West Nile Virus, the blood brain barrier and the elderly

[CausativeAgent]

My question is about West Nile Virus and why/how it is much more likely to cause encephalitis in the elderly. What I've found is that increased permeability of the BBB is what allows the virus to infect brain tissue which is how the majority of neurological damage is done. The rest of the neurological damage is caused by inflammation.

The main thing which helps the virus pass the blood brain barrier is stimulation of a certain kind of toll like receptors, Tlr3, which bring about an inflammatory response by signaling for infiltration of cytokines and other non specific immune system tools. Specifically, tumor necrosis factor alpha is the one which mediates increased BBB permeability. Here is an article I found about a study which shows that mice deficient Tlr3 experience reduced brain involvement during WNV infection: http://www.medscape.com/viewarticle/495916_3

Another article with some more explanation:
http://www.medscape.com/viewarticle/532913_3

Basically, what I've found is that this inflammatorry response is helpful in reducing viral replication in the periphery but has the horrible side effect of increasing BBB permeability. In addition, the inflammatorry response itself is also destructive to brain cells. The majority of damage is caused by direct viral infection of neurons. So ultimately the process does way more harm than good because if the virus stays mostly confined to the periphery our bodies almost always do a fine job of beating it, unless we are immunocompromised.


Based on my understanding of how the disease works and a couple semi-related studies I suspect it may have to do with increased permeability of the BBB in the elderly population. Here are a couple articles I've looked at recently about how many drugs cause greater CNS effects in the elderly. . .

http://www.medscape.com/viewarticle/408593_5

http://www.urotoday.com/375/browse_c...e_elderly.html

Based on this article I found about the Blood brain barrier: http://users.ahsc.arizona.edu/davis/bbb.htm , I'm thinking that it has to be one of two mechanisms: either physical, i.e. opening of tight junctions, or enzymatic. I'm strongly leaning toward disruption of tight junctions, because I don't think tumor necrosis factor, one of the things which causes BBB inflammation in WNV and the main molecule that increases permeability, effects enzyme activity.

But. . . I'm still lacking in any studies which specifically say that the BBB is more permeable in the elderly, and through what mechanisms this occurs. Also there may be other reasons why the elderly are more effected by WNV such as differences in their immune systems. Or maybe they have fewer neurons to begin with so destruction of the same amount is more damaging? That last one is very speculative. Any insight into these other possibilities is also appreciated. Links to articles or studies are especially awesome.

 

[CausativeAgent]

Well I did some more research and was able to find some studies about the relationship between the BBB and aging. What I found was that the physical integrity, i.e. tight junctions, of the BBB does not diminish significantly with age, which is the opposite of what I was hypothesising However certain chemical transport systems are altered with age, such as those for choline and glucose. Several diseases associated with aging also alter BBB permeability, including diabetes and hypertension. Both of these alter transport systems though, not tight junctions. The only two diseases I could find that disrupt tight junctions were multiple sclerosis and ischemia.

This leads me to believe that other more complex factors such as differences in immune system may play a larger part in how the elderly are effected by WNV.

 

[iansmith]

Did you think the virus might be internatilized by the brain endothelial cells and that TNF alpha might increase the number of receptor on those cells, thus facilitating uptake?

There's a few example with bacteria where TNF alpha increase the number of available docking sites and that these bacteria bind better to these TNF alpha stimulated endothelial cells.

The virus might infect the brain endothelial cells and cause the cell to lyse and compromise the integrity of the blood brain barrier. This would create a cascade effect. the integrity is compromise, virus infect the support cells, the tight junction is compromise and it allows virus to gain entry to the brain.

As far as I remember, elderly people have a different type and bias in terms of immune response and that may lead to an increase in the number of receptor on the brain endothelial cells (BEC). Furthermore, polymorphisms in certain genes linked to the immune response introduce a bias in the immune response and thus modify receptor expressed on the surface of the BEC. That would explained those odd cases where west Nile non-immune compromise individuals.

 

[CausativeAgent]

When you say brain endothelial cells are you referring to the cells of the BBB? I don't know a lot of terminology, all I've had is one semester of biology and am currently taking micro. If you are referring to the BBB, I have not read of WNV actually infecting endothelial cells. It mainly infects neurons. The main detrimental effect of tumor necrosis factor alpha in this disease, as far I have read, is that it disrupts tight junctions in the BBB.

You are right in the last big thing I need to look into is the difference in immune response in the elderly. If Toll like receptor 3 were expressed in greater amounts in the elderly that would be a perfect explanation. Mice known to be deficient in this receptor experience virtually no brain infiltration. Or it could be a deficiency in other things that are actually helpful.

 

[iansmith]

brain endothelial cells refers to the type cells that line the blood vessel, form the tight junction and interact with the astrocytes. As far as I know, any infectious agent that access the brain must interact with the brain endothelial cells in order to gain access to the brain.