Would you volunteer to have a bacterial infection?
The symptoms of a Campylobacter infection can include severe abdominal cramping, high fever, reactive arthritis, and bloody diarrhea – and believe it or not – some brave people willingly volunteer to become infected with it.
Our work encompasses a multi-continent collaboration between microbiologists, medical researchers, clinicians, and importantly, citizen volunteers, to study controlled human and non-human primate infections to further our understanding of Campylobacter disease and therapy. Our particular story began in 2010 after Dr. Patricia Guerry, an international leader in Campylobacter research, invited Professor Stephen Trent to give a talk at the US Navy Medical Research Center. Stephen’s lab was exploring how Campylobacter species modify various surface structures to promote bacterial fitness.
At the time, Pat was gearing up for several clinical trials including one to test a human Campylobacter vaccine her laboratory developed. Over dinner, the two investigators discussed the wealth of information that could be gained from controlled human infection models. What if, instead of just focusing on how humans respond to the infection, we also studied how the bacteria respond to the humans?
In a controlled human infection model, all volunteers are simultaneously infected with a single bacterial strain from the same inoculum. In this way, you can identify conserved and unique adaptations to human hosts. The conserved response may identify mechanisms Campylobacter consistently relies upon to be an effective human pathogen.
Now, eight years later, the collaboration they established that night finally bore fruit, see the published article here. In conjunction with a recent human challenge model established by the US Navy Pat sent infected diarrheal samples to Stephen’s lab for transcriptome analysis and genome sequencing of infection isolates.
Five of the infected volunteers were recurrently colonized with the challenge strain after they left the clinic despite antibiotic treatments. Although this is a terribly unfortunate circumstance for the volunteers, these samples yielded unique insights into persistent Campylobacter infections in humans. The significance of persistent infections has come to the forefront of Campylobacter research, as recent global epidemiology surveys found asymptomatic and sometimes persistent Campylobacter infections in children correlate with physical and cognitive deficits that extend into adulthood.
The samples from recurrently infected volunteers enabled us to identify genetic variations in Campylobacter that consistently arose in reinfection isolates. One of these variations turned on cipA, a gene known to increase host cell invasion, although the biochemical function of the gene was unknown. We identified that flagella become differentially glycosylated when cipA is turned on, and therefore this modification may link the ability of Campylobacter to invade host cells and persistently colonize humans. Perhaps the CipA-derived gene product will be a viable antigen to protect against persistent infections in future vaccine trials. We also discovered independent genetic variations that disable Campylobacter’s main mechanism for sensing bile concentrations - a surprising finding for an intestine-dwelling bacterium. Now that we know a major regulon in Campylobacter can be compromised during human infection, future therapies should consider the possible in vivo expression patterns of their target.
This work required strong interdisciplinary collaborations, courageous volunteers, and “enlightening” discussions about diarrhea. Whenever we need some motivation in the lab, we just think about the volunteers who knowingly drank a culture of infectious bacteria to further our scientific research – talk about inspiration!