Understanding how Salmonella Typhi infects humans (Bottlenecks)
Research type
Research Study
Full title
Exploring the bottleneck hypothesis of the pathogenesis of bacteraemia in an ambulatory outpatient experimental human experimental infection of Salmonella Typhi
IRAS ID
249093
Contact name
Andrew Pollard
Contact email
Sponsor organisation
Clinical Trials and Research Governance, University of Oxford
Duration of Study in the UK
2 years, 0 months, 0 days
Research summary
Summary of Research
Typhoid fever is an infection caused by the bacteria Salmonella Typhi. It causes illness in approximately 22 million people annually and up to 200,000 deaths, mostly in children. Transmission occurs when faeces from an infected person contaminate food and water. Symptoms of infection include headache, fever and general aches and pains. If not treated properly typhoid infection can lead to severe complications and even death. Sanitation and access to clean water is the best way to reduce typhoid but for the countries that are most affected these measures are hard to put in place. Vaccinating against typhoid has been identified as a cost-effective way of reducing disease.
Vaccines for typhoid are available but they are often less effective in young children who are at the greatest risk. Understanding how the bacteria causes disease is vital to be able to design new vaccines to prevent disease in the most vulnerable.
We aim to understand how Salmonella Typhi causes infection. Salmonella Typhi bacteria must cross from the gut into the bloodstream. We don’t know if only a single bacteria or if lots of bacteria cross into the bloodstream. Once in the bloodstream we know they multiply and cause disease. The idea that only one bacteria crosses the gut lining (rather than many) is known as the ‘bottleneck’ hypothesis.
We will give between 6 and 15 participants a ‘challenge’ with a mixture of two different types of Salmonella Typhi. This means giving the bacteria to participants in a drink. We then monitor them very closely for two weeks and we treat them with antibiotics as soon as they are diagnosed with typhoid disease. If they don’t develop disease they also receive treatment. We expect many participants to develop a bloodstream infection and we will then look to see if it is caused by a combination of the two types of Salmonella Typhi or only one type. If we only see one type this may suggest only one bacteria crossed the gut lining, supporting the idea of the ‘bottleneck’ hypothesis. Understanding this will help in the design of new vaccines in the future.
Summary of Results
This study sought to explore the population dynamics of Salmonella Typhi using a Controlled Human Infection Model (CHIM).
Methods: Participants were enrolled between May 2019 and January 2020. Eleven participants were enrolled and ten were exposed to ('challenged' with) 1-5 x 10^4 colony forming units (CFU) of Salmonella Typhi. The dose all the participants received contained equal proportions of two genetically similar but distinct strains of Salmonella Typhi ('Quailes' and 'SB6000'). Participants were closely monitored after challenge with daily blood BACTEC blood cultures, Ox bile culture-PCR and colony quantification testing.
Results: 50% of participants were diagnosed with typhoid. All diagnosed participants (5/5) had evidence of both the Quailes and SB6000 strain that they were exposed to in their BACTEC blood culture from at least one timepoint though all diagnosed participants had at least one timepoint where a single strain alone was detected. All diagnosed participants had at least one timepoint where a colony was identified on quantification testing. Overall colony counts at diagnosis from four diagnosed participants showed a bacterial burden of 0.5 – 2.65 CFU/ml (one participant had a negative colony count at diagnosis). 60% (3/5) of diagnosed participants had approximately equal proportions of colonies of each strain. One participant had colonies of only a single strain, but culture methods detected both strains. 80% of participants returned at least one positive stool culture, 8/23 (38%) had both strains detected.
Conclusion: This study demonstrated no evidence of a single cell bottleneck using co-infection in a CHIM of Salmonella Typhi.REC name
South Central - Hampshire A Research Ethics Committee
REC reference
19/SC/0024
Date of REC Opinion
18 Jan 2019
REC opinion
Favourable Opinion