Brooke Deatherage received her Ph.D. in microbiology from the University of Washington in December of 2009 for her work with Salmonella. Since the publication of her first article, “Biogenesis of Bacterial Membrane Vesicles,” in the June 2009 issue of Molecular Microbiology, Deatherage has built upon this knowledge to move closer to developing a new Salmonella vaccine.
Food Safety News recently sat down with Deatherage to discuss her research on Salmonella and vaccine development.
Q: How did you determine which serotype(s) of Salmonella to focus your research on?
A: When a mouse becomes infected with Salmonella enterica serovar Typhimurium (S. Typhimurium), it exhibits a typhoid fever-like response similar to what a human would experience if infected by S. Typhi, or the response an immunocompromised person would have when infected with S. Typhimurium. In individuals that are immunocompromised, without the proper immune system mechanisms to respond to a gastrointestinal infection, a systemic disease develops. This systemic disease is difficult to treat, and is contributing significantly to Salmonella-related deaths. For these reasons, we are interested in studying S. Typhimurium in the mouse model in order to understand systemic infections in humans.
Q: How closely are S. Typhi and S. Typhimurium related? Will the vaccine be effective against both Salmonella serotypes?
A: S. Typhi and S. Typhimurium are very closely related on a genetic level, but they have very different host specificities. S. Typhi is a human-restricted pathogen, while S. Typhimurium is more promiscuous and can infect a wide range of hosts. The reason for this difference isn’t fully understood. The design of this vaccine, which includes antigens from the bacterial cell surface that are similar between S. Typhi and S. Typhimurium, has the potential to confer some immunity against both organisms.
Q: Salmonella bacteria are constantly undergoing slight mutations that make them distinguishable from one another through genetic testing. We’ve seen strains of Salmonella Typhimurium implicated in foodborne illness outbreaks that vary only slightly. Will the vaccine be effective against all strains of S. Typhi and S. Typhimurium, or will it need to be “tweaked” occasionally to protect against different strains, like the regular flu vaccine?
A: The basis for this vaccine is somewhat different from what is used in vaccines such as the influenza vaccine. We are using a non-viable part of the Salmonella surface that is released during growth of the bacterial cells, called membrane vesicles. They literally “bleb” off the cell surface like a bubble. You can imagine these vesicles to look like miniature versions of a Salmonella cell on the surface, with all the important antigens that our bodies would respond to during infection. However, they don’t have any of the interior contents, like DNA, that a bacterial cell would have and therefore they are not alive, and importantly, they cannot cause disease. The majority of the abundant protein antigens on the surface of S. Typhimurium and S. Typhi are very similar and well conserved, so it is less likely that these important antigens would vary enough that tweaking of the strain or membrane vesicles would be necessary to achieve protective immunity.
Q: Your vaccine could be considered a subunit vaccine, meaning it uses bacterial parts instead of live cells to generate immunity. How does this type of vaccine differ from live attenuated or killed whole-cell vaccines?
A: The underlying mechanism of vaccination relies on administration of bacterial or viral antigens into our bodies which stimulate various parts of our immune systems to generate responses such as antibodies. Armed with these antibodies and/or other cells that “remember” the vaccine components, we are better able to quickly respond to an infection if we are faced with that organism later.
From microbe to microbe, the type of response that is necessary to protect us from infection varies. For some infections, a killed whole cell vaccine (in which, for instance, bacterial cells are heated or chemically treated so they lose viability) is very effective. However, for protection against Salmonella infections, the best immune response is generated following infection with a live “attenuated” version of the bacteria. This basically means the bacterial cells have a defect that makes them grow slower in the host, providing the host an opportunity to respond to the infection that otherwise may grow too quickly out of control to cause disease. The problem with this is that attenuated organisms can still cause disease in immunocompromised hosts. So, for Salmonella infection, the immunocompromised population is already more susceptible to systemic disease, and can’t be given the most effective vaccine (live attenuated), requiring us to think about an alternative mechanism of generating protective immunity in these individuals.
Our approach has been to use membrane vesicles, which aren’t viable and contain important antigens (bacterial “subunits”) that the immune system of humans and mice would normally respond to during immunization or infection. This type of “subunit” vaccine has proven effective in our studies with Salmonella, and other groups have had success with membrane vesicle-based vaccines in other host-pathogen systems as well.
Q: What stage of trials are you in? Will you test on humans soon?
A: All of our studies have been in the mouse model of S. Typhimurium infection, which is a first step in understanding what type of immune responses are generated to this vaccine, the tolerability of the sample during immunization, and whether the vaccine generates an immune response that is protective against subsequent challenge. At this point, we don’t have immediate plans to move into human testing. Rather, we are trying to better understand the detailed mechanisms by which membrane vesicles generate immune responses in order to make the best possible vaccine. Although we haven’t entered human trials, there is a relatively long history of clinical trials in humans using membrane vesicles from Neisseria meningitidis serogroup B, which is another organism that is difficult to vaccinate against using typical methods. These trials are ongoing with much success in countries where this organism causes extensive disease (meningitis) and death.
Deatherage and colleagues are continuing studies in the field of membrane vesicle-based vaccination against Salmonella, with plans to publish on these findings soon.
Pictured: The colonial growth pattern displayed by Salmonella typhimurium bacteria cultured on a Hektoen enteric (HE) agar medium. CDC.