.

FIG 1

The evolutionary history and phylogenetic and host specificities of Salmonella. The currently accepted nomenclature divides the bacterial genus Salmonella into two species, S. bongori, which was separated from an E. coli common ancestor about 100 million to 160 million years ago, and S. enterica, which evolved from S. bongori between 40.0 million and 63.4 million years ago. Both speciation events were facilitated by the horizontal acquisitions of Salmonella pathogenicity island 1 (SPI-1) and SPI-2, respectively. The species S. enterica is further classified into 7 subspecies, including Salmonella enterica subsp. enterica (subsp. I), Salmonella enterica subsp. salamae (subsp. II), Salmonella enterica subsp. arizonae (subsp. IIIa), Salmonella enterica subsp. diarizonae (subsp. IIIb), Salmonella enterica subsp. houtenae (subsp. IV), Salmonella enterica subsp. indica (subsp. VI), and Salmonella enterica subsp. VII. S. enterica subsp. I contains 1,586 distinct serovars, many of which are associated with infections of human and warm-blooded animals (shown in red boxes). S. bongori and other S. enterica subspecies are frequently associated with infections of cold-blooded animals (shown in blue boxes). Examples of generalist serovars (S. Typhimurium, S. Enteritidis, and S. Infantis), which are capable of infecting a broad range of hosts, and specialist serovars (S. Typhimurium DT2, S. Gallinarum, S. Dublin, and S. Choleraesuis), which are host specific, are also indicated. Salmonella serovars Typhi, Paratyphi, and Sendai are all human-specific serovars and the causative agents of enteric fever.

FIG 2

The course of Salmonella infection. Disease caused by Salmonella occurs after ingestion of food or beverage contaminated with the bacterium (1). After gaining access to the gut lumen, Salmonella bacteria can cross the apical pole of the epithelial barrier either by a passive mechanism facilitated by dendritic cells that emit pseudopods between epithelial cells (2) or by invasion through the M cells of Payer’s patches in the ileal portion of the small intestine (3). Active crossing of epithelial cells occurs as well and requires the delivery of distinct effector proteins injected directly into host cells using a type III secretion system that is encoded by SPI-1, which also triggers gut inflammation. In immunocompetent individuals, the induced inflammation limits the dissemination of NTS to underlying tissues and systemic sites. However, invasive NTS in immunodeficient patients or typhoidal salmonellae are capable of evading the immune system, enter subepithelial phagocytic cells such as macrophages, and survive within them. Phagocytic cells can then transport Salmonella bacteria via the lymphatic system and disseminate the bacteria systemically (mainly to the liver, spleen, and lymph nodes). Within the intracellular environment, Salmonella bacteria establish a specialized vacuole known as the Salmonella-containing vacuole (SCV), which supports bacterial survival and replication (4 and 5). This stage requires the expression of SPI-2 genes, which encode a second type III secretory system that allows injection of a different set of effectors from the SCV into the host cell cytoplasm. The presence of Salmonella bacteria within the cells may lead to cytokine secretion, triggering inflammation and/or programmed cell death (apoptosis) (6). Salmonella bacteria may also reseed into the gut by basolateral invasion (7 and 8), excretion into the feces, and bacterial shedding. (Originally posted on http://galmor-lab.com/salmonella/.)

FIG 3

Selective media for Salmonella diagnosis. E. coli strain R 27, S. Typhimurium SL1344 (STM), S. Typhi CT18 (STY), and S. Paratyphi A 45157 (SPA) were plated on selective media, including MacConkey agar (catalog number PD-032), Hektoen enteric (HE) agar (catalog number AGR-10407), XLD agar (catalog number PD-104), salmonella-shigella (SS) agar (catalog number PD-046), brilliant green agar (catalog number PD-104), and CHROMagar Salmonella plus (catalog number PD-409). All plates were obtained from Hy Laboratories Ltd. Plates were incubated at 37°C for 18 to 24 h and imaged using a Pentax K5 camera. Note that S. Typhi and S. Paratyphi A do not create black colonies on HE and SS agar due to low-level production (S. Typhi) or no production (S. Paratyphi A) of H₂S.

FIG 4

Host response to persistent Salmonella infection. The host immune response to acute and persistent infection is illustrated by the Th1-to-Th2 ratio (left y axis) and by the levels of the prototypic cytokines secreted in response to the different stages of infection. The bacterial load (shown by the right y axis) increases during acute infection. As a result, a strong Th1 response (secretion of IFN-γ, IL-12, TNF-α, and nitric oxide) is elicited, reducing the bacterial burden toward convalescence. During Salmonella persistence, a reduced Th1 response but an induced Th2 response occurs with the secretion of IL-10, IL-4, IL-5, and IL-13. At the early stage of persistence, due to low activity of effector T cells (shown as blue double circles), a moderate increase in the Salmonella burden occurs. At the second phase of persistence, a robust activation of effector T cells and a reduction in the suppressive potency of FOXP3⁺ Treg cells lead to decreases in the bacterial loads in privileged niches and an equilibrium between the pathogen and the host throughout persistence.