Steve Jacobson, PhD and his team at the National Institute of Neurological Disorders and Stroke have published a new study that suggests HHV-6A can cause neurological disease by transmission through the nose. It is well-known that loss of smell is a common prelude to many neurological diseases, but the reasons have never been understood.
Jacobson’s team found that HHV-6A can infect the olfactory ensheathing cells that connect the nasal passages to the brain, giving the virus a direct pathway to the brain. See Science News article on this subject here. The finding has potentially enormous implications because it suggests that not one but several neurological conditions associated with loss of smell could be caused by virus.
Olfaction losses are found in the early stages of MS, Alzheimer’s, Parkinson’s schizophrenia and depression. (See Strous 2006 for a review.) Loss of smell is one of the first abnormalities and pathological abnormalities in the olfactory bulb are noticed early in the disease in Parkinson’s Disease. Importantly, the side with the worst loss of smell is opposite to the side with the worst movement disorder. (Zucco 2001)
Varicella virus and HSV-1 can also be found in the olfactory bulbs and an earlier study showed that HSV-1 infection via the nose led to virus latency in the amygdala and hippocampus in mice (Becker 1995). Could these viruses cause quiet brain disease, smoldering in the brain tissue with no evidence in the blood? It is certainly an important question to study. Evidence has accumulated in recent years that strongly suggests that HSV-1 may play a major role in Alzheimer’s disease (Itzhaki 2008).
HHV-6A tie to MS
A group in Spain led by Roberto Alavarez-Lafuente has published several studies demonstrating that HHV-6A can be found in the serum and spinal fluid in a subset of relapsing remitting MS patients during active flares, but not during remission. Furthermore, he has found that HHV-6A reactivation in a subset of MS patients is strongly associated with two specific polymorphisms – IRF5 (which causes a reduction in interferon production) and MHC2TA (which affects MHC class II genes). The Spanish group has found no evidence of HHV-6B. Could this be because the olfactory ensheathing cells selectively allow HHV-6A but not HHV-6B access to the brain?
HHV-6A and oligodendrocyte precursor cells, astrocytes.
Of interest, David Mock’s group at University of Rochester reported in 2004 that HHV-6A establishes an abortive infection in oligodedrocyte precursors. This is significant because the abortive infection was associated with a profound reduction in the number of mature oligodendrocytes which are essential for the repair process. In fact, transplanted oligodendrocyte progenitor cells have recently been shown to remyelinate and restore spinal cord injury in mice. The olfactory ensheathing cells also play a role in the repair process as they have significant neuro-regenerative properties as well. Both Jacobson and Yoshikawa in Japan have previously published that HHV-6A but not HHV-6B can infect astrocytes (u251 cells), important glial cells involved in axonal regeneration.
Virus and demyelination
Recently, researchers at the Oregon National Primate Research Center isolated a herpesvirus that they say has caused symptoms identical to MS in a small percentage of macaque monkeys every year. This suggests that HHV-6A – and perhaps other herpesvirus such as EBV and VZV may be involved in the pathogenesis of MS, in different subsets of MS.
This finding came as no surprise to HHV-6 investigators who have attended the HHV-6 Foundation conferences. In March 2011, Jacobson’s NINDS group demonstrated that HHV-6A intranasal inoculation in marmoset monkeys caused neurological disease very similar to MS. Of note, these monkeys showed no evidence of the viral DNA in the serum. (Download abstract) Claude Genain presented similar evidence of HHV-6A induced neurological disease in marmosets at the 2008 conference (Download abstract), but was unable to find funding to expand his studies. A group led by Brenda Horvat in France has also found that HHV-6A can cause brain lesions in CD46 transgenic mice. (Download abstract)