Embracing Diversity: Differences in Virulence Mechanisms, Disease Severity, and Host Adaptations Contribute to the Success of Nontyphoidal Salmonella as a Foodborne Pathogen

Abstract

Not all Salmonella enterica serovars cause the same disease. S. enterica represents an incredibly diverse species comprising >2,600 unique serovars. While some S. enterica serovars are host-restricted, others infect a wide range of hosts. The diseases that nontyphoidal Salmonella (NTS) serovars cause vary considerably, with some serovars being significantly more likely to cause invasive disease in humans than others. Furthermore, while genomic analyses have advanced our understanding of the genetic diversity of these serovars, they have not been able to fully account for the observed clinical differences. One overarching challenge is that much of what is known about Salmonella's general biology and virulence strategies is concluded from studies examining a select few serovars, especially serovar Typhimurium. As targeted control strategies have been implemented to control select serovars, an increasing number of foodborne outbreaks involving serovars that are less frequently associated with human clinical illness are being detected. Harnessing what is known about the diversity of NTS serovars represents an important factor in achieving the ultimate goal of reducing salmonellosis-associated morbidity and mortality worldwide. In this review we summarize the current understanding of the differences and similarities among NTS serovars, highlighting the virulence mechanisms, genetic differences, and sources that characterize S. enterica diversity and contribute to its success as a foodborne pathogen.

Keywords: food safety; foodborne pathogen; nontyphoidal Salmonella; serovars; virulence.

FIGURE 1

Phylogeny of Salmonella. Phylogenetic analysis reconstructed from Desai et al. (2013). Subspecies identifiers preceding the subspecies (ssp.) name are shown in parentheses. The number of currently recognized serovars (Issenhuth-Jeanjean et al., 2014) within each species or subspecies is listed in blue.

FIGURE 2

Not all nontyphoidal salmonellosis infections are alike. The morbidity and mortality associated with nontyphoidal salmonellosis exists as an interplay between the host’s immune response as well as the overall fitness of the serovar/strain. Factors listed adjacent to red arrows have been previously established as contributing to increased disease severity, whereas factors listed adjacent to green arrows are associated with a decrease in disease severity.

FIGURE 3

Illustration of NTS O- and H-antigens, comprising the serotyping scheme defined by Kauffman-White-Le Minor. The antigenic formula of a serovar is composed of the subspecies (I -VI), the O-antigen (numbered), and the flagellar antigens called phase 1, phase 2, and phase 3 (if present). Some serovars have lost their phase 1 and/or phase 2 antigen and others have gained additional flagellar antigens (phase 3). The O-antigen illustrated represents the terminal side chain of lipopolysaccharide (LPS) on the cell wall of Gram-negative bacteria, such as Salmonella, which is composed of an inner and outer core of primarily polysaccharides bound to Lipid A; the O side chain is composed of repeating saccharide units, and is the subunit of LPS that differs between serogroups. Salmonella enterica subsp. enterica serovar Heidelberg, the NTS serovar modeled here, is the common name of the serovar having antigenic formula I 1,4,[5],12:r:1,2.

FIGURE 4

Global distribution of the top 5 NTS serovars associated with human clinical disease. Bar charts represent the top 5 NTS (i.e., serovar Typhi was excluded) serovars reported for Argentina (2007) (Hendriksen et al., 2011), Australia (2011) (OzFoodNet Working Group, 2015), Brazil (2007) (Hendriksen et al., 2011), Canada (2007) (Hendriksen et al., 2011), China (2008) (Ran et al., 2011), the European Union (2016) (European Food Safety Authority [EFSA] and European Centre for Disease Prevention, and Control [ECDC], 2017), Senegal (2007) (Hendriksen et al., 2011), Thailand (2004) (Hendriksen et al., 2009), Tunisia (2007) (Hendriksen et al., 2011), and the United States (2016) (Centers for Disease Control and Prevention [CDC], 2016). Only human clinical cases are reported; data were reported from 2004 to 2016.

FIGURE 5

Proposed evolution of NTS virulence plasmids. The ancestral IncFIIA evolved into plasmids pSDV (Dublin) and pSPV (Gallinarum/Pullorum), or fused with replicon IncFIB in the pSTV (Typhimurium) lineage (Rychlik et al., 2006). pSCV (Choleraesuis) and pSEV (Enteritidis) are derived from pSTV (Chu and Chiu, 2006). Colored segments indicate gene clusters. Hatched lines indicate loss of function of the tra locus (Rotger and Casadesús, 1999). Although pSPV encodes tra genes, this plasmid is mobilized via the F-plasmid (Chu and Chiu, 2006). Plasmids and genes are not drawn to scale. This figure is inspired by the theories proposed by Rychlik et al. (2006) and others (Feng et al., 2012).

FIGURE 6

NTS causing overall vs. confirmed outbreak-associated infections in humans. The contribution of select NTS serovars to (A) overall human clinical infections vs. (B) human clinical infections confirmed from a foodborne outbreak are shown as percent infection for a given category. Data are modified from Centers for Disease Control and Prevention [CDC] (2016, .

FIGURE 7

NTS serovar prevalence from reported human clinical cases of salmonellosis and surveillance of different animal food sources. The ten serovars most frequently identified in human disease (colored) are listed in order of their prevalence for each of the indicated sources (United States Department of Agriculture [USDA], 2014, 2017; Centers for Disease Control and Prevention [CDC], 2016; Sonnier et al., 2018). When a serovar represents ≥10% of Salmonella identified from a source other than humans, it is shown in gray under that source.

FIGURE 8

NTS serovars associated with zoonotic infections in the United States from 1999 to 2015. The number of human clinical infections resulting from animal contact is shown according to the source of the infection (Centers for Disease Control and Prevention [CDC], 2001; Wright et al., 2005; Loharikar et al., 2012; Bartholomew et al., 2014; Nakao et al., 2015; Anderson et al., 2016, 2017; Gambino-Shirley et al., 2018).