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CausativeAgent
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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 explination:
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.
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 explination:
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.
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