Feverlike Temperature is a Virulence Regulatory Cue Controlling the Motility and Host Cell Entry of Typhoidal Salmonella

Elhadad, Dana; McClelland, Michael; Rahav, Galia; Gal-Mor, Ohad

doi:10.1093/infdis/jiu663

Cited by 24 publications

(32 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, we showed that typhoidal serovars, but not S. Typhimurium, respond to fever-like temperature (39 to 42°C) by decreasing their motility and host cell invasion compared to 37°C. We also showed that this phenotype is mediated at the transcriptional level (55). Taken together, our observations reveal novel differences in the regulatory pathways controlling motility and invasion between typhoidal and NTS serovars.…”

Section: Resultssupporting

confidence: 57%

Flagellin Is Required for Host Cell Invasion and Normal Salmonella Pathogenicity Island 1 Expression by Salmonella enterica Serovar Paratyphi A

et al. 2015

Self Cite

View full text Add to dashboard Cite

Salmonella enterica serovar Paratyphi A is a human-specific serovar that, together with Salmonella enterica serovar Typhi and Salmonella enterica serovar Sendai, causes enteric fever. Unlike the nontyphoidal Salmonella enterica serovar Typhimurium, the genomes of S. Typhi and S. Paratyphi A are characterized by inactivation of multiple genes, including in the flagellum-chemotaxis pathway. Here, we explored the motility phenotype of S. Paratyphi A and the role of flagellin in key virulence-associated phenotypes. Motility studies established that the human-adapted typhoidal S. Typhi, S. Paratyphi A, and S. Sendai are all noticeably less motile than S. Typhimurium, and comparative transcriptome sequencing (RNA-Seq) showed that in S. Paratyphi A, the entire motility-chemotaxis regulon is expressed at significantly lowers levels than in S. Typhimurium. Nevertheless, S. Paratyphi A, like S. Typhimurium, requires a functional flagellum for epithelial cell invasion and macrophage uptake, probably in a motility-independent mechanism. In contrast, flagella were found to be dispensable for host cell adhesion. Moreover, we demonstrate that in S. Paratyphi A, but not in S. Typhimurium, the lack of flagellin results in increased transcription of the flagellar and the Salmonella pathogenicity island 1 (SPI-1) regulons in a FliZ-dependent manner and in oversecretion of SPI-1 effectors via type three secretion system 1. Collectively, these results suggest a novel regulatory linkage between flagellin and SPI-1 in S. Paratyphi A that does not occur in S. Typhimurium and demonstrate curious distinctions in motility and the expression of the flagellumchemotaxis regulon between these clinically relevant pathogens. Salmonella enterica is one of the most prevalent human and animal pathogens, consisting of more than 2,500 serovars. Some Salmonella serovars, such as Salmonella enterica serovar Typhimurium, are ubiquitous pathogens that can infect a broad range of animal and human hosts. In contrast, other Salmonella serovars are host restricted and highly adapted in their pathogenesis. Salmonella enterica serovar Typhi, Salmonella enterica serovar Paratyphi A, and Salmonella enterica serovar Sendai are humanrestricted serovars and the causative agents of enteric fever (1, 2). This is an invasive, life-threatening systemic disease with a global annual estimation of over 25 million cases, resulting in more than 200,000 deaths (3). In recent years, the occurrence of infection with S. Paratyphi A has been rising, and in some regions of the world (particularly in eastern and southern Asia), it is accountable for up to 50% of all enteric fever cases (4, 5). Increasing rates of infection, the lack of a commercially available vaccine, and steadily increasing resistance of S. Paratyphi A isolates to antimicrobial agents make S. Paratyphi A infections a significant public health concern.Bacterial invasion of nonphagocytic cells is one of the hallmarks of S. enterica and is pivotal for its pathogenicity. Active invasion by Salmonella of eukaryotic ...

show abstract

Section: Resultssupporting

confidence: 57%

Flagellin Is Required for Host Cell Invasion and Normal Salmonella Pathogenicity Island 1 Expression by Salmonella enterica Serovar Paratyphi A

