Gut microbiota: more awesome than before
After 15 straight days of bonus point summaries from students, today brings a special treat as it falls to me to fill the space with content. This was a cool story, spotted via Microbe World from a news story on NPR, detailing work by researchers at Georgia State University and published in the journal Science this week. We are aware in BIO230 of the critical importance of the normal microbiota in helping us to resist pathogens and disease, however much of this benefit is due to the fact that we have developed a state of peaceful co-existence with them (meaning that they do not generally cause disease), and they are able to out-compete the bad guys. On the face of it, this is a rather boring picture, however the research outlined here shows that it is much more interesting and complicated than we might think.
The researchers were interested in developing treatments for a common gastrointestinal infection due to rotavirus. Rotavirus is a highly contagious agent that causes vomiting and severe diarrhea that can last for up to a week. According to the Centers for Disease Control, prior to 2006 rotavirus infections in United States accounted for around a half million doctors’ office visits, with a large number (greater than 50,000) of hospitalizations. Worldwide, there have been about a half million deaths due to rotavirus annually, mainly in children under the age of 5, and indeed young children everywhere are the most susceptible to infection and have the most severe signs and symptoms. Since the deployment of a vaccine in the last decade, hospitalizations due to rotavirus have begun to decrease, and epidemiologists believe that the unvaccinated are now beginning to see some of the benefits of the vaccine through herd immunity. Currently, there are no antiviral treatments for rotavirus infection, and of course antibiotics actually will prolong the disease course by eliminating the normal bacterial microbiota. The main treatments for rotavirus are to avoid dehydration caused by vomiting and diarrhea. Consequently, there is strong interest in identifying novel, oustide the box approaches for actually treating these types of infection when they occur.
The researchers introduced a bacterial antigen (flagellin), which is the major component of the prokaryotic flagella, under the skin into either healthy mice or mice infected with rotavirus, and observed that healthy mice did not subsequently develop rotavirus when infected (disease was prevented), and in the already infected mice the disease course was stopped (i.e. the mice were cured). The protection was independent of an adaptive immune response, meaning that no prior exposure to the virus was necessary in order to induce the response. The responses to the virus depended on two innate immune pattern recognizing proteins, Toll-like receptor TLR5 and NOD-like receptor NLRC4. The binding of flagellin to immune cells via TLR5 led to the production of a signalling molecule by those immune cells called Interleukin 22 (IL-22), which bound to intestinal epithelial cells and protected them from rotavirus infection. Production of a second Interleukin (IL-18) following stimulation by flagellin through NLRC4 actually eliminated rotavirus-infected cells.
The model being proposed is rather interesting. Bacteria in the gut do not normally cause disease, however components on their surface seem to have powerful immune stimulating capabilities in preventing infection by other, structurally unrelated pathogens. The researchers stress that this study demonstrates the protective nature of flagellin works in mice, which are not humans, and therefore a lot of work still needs to be done to show this holds true for us as well. Fortunately, the basic pattern recognition and signalling pathways are highly conserved between mammals, so there is no a priori reason to expect that these experiments will fail. As indicated in the introductory paragraph, we currently have a pretty good vaccine for rotavirus infection here in the US, which is starting to show real promise in reducing the numbers of rotavirus infection just since its introduction a few years ago. However, the vaccine seems to be poorly effective outside the US, possibly due to genetic variation between strains of the virus in different parts of the world. This approach, if it works in humans, will offer a way to circumvent this problem as it is takes advantage of a generalized innate immune response to a pathogen, as opposed to the specific adaptive immune response promoted by a vaccine. Since it is an innate immune response, there is also no reason to expect that it might not be effective against other virus pathogens that gain access via the gastrointestinal route..
BONUS: Given the discussion above, list in the comment thread ONE microorganism that might offer this protective effect, along with where you found that information. No repeats. You may have to do some research to find this. Offer runs through the end of Thanksgiving Break!!!!