Salmonella enterica ssp. enterica serovar Typhi (S. Typhi) caused an estimated 10 million typhoid cases and 117,000 deaths in 2017 (Global Burden of Disease 2017). S. Typhi strains that are resistant to multiple antibiotics have emerged (Klemm et al. 2018) and are stretching health systems in multiple low- and middle-income settings (Andrews et al. 2018). Humans are believed to be the only natural host of S. Typhi (Wain et al. 2002). Infections result when contaminated food or water is consumed, and transmission by the fecal-oral route requires the organism to survive in the environment in between human infections. This has implications for the interventions necessary to eliminate typhoid as a public health problem—if environmental niches exist that sustain the survival and promote transmission of S. Typhi, improvements in water and sanitation and accessible vaccines are likely both necessary to halt transmission and eliminate disease. Additionally, we know little about the selection pressures on S. Typhi in the environment, and it is possible that exposure to antibiotics, both in the clinic and in the environment, is driving the development of antibiotic resistant S. Typhi strains. Though typhoid has been eliminated from various geographies, it is unclear if the low-income settings where typhoid persists today harbor environmental niches conducive to longer-term survival of the typhoid bacterium.
Evidence suggests that S. Typhi survival in the environment is enhanced in the presence of protozoans such as Acanthamoeba castellani (Frédéri Douesnard-Malo and Daigle 2011). Salmonella Typhimurium survives within Acanthamoeba polyphaga; whereas this survival is dependent on genes in the Salmonella Pathogenicity Island 2 (which have been shown to be necessary for virulence and invasion of macrophages), we might ask if the original function of these genes was to enhance environmental survival (Bleasdale et al. 2009). S. Dublin also exists within an amoeba, Acanthamoeba rhysodes (Tezcan-Merdol et al. 2004), and whether S. Typhi similarly can survive within a protozoan or other aquatic species is unknown. Shellfish have been shown to be a source of S. Typhi infection among humans, but the duration of S. Typhi survival in shellfish, especially in warm, tropical waters, is unknown (Jordan 1925). Other niches may exist in the soil and in water. S. Typhi DNA has been detected in drinking water from Kathmandu, Nepal, and in Dhaka, Bangladesh, but whether this represents a viable, pathogenic organism remains unknown (Karkey et al. 2016; Saha et al. 2019). In this grand challenge, we are interested in learning if environmental niches exist in which S. Typhi can survive, and whether (and how much) such niches contribute to transmission of disease in humans.
Additionally, these environmental niches may play a role in the development of antibiotic resistance in pathogens (Forsberg et al. 2012). We are interested in understanding whether S. Typhi survival in the environment is impacted by antibiotics and their residuals, and whether environmental exposure to antibiotics impacts the development of antibiotic resistance and the transmissibility of S. Typhi.
In this new grand challenge, we solicit proposals to examine the environmental niches of S. Typhi. We are interested in understanding:
- Survival of S. Typhi in the context of the soil and water microbiomes. S. Typhi survives for 3 weeks in the presence of A. castellani, but for no more than 10 days by itself (Frédéric Douesnard-Malo and Daigle 2011). Do interactions with other organisms impact survival of S. Typhi? How do they impact transmissibility of the bacterium?
- Survival of S. Typhi within other organisms. Similar to V. cholerae, which thrives within zooplankton (Lipp, Huq, and Colwell 2002), does S. Typhi interact with aquatic multicellular organisms? If yes, how does this impact the transmission and epidemiology of typhoid?
- Impact of environmental niches on the development of antibiotic resistance in S. Typhi. What is the relative amount of time S. Typhi spends in the environment compared to in infected individuals? How does this impact its exposure to antibiotics, and the development of antibiotic resistance in S. Typhi strains?
What we are interested in funding:
- Studies of S. Typhi in the context of soil and water microbiomes, with clear implications for survival, virulence, or antibiotic resistance.
- Examining survival of S. Typhi within or in the presence of free-living protozoans
- Examining the role of the environment (soil, water, residual antibiotics) in the development of AMR in S. Typhi
- Transcriptome analysis and mutagenesis of S. Typhi to identify genes associated with particular environmental niches.
In all cases, the relevance of findings to the epidemiology of typhoid must be clear.
What we will not fund:
- Studies of only other Salmonella enterica serovars, without a focus on S. Typhi
- Clinical studies of typhoid with no environmental focus
- Solely lab-based mutagenesis studies of S. Typhi with no data to link findings to environmental samples or typhoid epidemiology
Andrews, Jason R., Farah N. Qamar, Richelle C. Charles, and Edward T. Ryan. 2018. "Extensively Drug-Resistant Typhoid — Are Conjugate Vaccines Arriving Just in Time?" New England Journal of Medicine 379 (16): 1493–95. https://doi.org/10.1056/NEJMp1803926.
