Thread by @tony_breu

1/15
Why does herpes simplex virus type 1 (HSV-1) encephalitis localize to the temporal lobe? There are so many brain structures, and yet the virus has a tropism for this exact area.

The explanation says something about our history, and the history of viruses.

2/
Let's start with a question.

Which of the following routes to the brain is HSV-1 most likely to utilize?

3/
To understand the answer (nose → brain), we must first explore the close evolutionary history of herpesviruses and humans.

Amazingly, HSV-1 has evolved alongside humans since we diverged from primates millions of years ago.

ncbi.nlm.nih.gov/pubmed/7714900

4/
If HSV-1 co-evolved with humans, its neurotropism might localize to more primitive areas of the brain.

Areas like those included in the limbic system.

[Recall that the limbic system includes interconnected areas of the brain involved in motivation and emotion.]

5/
The limbic system structures include many areas of the temporal lobe affected by HSV-1 (e.g., the amygdala and hippocampus).

It also includes non-temporal lobe structures (e.g., the orbitofrontal cortex) affected by HSV-1.

ncbi.nlm.nih.gov/pubmed/6284882

6/
Damasio and Van Hoesen note that HSV-1 'respects' the cytoarchitectural boundary between limbic and nonlimbic structures, sparing the latter.

It may be more accurate to say that HSV-1 has a tropism for limbic structures, rather than the temporal lobe.

ncbi.nlm.nih.gov/pubmed/3998736

7/
The affinity for limbic structures may explain why personality changes are common in HSV-1 encephalitis.

Up to 92% of patients experience personality and/or behavioral disturbances.

And, many survivors have significant neuropsychiatric sequelae.

ncbi.nlm.nih.gov/pubmed/28251511

8/
If HSV-1 has a tropism for the "primitive" limbic system (including some regions of the temporal lobe), maybe it uses another primitive route for entry.

This leads to a question.

Which of the following senses is considered most "primitive"?

9/
Olfaction, a form of chemoreception, may be the most primitive sense.

To see the potential relevance of this to HSV-1 encephalitis, look back at tweet 4.

bigthink.com/videos/the-evo…

10/
The olfactory system is directly connected to the limbic system. This explains why odors can elicit emotional responses.

And, the tight connection between the olfactory bulb and the limbic system may provide a portal of entry for HSV-1.

Is there any evidence for this?

11/
Yes!

There is evidence supporting an olfactory portal of entry of HSV-1.

Autopsy studies have demonstrated virions in the olfactory bulb of patients who died of HSV encephalitis.

ncbi.nlm.nih.gov/pubmed/7437807

12/
And intranasal inoculation of HSV-1 in mice can produce encephalitis that spreads in a similar fashion to that which is seen in humans.

ncbi.nlm.nih.gov/pubmed/6313868

13/
But, it is far from certain that the olfactory bulb is the route into the brain.

Given that the trigeminal nerve is the main site of latency, reactivation of virus from this structure is also a possible mechanism of encephalitis.

ncbi.nlm.nih.gov/pubmed/426465

14/
Before closing, let's ask one more question:

Which of the following might be noted in survivors of HSV-1 encephalitis?

15/15 Summary
➢ HSV-1 co-evolved alongside humans
➢ HSV-1 encephalitis localizes to the primitive limbic system (including temporal lobe structures)
➢ A portal of entry may be the olfactory system
➢ Anosmia has been noted after HSV-1 encephalitis: ncbi.nlm.nih.gov/pubmed/19820982