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…Moreover, we previously demonstrated that S. Paratyphi A, but not S. Typhimurium, invasion into epithelial cells responds to temperature stimuli and is impaired at elevated physiological temperatures equivalent to fever (39 to 42°C). Under these fever-like conditions, the impaired invasion also was shown to be associated with the downregulation of the T3SS-1 genes and classes II and III of the flagellum chemotaxis regulon (47). Collectively, these results demonstrate significantly lower expression of flagellar and T3SS-1 genes, which can serve as PAMPs, in S. Paratyphi A than in S. Typhimurium, and that their invasion and motility programs respond differently to certain environmental or physiological cues.…”

Section: Discussionmentioning

confidence: 77%

Differences in Host Cell Invasion and Salmonella Pathogenicity Island 1 Expression between Salmonella enterica Serovar Paratyphi A and Nontyphoidal S . Typhimurium

et al. 2016

Self Cite

View full text Add to dashboard Cite

Active invasion into nonphagocytic host cells is central to Salmonella enterica pathogenicity and dependent on multiple genes within Salmonella pathogenicity island 1 (SPI-1). Here, we explored the invasion phenotype and the expression of SPI-1 in the typhoidal serovar S. Paratyphi A compared to that of the nontyphoidal serovar S. Typhimurium. We demonstrate that while S. Typhimurium is equally invasive under both aerobic and microaerobic conditions, S. Paratyphi A invades only following growth under microaerobic conditions. Transcriptome sequencing (RNA-Seq), reverse transcription-PCR (RT-PCR), Western blot, and secretome analyses established that S. Paratyphi A expresses much lower levels of SPI-1 genes and secretes lesser amounts of SPI-1 effector proteins than S. Typhimurium, especially under aerobic growth. Bypassing the native SPI-1 regulation by inducible expression of the SPI-1 activator, HilA, considerably elevated SPI-1 gene expression, host cell invasion, disruption of epithelial integrity, and induction of proinflammatory cytokine secretion by S. Paratyphi A but not by S. Typhimurium, suggesting that SPI-1 expression is naturally downregulated in S. Paratyphi A. Using streptomycin-treated mice, we were able to establish substantial intestinal colonization by S. Paratyphi A and showed moderately higher pathology and intestinal inflammation in mice infected with S. Paratyphi A overexpressing hilA. Collectively, our results reveal unexpected differences in SPI-1 expression between S. Paratyphi A and S. Typhimurium, indicate that S. Paratyphi A host cell invasion is suppressed under aerobic conditions, and suggest that lower invasion in aerobic sites and suppressed expression of immunogenic SPI-1 components contributes to the restrained inflammatory infection elicited by S. Paratyphi A. Salmonella enterica is a highly diverse and ubiquitous pathogen containing more than 2,600 different serovars classified by their antigenic presentation (1). Salmonella serovars differ by their host specificity and by the clinical syndromes they cause, ranging from asymptomatic carriage to invasive systemic disease. While many nontyphoidal Salmonella (NTS) serovars, such as Typhimurium and Enteritidis, are generalist pathogens with broad host specificity, a few S. enterica serovars, including Typhi, Sendai, and Paratyphi A, are highly adapted to humans. These specialist pathogens, collectively referred to as typhoidal Salmonella serovars, are the causative agents of enteric fever, posing an estimated global annual burden of over 27 million cases, resulting in more than 200,000 deaths (2). While NTS cause inflammatory gastroenteritis that is confined to the terminal ileum and colon in immunocompetent patients, typhoidal serovars do not induce a strong inflammatory response during the initial invasion of the intestinal mucosa (3-5). This noninflammatory phase associated with typhoidal infections is thought to facilitate its dissemination to systemic sites (6).Regardless of the clinical manifestation, both typhoidal and NTS ...

show abstract

“…In addition, the infectivity of Yersinia pestis (formerly Pasteurella pestis) decreases 100-fold when cultivated at temperatures below the host body temperature (45). More recently, Elhadad et al demonstrated that Salmonella bacteria causing typhoid fever alter gene regulation and invasion in response to temperatures consistent with a febrile response (46). After ϳ6 days posthatch, the body temperature of chickens stabilized near 42°C (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Although our data support the idea of a reduced ability of these two serovars to reach the livers and spleens of chicks, a thorough screening performed with additional isolates from these serovars may reveal more-invasive phenotypes. Recent work shows that S. Typhimurium isolates exhibit broad ranges of invasive phenotypes (46).…”