Bleasdale, Benjamin, Penelope J Lott, Aparna Jagannathan, Mark P Stevens, Richard J Birtles, and Paul Wigley. 2009. "The Salmonella Pathogenicity Island 2-Encoded Type III Secretion System Is Essential for the Survival of Salmonella Enterica Serovar Typhimurium in Free-Living Amoebae." Applied and Environmental Microbiology 75 (6): 1793–95. https://doi.org/10.1128/AEM.02033-08.
Douesnard-Malo, Frédéri, and France Daigle. 2011. "Increased Persistence of Salmonella Enterica Serovar Typhi in the Presence of Acanthamoeba Castellanii." Applied and Environmental Microbiology 77 (21): 7640–46. https://doi.org/10.1128/AEM.00699-11.
Douesnard-Malo, Frédéric, and France Daigle. 2011. "Increased Persistence of Salmonella Enterica Serovar Typhi in the Presence of Acanthamoeba Castellanii." Applied and Environmental Microbiology 77 (21): 7640–46. https://doi.org/10.1128/AEM.00699-11.
Forsberg, Kevin J., Alejandro Reyes, Bin Wang, Elizabeth M. Selleck, Morten O.A. Sommer, and Gautam Dantas. 2012. "The Shared Antibiotic Resistome of Soil Bacteria and Human Pathogens." Science 337 (6098): 1107–11. https://doi.org/10.1126/science.1220761.
Global Burden of Disease. 2017. "GBD Results Tool | GHDx". http://ghdx.healthdata.org/gbd-results-tool.
Jordan, Edwin O. 1925. "THE VIABILITY OF TYPHOID BACILLI IN SHELL OYSTERS." JAMA: The Journal of the American Medical Association 84 (19): 1402. https://doi.org/10.1001/jama.1925.02660450010006.
Karkey, Abhilasha, Thibaut Jombart, Alan W. Walker, Corinne N. Thompson, Andres Torres, Sabina Dongol, Nga Tran Vu Thieu, et al. 2016. "The Ecological Dynamics of Fecal Contamination and Salmonella Typhi and Salmonella Paratyphi A in Municipal Kathmandu Drinking Water." PLoS Neglected Tropical Diseases 10 (1): 1–18. https://doi.org/10.1371/journal.pntd.0004346.
Klemm, Elizabeth J, Sadia Shakoor, Andrew J Page, Farah Naz Qamar, Kim Judge, Dania K Saeed, Vanessa K Wong, et al. 2018. "Emergence of an Extensively Drug-Resistant Salmonella Enterica Serovar Typhi Clone Harboring a Promiscuous Plasmid Encoding Resistance to Fluoroquinolones and Third-Generation Cephalosporins" https://mbio.asm.org/content/9/1/e00105-18.
Lipp, Erin K, Anwar Huq, and Rita R Colwell. 2002. "Effects of Global Climate on Infectious Disease: The Cholera Model." Clinical Microbiology Reviews 15 (4): 757–70. https://doi.org/10.1128/CMR.15.4.757-770.2002.
Saha, Senjuti, Arif M. Tanmoy, Jason R. Andrews, Mohammad S. I. Sajib, Alexander T. Yu, Stephen Baker, Stephen P. Luby, and Samir K. Saha. 2019. "Evaluating PCR-Based Detection of Salmonella Typhi and Paratyphi A in the Environment as an Enteric Fever Surveillance Tool." The American Journal of Tropical Medicine and Hygiene 100 (1): 43–46. https://doi.org/10.4269/ajtmh.18-0428.
Tezcan-Merdol, Dilek, Marianne Ljungström, Jadwiga Winiecka-Krusnell, Ewert Linder, Lars Engstrand, and Mikael Rhen. 2004. "Uptake and Replication of Salmonella Enterica in Acanthamoeba Rhysodes." Applied and Environmental Microbiology 70 (6): 3706–14. https://doi.org/10.1128/AEM.70.6.3706-3714.2004.
Wain, John, Deborah House, Julian Parkhill, Christopher Parry, and Gordon Dougan. 2002. "Unlocking the Genome of the Human Typhoid Bacillus." The Lancet. Infectious Diseases 2 (3): 163–70. https://doi.org/10.1016/S1473-3099(02)00225-6.