Thursday, November 27, 2014

Potential New Roles for Bacteria and B Cells in Promoting the Stomach Flu

A CDC infographic highlighting the infectivity of
Norovirus. <Source>


We are all unfortunately familiar with the notorious stomach flu.  Most of us have experienced that awful nausea, vomiting, diarrhea, and tiredness associated with catching some stomach bug.  While there are many viral causes of the stomach flu (also called gastroenteritis), one of the most common is the Norovirus.  The Norovirus is a common and contagious virus that is currently the leading cause of viral gastroenteritis.  The infection can last a few days and, while most people recover, it can cause serious issues such as dehydration, and jeopardize the health of many at-risk populations.  There is also no vaccine against the Norovirus right now (the flu vaccine does not protect you from the stomach flu), although researchers are working on it.

In an effort to better understand and treat Norovirus infections, Melissa K Jones et al, from the University of Florida, recently reported some interesting findings related to human and mouse Norovirus biology.  Although this is one cool paper, they actually describe two cool and important findings.  The first is their description of the cells the virus infects, which has remained unknown until now.  The second is their observation that bacteria are able to promote the Norovirus infection.

A New Infectious Host for Noroviruses

An electron micrograph of Norovirus. <Source>
The first issue this research group addressed was discovering the unknown Norovirus host cells (this has been unknown since the virus was discovered in 1972).  This is an issue for developing treatments against the virus, since we don't know what it is attacking.  This is also a problem for researchers who are unable to grow the virus in their lab for study.  It is therefore clear that an understanding of what cells host Norovirus is important for researching and treating the virus.  Without going into too much detail (I will leave that to the paper itself, which is a good read and well written), the group used various B cell lines (the cells that make your antibodies) to show pretty good evidence that Noroviruses infect B cells in vitro (in cell cultures, outside the body).  The group further showed reduced viral titers (concentrations of the virus) in B cell deficient mice, presence of viral genomes within B cells isolated from infected mice, viral protein present in isolated B cells, and other evidence supporting B cells as Norovirus hosts in vivo, in mice.  Finally, the group showed evidence for this occurring in humans.

A Role for Bacteria in Promoting Norovirus Infection

The second main point of the paper, and honestly the one that most caught my attention, was the role for bacteria in B cell Norovirus infections.  As the authors mention in their paper, they first thought bacteria might play a role in Norovirus infectivity when they observed that filtered fecal samples, which retained the virus but lost the fecal bacteria, were markedly less efficient.  The group went on to support their hypothesis by showing that a human Norovirus strain regained infectivity in a dose dependent manner when it was incubated with the bacteria E. cloacae before being exposed to its B cell hosts in cell culture.  What was really cool was that the group took this finding even further by showing that histo-blood group antigens (HBGAs), which are known to bind to Noroviruses, likely play a role in this bacteria mediated virus infectivity.  They supported this role of HBGA by showing, among other things, that bacteria which do not express these antigens, and bacterial components without these antigens (specifically LPS), failed to improve the viruses infectivity.

Finally, the group took this finding to mice to show that antibiotics, which reduced the overall number of bacteria (measured as colony forming units), also reduced the virus titers in infected mice.  This is really cool, but as the authors point out, not entirely unexpected.  Other viruses, including polio, have also been suggested to rely on commensal bacteria to promote their own infectious replication.  Additionally, while this suggests bacterial communities may play a role in infectivity, more work is needed to confirm these results and further tease apart what is specifically going on.

Conclusions and Perspectives

The current working model for
Norovirus infection. Read
more at the source. <Source>
So in the end, what can we say about this study?  I thought that this was a really cool and relatively straightforward paper, with some really interesting implications for future research.  For starters, I think the fact that they discovered a host cell type for Norovirus will be very important for Norovirus researchers, and will probably also provide some insight into clinical and pharmaceutical endeavors which are trying to treat infection with this virus.  Something that especially caught my eye while reading this paper was that, although virus titers were reduced in B cell deficient mice, there were still viruses present, and in the colon there was no change in virus titer.  It is important to note that this could be caused by multiple factors, such as the fact that there still might be some B cells in the mouse model they used, or that they are residual viruses that have not yet passed through the system.  However another explanation could be that the viruses are still replicating in a different host cell type.  I will be interested to see what kind of followup work is done, and am excited to learn more about this virus' infection cycle as research continues.

The findings supporting a role for bacteria in Norovirus infection were also really cool.  Of course more work will need to be done to confirm/support this model and figure out the details of what is going on, but it is a really cool initial finding.  The fact that viral infections can be affected by normal human bacteria really highlights the importance of thinking about microbes in the context of their environment, instead of the more traditional, single pathogen approach.  Even the most simple microbes live and act in complex environments, and this knowledge will be especially important moving forward in drug/treatment development and clinical treatment.

It was also very interesting that antibiotic treatment in the mice reduced Norovirus titers and decreased viral replication.  This left me wondering if antibiotics could be used to treat Norovirus or other viral infections (provided those viruses depend on bacteria in the community).  In most cases, it would be clinically impractical to treat Norovirus infection with antibiotics since the infection is short lived, but it may be an interesting and important proof of concept.  Showing that antibiotics could reduce the severity of a viral infection would be incredibly interesting and might even open therapeutic doors in the future.  As far as I know, there are currently no antibiotics used to treat viral infections.  Although it is exciting to think about the groundbreaking implications this might have in future treatments for viral infections, it is important to remember that there is still much work to be done, and this is mostly speculation for now.

Works Cited & Further Reading

Jones, M., Watanabe, M., Zhu, S., Graves, C., Keyes, L., Grau, K., Gonzalez-Hernandez, M., Iovine, N., Wobus, C., Vinje, J., Tibbetts, S., Wallet, S., & Karst, S. (2014). Enteric bacteria promote human and mouse norovirus infection of B cells Science, 346 (6210), 755-759 DOI: 10.1126/science.1257147

"Researchers Grow Norovirus in Human Cells". Morgan Sherburne. 2014.

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