One species, different diseases: the unique molecular mechanisms that underlie the pathogenesis of typhoidal Salmonella infections

Wang, Benjamin; Butler, Daniel; Hamblin, Meagan; Monack, Denise M.

doi:10.1016/j.mib.2022.102262

Cited by 13 publications

(8 citation statements)

References 111 publications

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“…Typhi and have speculated that the evolution of S. Typhi likely involved both gain of function and loss of function as it evolved to selectively infect humans (8). Although systemic murine infection with S. Typhimurium models human disease, fundamental genetic differences between typhoidal and non-typhoidal Salmonella serovars limits the ability of this model to identify human-specific virulence mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…We next interrogated which T3SS effectors contribute to S. Typhi replication in human macrophages. To this end, we constructed 25 mutant strains that are deficient for previously identified T3SS-effectors and putative pseudogenes in S. Typhi (8). We then tested these mutants for replication defects in human macrophages using our time-lapse florescence dilution assay in 96-well dishes to facilitate higher throughput.…”

Section: S Typhi T3ss-dependent Effectors Contribute To Intramacropha...mentioning

confidence: 99%

“…S. Typhi and S. Typhimurium have differentially evolved to encode distinct virulence factors (6)(7)(8). Researchers have identified many genes essential for S. Typhimurium pathogenesis in mice, some of which are absent, functionally null, or dispensable in S. Typhi pathogenesis studies.…”

Section: Introductionmentioning

confidence: 99%

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Salmonella entericaserovar Typhi uses two type 3 secretion systems to replicate in human macrophages and to colonize humanized mice

Hamblin¹,

Schade²,

Narasimhan³

et al. 2023

Preprint

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Salmonella enterica serovar Typhi (S. Typhi) is a human-restricted pathogen that replicates in macrophages. In this study, we investigated the roles of the S. Typhi Type 3 secretion systems (T3SSs) encoded on Salmonella Pathogenicity Islands (SPI) -1 (T3SS-1) and -2 (T3SS-2) during human macrophage infection. We found that mutants of S. Typhi deficient for both T3SSs were defective for intramacrophage replication as measured by flow cytometry, viable bacterial counts, and live time-lapse microscopy. T3SS-secreted proteins PipB2 and SifA contributed to S. Typhi replication and were translocated into the cytosol of human macrophages through both T3SS-1 and -2, demonstrating functional redundancy for these secretion systems. Importantly, an S. Typhi mutant strain that is deficient for both T3SS-1 and -2 was severely attenuated in the ability to colonize systemic tissues in a humanized mouse model of typhoid fever. Overall, this study establishes a critical role for S. Typhi T3SSs during its replication within human macrophages and during systemic infection of humanized mice.

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Section: Discussionmentioning

confidence: 99%

Section: S Typhi T3ss-dependent Effectors Contribute To Intramacropha...mentioning

confidence: 99%

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Salmonella entericaserovar Typhi uses two type 3 secretion systems to replicate in human macrophages and to colonize humanized mice

Hamblin¹,

Schade²,

Narasimhan³

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Typhi and S . Typhimurium have differentially evolved to encode distinct virulence factors ( 6 - 8 ). Researchers have identified many genes essential for S .…”

Section: Introductionmentioning

confidence: 99%

Salmonella enterica serovar Typhi uses two type 3 secretion systems to replicate in human macrophages and colonize humanized mice

Hamblin

Schade

Narasimhan

et al. 2023

mBio

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Salmonella enterica serovar Typhi ( S . Typhi) is a human-restricted pathogen that replicates in macrophages. In this study, we investigated the roles of the S . Typhi type 3 secretion systems (T3SSs) encoded on Salmonella pathogenicity islands (SPI)-1 (T3SS-1) and SPI-2 (T3SS-2) during human macrophage infection. We found that mutants of S . Typhi deficient for both T3SSs were defective for intramacrophage replication as measured by flow cytometry, viable bacterial counts, and live time-lapse microscopy. T3SS-secreted proteins PipB2 and SifA contributed to S . Typhi replication and were translocated into the cytosol of human macrophages through both T3SS-1 and T3SS-2, demonstrating functional redundancy for these secretion systems. Importantly, an S . Typhi mutant strain that is deficient for both T3SS-1 and T3SS-2 was severely attenuated in the ability to colonize systemic tissues in a humanized mouse model of typhoid fever. Overall, this study establishes a critical role for S . Typhi T3SSs during its replication within human macrophages and during systemic infection of humanized mice. IMPORTANCE Salmonella enterica serovar Typhi is a human-restricted pathogen that causes typhoid fever. Understanding the key virulence mechanisms that facilitate S . Typhi replication in human phagocytes will enable rational vaccine and antibiotic development to limit the spread of this pathogen. While S . Typhimurium replication in murine models has been studied extensively, there is limited information available about S . Typhi replication in human macrophages, some of which directly conflict with findings from S . Typhimurium murine models. This study establishes that both of S . Typhi’s two type 3 secretion systems (T3SS-1 and T3SS-2) contribute to intramacrophage replication and virulence.

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“…Infections by Salmonella represent a considerable burden in both developing and developed countries with more than 110 million cases in humans reported every year 5 , 6 . Depending on serovar/host combinations, Salmonella infections are generally either localized to the gastrointestinal tract, resulting in mild gastroenteritis, or disseminated further to extraintestinal sites, causing severe systemic diseases such as typhoid fever 7 – 9 . Salmonella enterica serovar Typhimurium ( S .…”

Section: Introductionmentioning

confidence: 99%

Nitric oxide is a host cue for Salmonella Typhimurium systemic infection in mice

Jiang

Hou

et al. 2023

Commun Biol

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Nitric oxide (NO) is produced as an innate immune response against microbial infections. Salmonella Typhimurium (S. Typhimurium), the major causative pathogen of human gastroenteritis, induces more severe systemic disease in mice. However, host factors contributing to the difference in species-related virulence are unknown. Here, we report that host NO production promotes S. Typhimurium replication in mouse macrophages at the early infection stage by activating Salmonella pathogenicity island-2 (SPI-2). The NO signaling-induced SPI-2 activation is mediated by Fnr and PhoP/Q two-component system. NO significantly induced fnr transcription, while Fnr directly activated phoP/Q transcription. Mouse infection assays revealed a NO-dependent increase in bacterial burden in systemic organs during the initial days of infection, indicating an early contribution of host NO to virulence. This study reveals a host signaling-mediated virulence activation pathway in S. Typhimurium that contributes significantly to its systemic infection in mice, providing further insights into Salmonella pathogenesis and host–pathogen interaction.

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One species, different diseases: the unique molecular mechanisms that underlie the pathogenesis of typhoidal Salmonella infections

Cited by 13 publications

References 111 publications

Salmonella entericaserovar Typhi uses two type 3 secretion systems to replicate in human macrophages and to colonize humanized mice

Salmonella entericaserovar Typhi uses two type 3 secretion systems to replicate in human macrophages and to colonize humanized mice

Salmonella enterica serovar Typhi uses two type 3 secretion systems to replicate in human macrophages and colonize humanized mice

Nitric oxide is a host cue for Salmonella Typhimurium systemic infection in mice

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