Section: Discussionmentioning

confidence: 99%

Poultry Body Temperature Contributes to Invasion Control through Reduced Expression of Salmonella Pathogenicity Island 1 Genes in Salmonella enterica Serovars Typhimurium and Enteritidis

Troxell

Petri

Daron

et al. 2015

Appl Environ Microbiol

View full text Add to dashboard Cite

b Salmonella enterica serovars Typhimurium (S. Typhimurium) and Enteritidis (S. Enteritidis) are foodborne pathogens, and outbreaks are often associated with poultry products. Chickens are typically asymptomatic when colonized by these serovars; however, the factors contributing to this observation are uncharacterized. Whereas symptomatic mammals have a body temperature between 37°C and 39°C, chickens have a body temperature of 41°C to 42°C. Here, in vivo experiments using chicks demonstrated that numbers of viable S. Typhimurium or S. Enteritidis bacteria within the liver and spleen organ sites were >4 orders of magnitude lower than those within the ceca. When similar doses of S. Typhimurium or S. Enteritidis were given to C3H/HeN mice, the ratio of the intestinal concentration to the liver/spleen concentration was 1:1. In the avian host, this suggested poor survival within these tissues or a reduced capacity to traverse the host epithelial layer and reach liver/spleen sites or both. Salmonella pathogenicity island 1 (SPI-1) promotes localization to liver/spleen tissues through invasion of the epithelial cell layer. Following in vitro growth at 42°C, SPI-1 genes sipC, invF, and hilA and the SPI-1 rtsA activator were downregulated compared to expression at 37°C. Overexpression of the hilA activators fur, fliZ, and hilD was capable of inducing hilA-lacZ at 37°C but not at 42°C despite the presence of similar levels of protein at the two temperatures. In contrast, overexpression of either hilC or rtsA was capable of inducing hilA and sipC at 42°C. These data indicate that physiological parameters of the poultry host, such as body temperature, have a role in modulating expression of virulence. Salmonella enterica serovars Typhimurium (S. Typhimurium) and Enteritidis (S. Enteritidis) are major causes of foodborne diseases worldwide. In the United States, S. Typhimurium and S. Enteritidis accounted for the majority of confirmed cases of Salmonella outbreaks between 1970 and 2011 (1). These two are nontyphoid Salmonella (NTS) serovars that are capable of causing disease signs in a variety of animals, which contrasts with typhoid fever serovars that exclusively infect humans. Numerous food products have been associated with Salmonella outbreaks and illnesses in humans; however, poultry products are frequently implicated in outbreaks associated with NTS (www.cdc.gov /Salmonella/outbreaks.html). In 2010, a major poultry-related outbreak occurred that involved S. Enteritidis infections across 11 states and resulted in the recall of 380 million eggs (2).S. Typhimurium invades the host epithelial cell layer and migrates to liver and spleen tissue sites through the action of a type 3 secretion system (T3SS), encoded by Salmonella pathogenicity island 1 (SPI-1). SPI-1 is a DNA segment that is approximately 40 kb in size and encodes the structural components of the secretion system, secreted and chaperone proteins, and transcription factors that activate expression of the SPI-1 genes (3-5). Three regulators that are carried wi...

show abstract

Feverlike Temperature is a Virulence Regulatory Cue Controlling the Motility and Host Cell Entry of Typhoidal Salmonella

Cited by 24 publications

References 26 publications

Flagellin Is Required for Host Cell Invasion and Normal Salmonella Pathogenicity Island 1 Expression by Salmonella enterica Serovar Paratyphi A

Flagellin Is Required for Host Cell Invasion and Normal Salmonella Pathogenicity Island 1 Expression by Salmonella enterica Serovar Paratyphi A

Differences in Host Cell Invasion and Salmonella Pathogenicity Island 1 Expression between Salmonella enterica Serovar Paratyphi A and Nontyphoidal S . Typhimurium

Poultry Body Temperature Contributes to Invasion Control through Reduced Expression of Salmonella Pathogenicity Island 1 Genes in Salmonella enterica Serovars Typhimurium and Enteritidis

Contact Info

Product

Resources

About