We all know by now how the microbiota can positively or negatively influence the course of a wide range of bacterial infections. However, maybe less predictably, the microbiota can also influence viral infection. A recent study has serendipitously found that the host’s normal microbiota can influence infections caused by rotavirus. This is especially important given the recent review publication outlining how rotavirus infection might play a role in the development of Type 1 diabetes.
Rotavirus, a democratic virus?
Rotavirus (RV), a double-stranded RNA virus belonging to the Reoviridae family, is the major cause of severe acute gastroenteritis in children (adults are generally asymptomatically infected, except for the elderly). Each year, RVs cause approximately 111 million episodes of gastroenteritis in children, which results in 25 million visits to clinics, 2 million hospitalizations, and 352,000 to 592,000 deaths.
Highly contagious and resistant to several disinfectants, the virus enters the body by an oral route and infects the villous epithelium in the small intestine. Viral replication causes damage to the intestinal mucosa, which fails to absorb nutrients, leading to isotonic diarrhea, dehydration, electrolyte imbalance, and metabolic acidosis. Because of this extended time of viral shedding, a person can spread the virus even while not expressing symptoms.
Bacteria power…
Although most humans are exposed to RV multiple times, susceptibility to infection can vary among individuals and regions: some infections result in only mild disease, whereas others cause severe, life-threatening gastroenteritis. A team of scientists from Georgia State University might have discovered why there is such a difference in RV disease penetrance and severity.
Serendipitously, the researchers happened to reproduce in mice what has been observed in humans: they unintentionally developed a breeding colony of mice that were completely protected against RV. When they compared this breed with another colony that was instead highly susceptible to RV infection, they found that microbiota composition was a key variable in determining the severity of RV infection. In particular, the presence of a single bacterial species, Segmented Filamentous Bacteria (SFB), was a strong contributor to resistance to RV disease. The SFB containing mice were able to clear RV more efficiently, supporting the idea that this bacterial species imparts an antiviral benefit. Also, administration of faecal microbiota transplants from resistant to susceptible mice transferred rotavirus resistance to the new hosts.
Moreover, it was previously reported that SFB is normally present in the microbiome of infants and young children in China, a country that seems to lack the severe RV-induced disease burden seen in some countries (despite the limited use of RV vaccines).
By what mechanism does SFB protect against RV infection?
SFB has been implicated in the modulation of the host immune system. Due to the intimate association with the intestinal epithelium, SFB seems to have an ability to induce post-natal maturation of virtually all immune system components. For example, SFB colonization of human terminal ileum is associated with the activation of T and B cell receptor signaling pathways. The Georgia State researchers found that SFB might be able to directly reduce RV capacity to bind and infect epithelial cells in vitro by causing epithelial cells to be shed and replaced with new, uninfected cells. Although the exact mechanism by which SFB leads to RV resistance remains to be further clarified, the findings of this paper suggest a previously unappreciated innate antiviral signaling pathway, whereas the microbiota itself might be a possible source of antiviral agents and might be harnessed to develop new, potentially broad-spectrum antiviral strategies.
This appears to be particularly important if we take into consideration a front matter article published in PLOS Pathogens by Leonard C. Harrison, which implicates rotavirus in the development of Type 1 diabetes in genetically susceptible children.
Although Type 1 diabetes tends to run in families, the available data suggest that there must be environmental factors (e.g., the chance that an identical twin will develop this condition is only 35% if the other twin has Type 1 diabetes). The researchers at the University of Melbourne presents several lines of evidence on how RV infection might be the environmental trigger in those with a genetic predisposition. In these groups, RV seems to stimulate an immune response that triggers the killing of insulin-producing cells in pancreatic islets, which in turn leads to the inability to produce insulin resulting in Type 1 diabetes. In the article, the authors report a 15% decrease in the incidence of Type 1 diabetes in Australian children following the recent introduction of RV vaccination.
If ecologic and/or cohort/case-control studies in other regions can confirm a reduction in Type 1 diabetes following vaccination, it will be important to identify, if possible, those children that are most likely to be protected by RV vaccination. Also, considering the above-cited work, strategies aimed at developing a functioning microbiota that could potentially protect children via activation of the immune system seem promising.
