Genetic and functional investigations of the pathogenesis of African salmonella typhimurium isolates that cause systemic disease
Abstract/Contents
- Abstract
- Salmonella enterica serovars can cause a range of disease in human hosts. The human-adapted Salmonella enterica serovar Typhi causes enteric (typhoid) fever by entering through the gastrointestinal tract to invade systemic sites such as the blood, liver, spleen, and bone marrow. In contrast, non-typhoidal serovars of Salmonella enterica are primarily confined to gut tissues in otherwise healthy humans. Across Africa, outbreaks of systemic bloodstream infections with Salmonella have caused increased morbidity and mortality. These cases of disease are notably caused by isolates belonging to non-typhoidal Salmonella serovars Enteritidis, Choleraesuis, and Typhimurium. Such invasive non-typhoidal Salmonella (iNTS) infections appear to be associated with age (the very young and elderly) and co-morbidities like malaria, HIV, or malnutrition. Salmonella enterica serovar Typhimurium (S. Typhimurium) is a major contributor to iNTS disease burden in sub-Saharan Africa. The outbreaks of iNTS disease due to S. Typhimurium serovars are clonally-related and many of these isolates classify as sequence-type 313 (ST313). To understand this evolution in pathogenesis of S. Typhimurium iNTS, we compared the genomes of African S. Typhimurium ST313 isolates with other S. Typhimurium from sequence-types that have mainly caused outbreaks of gastrointestinal disease. This comparative genomic analysis revealed several macA and macB gene variants unique to African isolates of iNTS. MacAB forms a tripartite efflux pump with TolC and has been shown in mouse infection models to be important for S. Typhimurium pathogenesis. We show that macAB transcription is upregulated during macrophage infection and after antimicrobial peptide exposure, with macAB transcription being supported by the PhoP/Q two-component system. Constitutive expression of macAB improves survival of Salmonella in the presence of the antimicrobial peptide C18G. Furthermore, African S. Typhimurium ST313 macAB variants affect replication in macrophages and influence fitness during colonization of the murine gastrointestinal tract. Importantly, the infection outcome resulting from these S. Typhimurium ST313 macAB variants depends upon both the S. Typhimurium genetic background and the host gene Nramp1, an important determinant of innate resistance to intracellular bacterial infection. Our studies provide additional mechanistic insights into the functional role of the MacAB-TolC efflux pump for Salmonella pathogenesis. Furthermore, the variations we have identified in the MacAB-TolC efflux pump in African S. Typhimurium ST313 may be an example of convergent evolution toward loss of MacAB function that reflects adaptation to particular human host populations with compromised ability to control intracellular bacterial infections. This dissertation furthers our knowledge about this important group of Salmonella that remain a substantial disease burden in Africa
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2020; ©2020 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Honeycutt, Jared David |
|---|---|
| Degree supervisor | Monack, Denise M |
| Thesis advisor | Monack, Denise M |
| Thesis advisor | Bhatt, Ami (Ami Siddharth) |
| Thesis advisor | Chien, Yueh-Hsiu |
| Thesis advisor | Sonnenburg, Justin, 1973- |
| Degree committee member | Bhatt, Ami (Ami Siddharth) |
| Degree committee member | Chien, Yueh-Hsiu |
| Degree committee member | Sonnenburg, Justin, 1973- |
| Associated with | Stanford University, Program in Immunology. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Jared David Honeycutt |
|---|---|
| Note | Submitted to the Program in Immunology |
| Thesis | Thesis Ph.D. Stanford University 2020 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Jared David Honeycutt
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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