Understanding How Salmonella Typhi Infects Humans (Bottlenecks)
Condition: Salmonella Typhi Infection
MeSH terms: Infections; Communicable Diseases; Typhoid Fever
Study type: Interventional

Summary: 
      Typhoid fever is an infection caused by the bacteria Salmonella Typhi (S. Typhi). S. Typhi
      causes disease principally in developing countries where communities do not have access to
      safe water or adequate sanitation. It is thought to cause illness in approximately 22 million
      people every year and up to 200,000 deaths, mostly in children. The bacteria are spread when
      faeces from infected individuals contaminate food and water sources. 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.

      In this study the investigators aim to understand more about the S. Typhi bacteria and how S.
      Typhi causes a bloodstream infection after it has been ingested and passed into the gut. In
      spite of the extensive morbidity and mortality associated with bacterial blood stream
      infections (BSI), comparatively little is known about the pathogenesis. At a time of
      increasing antimicrobial resistance and a lack of new antimicrobial agents, understanding the
      pathogenesis of BSI is essential for efforts directed at prevention both of Salmonella Typhi
      and other bacterial species, particularly those that are restricted to humans.
    

Detailed description: 
      The pathogenesis of bacteraemia for human restricted pathogens such as Streptococcus
      pneumoniae, Haemophilus influenzae type b and Salmonella enterica serovar Typhi (ST), have
      thus far only been investigated in imperfect animal models. The Salmonella Typhimurium mouse
      model is widely employed however there are key differences compared with S. Typhi. These
      bacteria are both genetically distinct and cause a different human disease phenotype . Data
      from a human model would be invaluable in furthering our understanding of bacteraemia in the
      human host. Animal studies with Salmonella species and other bacterial species show some
      evidence that there may be population bottlenecks in the development of blood stream
      infections.

      Inoculation with many microorganisms is often sufficient to cause a blood stream infection in
      a susceptible host, typically inoculation with a single microorganism is not. There are two
      principle theories as to how bacteraemia arises. The first is independent action whereby the
      bacteraemia that results from bacterial inoculation is derived from a single founder organism
      ('the bottleneck hypothesis'). Each organism has a chance of being that founder organism. A
      greater number of organisms make bacteraemia more likely. The second theory is synergy where
      there is cooperation between bacteria, multiple bacteria traverse the barrier to infection
      and therefore the bacteraemia is composed of multiple variants.

      The aim of this research project is to investigate the population bottleneck theory in the
      pathogenesis of bacteraemia in human infection model using a challenge combination of two
      isogenic strains of S. Typhi.

      The primary objective of the study is to compare the number of participants who develop
      bacteraemia post challenge from each S. Typhi variant or a combination of the two strains.
      From animal models the investigators hypothesize that in an individual participant a single
      strain will be isolated more commonly than a combination of the two. The secondary objectives
      are to quantify the burden of bacteraemia of the two strains and to characterise the stool
      shedding in participants given a mixed inoculum.

      Exploratory objectives include comparison of the number of participants who develop
      bacteraemia at various timepoints until 72 hours from each S. Typhi variant or a combination
      of the two strains. From animal models it is expected that any so-called 'primary
      bacteraemias' may involve a combination of the S. Typhi strains. The researchers also
      anticipate that stool cultures from study participants may culture a combination of the S.
      Typhi strains initially but that if a single isolate is cultured from the blood that this
      will be reflected in stool culture. The investigators will explore if quantitation of S.
      Typhi is possible in stool. They will also seek to evaluate the host immune response to
      challenge in terms of cytokine and blood transcriptional signatures.

      This is the first time in which the bottleneck theory has been explored in a human model of a
      bloodstream infection. It will not only be significant for understanding the pathogenesis of
      S. Typhi but also for other bacterial pathogens. If this hypothesis is supported this implies
      that the barrier for vaccine prevention of bacterial infection may be lower than previously
      thought, perhaps only very few or even a single organism must be prevented from invasion to
      provide individual protection.
    

Intervention name(s): Salmonella Typhi challenge
Intervention type(s): Biological
Intervention description(s): The challenge agents will be delivered in 30 ml of sodium bicarbonate solution, preceded by 120 ml of solution of sodium bicarbonate to neutralise gastric acid.
Intervention model: Single Group Assignment
Intervention model description: Ambulatory outpatient human experimental infection
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Enteric fever; Typhoid; Salmonella Typhi; Typhoid fever; Salmonella infections; Gram-negative bacterial infections; Human model of infection