Salmonella enterica serovar Typhi (S. Typhi) and the related serovar S. Paratyphi cause typhoid fever in humans, a devastating disease that results in ~500,000 deaths every year. Although most of the cases occur in developing countries, outbreaks occasionally occur in the United States. Unlike other Salmonella enterica serovars, which can infect a variety of hosts and can cause limited gastroenteritis (e. g. food poisoning), S. Typhi and S. Paratyphi are exclusive human pathogen and causes systemic, often lethal, disease. Despite being one of the earliest recognized pathogens in human history, the pathogenesis of S. Typhi still remains poorly understood. The molecular bases for S. Typhi's remarkable host specificity are also poorly understood. Genome sequence data suggest that a combination of genome degradation and acquisition of unique genetic information may account for S. Typhi's unique biology. One of the very few virulence factors that are unique to typhoidal serovars of S. enterica is Typhoid toxin, which was recently discovered in our laboratory. Typhoid toxin is an atypical AB toxin in that it has two enzymatically active subunits: an ADP ribosyl transferase (PltA) and a deoxyribonuclease (CdtB), which are homologs of the active subunits of pertussis and cytolethal distending toxins, respectively. These two subunits are covalently linked to one another and are associated to a homopentameric B subunit composed of PltB. We have recently discovered that systemic administration of purified typhoid toxin can recapitulate many of the symptoms of typhoid fever in mice. This is a very exciting discovery since it not only links typhoid toxin to the pathogenesis of typhoid fever but also provides concrete bases for the development of novel prevention as well as potentially life-saving therapeutic strategies. Typhoid toxin exhibits a remarkable biology in that it is only produced by intracellularly located bacteria, and after its synthesis and assembly, it is released into the Salmonella-containing vacuole. From this location, the toxin is then packaged into vesicle carriers and exported to the extracellular medium, from where it finds its way into target cells by interacting with specific surface receptors. Our laboratory has recently identified the surface receptors for typhoid toxin, which revealed unique insights into the biology of this toxin. In addition, we have discovered that a Rab32 and BLOC-3-dependent pathogen surveillance mechanism restricts the growth of S. Typhi in mice. We intend to leverage these exciting findings to carry out a series of research objectives that, through the study of typhoid toxin, we hope will deepen our understanding of typhoid fever and the pathogenesis of S. Typhi infection.

Public Health Relevance

Salmonella enterica serovar Typhi (S. Typhi), the cause of typhoid fever in humans, continues to be a very significant health problem. Unlike other Salmonella enterica serovars, which can infect a variety of hosts and can cause food poisoning, S. Typhi is an exclusive human pathogen where it causes typhoid fever, a life- threatening disease. It is estimated that there are ~20,000,000 cases of typhoid fever every year, resulting in 500,000 deaths. Although most of the cases occur in developing countries, outbreaks occasionally occur in the United States. There are no effective vaccines to protect against these infections. The studies proposed in this Grant application may serve as the foundation for novel therapeutic and prevention strategies against typhoid fever.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI114618-01
Application #
8799676
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Alexander, William A
Project Start
2014-09-16
Project End
2019-08-31
Budget Start
2014-09-16
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$505,354
Indirect Cost
$201,838
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Sun, Hui; Kamanova, Jana; Lara-Tejero, Maria et al. (2018) Salmonella stimulates pro-inflammatory signalling through p21-activated kinases bypassing innate immune receptors. Nat Microbiol 3:1122-1130
Fowler, Casey C; Galán, Jorge E (2018) Decoding a Salmonella Typhi Regulatory Network that Controls Typhoid Toxin Expression within Human Cells. Cell Host Microbe 23:65-76.e6
Spanò, Stefania; Galán, Jorge E (2018) Taking control: Hijacking of Rab GTPases by intracellular bacterial pathogens. Small GTPases 9:182-191
Fowler, Casey C; Chang, Shu-Jung; Gao, Xiang et al. (2017) Emerging insights into the biology of typhoid toxin. Curr Opin Microbiol 35:70-77
Hannemann, Sebastian; Galán, Jorge E (2017) Salmonella enterica serovar-specific transcriptional reprogramming of infected cells. PLoS Pathog 13:e1006532
Gao, Xiang; Deng, Lingquan; Stack, Gabrielle et al. (2017) Evolution of host adaptation in the Salmonella typhoid toxin. Nat Microbiol 2:1592-1599
Chang, Shu-Jung; Song, Jeongmin; Galán, Jorge E (2016) Receptor-Mediated Sorting of Typhoid Toxin during Its Export from Salmonella Typhi-Infected Cells. Cell Host Microbe 20:682-689
Galán, Jorge E (2016) Typhoid toxin provides a window into typhoid fever and the biology of Salmonella Typhi. Proc Natl Acad Sci U S A 113:6338-44
Spanò, Stefania; Gao, Xiang; Hannemann, Sebastian et al. (2016) A Bacterial Pathogen Targets a Host Rab-Family GTPase Defense Pathway with a GAP. Cell Host Microbe 19:216-26
Song, Jeongmin; Wilhelm, Cara L; Wangdi, Tamding et al. (2016) Absence of TLR11 in Mice Does Not Confer Susceptibility to Salmonella Typhi. Cell 164:827-8

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