Tuesday, February 27, 2018

JNeurosci: Another Study On The Neurocognitive Impact Of Influenza Infection

Credit CDC 2018 COCA Call On Severe Influenza


Although rare, there is no doubt that severe influenza infection can sometimes produce acute neurological effects, which can range from minor transient confusion to more serious events like cerebral vascular accidents (strokes), GBS (Guillain-Barré syndrome), and even death.

Credit CDC 2018 COCA Call On Severe Influenza

While the exact mechanism behind these neurological complications are not known - seasonal flu viruses are generally regarded as being non-neurotropic - suggesting that these neurological symptoms may be due to neuroinflammation induced by the host's immune response. 
We have seen some evidence that some influenza viruses - particularly novel flu types - can be more neuroaffective than others. 
In 2009, a PNAS study (link below) found that the H5N1 virus was highly neurotropic in lab mice, and in the words of the authors `could initiate CNS disorders of protein aggregation including Parkinson's and Alzheimer's diseases’.
Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration

Haeman Jang, David Boltz, Katharine Sturm-Ramirez, Kennie R. Shepherd, Yun Jiao, Robert Webster and Richard J. Smeyne
In 2015, after the death of the first imported H5N1 case in Canada, we saw a study (see CJ ID & MM: Case Study Of A Neurotropic H5N1 Infection - Canada), where the authors wrote:
These reports suggest the H5N1 virus is becoming more neurologically virulent and adapting to mammals. Despite the trend in virulence, the mode of influenza virus transmission remains elusive to date. It is unclear how our patient acquired the H5N1 influenza virus because she did not have any known contact with animals or poultry.
Similarly, in a Scientific Reports open access study on the genetics of the H5N1 clade virus - Highly Pathogenic Avian Influenza A(H5N1) Virus Struck Migratory Birds in China in 2015 – the authors warned: 
This suggests that the novel Sanmenxia Clade H5N1 viruses possesses tropism for the nervous system in several mammal species, and could pose a significant threat to humans if these viruses develop the ability to bind human-type receptors more effectively.
Far less certain are the long-term neurological impacts of severe (or repeated) influenza infections, although we've seen studies suggesting links to Parkinson's, Schizophrenia, and even Alzheimer's.

In 2011 a study by Boise State biology professor Troy Rohn  appeared in PLOS ONE , which unexpectedly found immunohistochemical evidence of prior influenza A infection in the post-mortem brain tissues of 12 Parkinson’s patients they tested.
Immunolocalization of Influenza A Virus and Markers of Inflammation in the Human Parkinson's Disease Brain
Troy T. Rohn*, Lindsey W. Catlin
The following year, in Revisiting The Influenza-Parkinson’s Link, we looked at another study, conducted by the University of British Columbia, that found a linkage between a past history of severe bouts of influenza and the likelihood of developing Parkinson’s disease later in life.
According to their research, a severe bout of influenza doubled a person’s chances of developing the neurological condition (Severe flu increases risk of Parkinson's: UBC research).
Last summer the journal Nature published a brief communications with the daunting title of Synergistic effects of influenza and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can be eliminated by the use of influenza therapeutics: experimental evidence for the multi-hit hypothesis that raised (again) the theory that certain types of influenza infections may increase a person's chances of developing neurological disorders like Parkinson's disease (PD). 
My full review may be found at  Nature Comms: Revisiting The Influenza-Parkinson's Link.
We've also looked at the potential impact of maternal influenza infection on the developing fetus in Pregnancy, Influenza & Elevated Psychosis Risks In Adult Offspring and in Pregnancy, Influenza, & Bipolar Disorder In Offspring.
It should be noted that these studies are small and less than conclusive, and while they suggest an increase in relative risk over pregnancies without fever or viral infection – in terms of absolute riskthe odds that a mother’s fever or viral infection during pregnancy would result in a developmentally challenged child remains low.
All of which brings us to a new study, published yesterday in the Journal of Neuroscience (but which was unavailable when I tried to access it), produced by researchers at the Technical University of Braunschweig, which finds long-term neurocognitive impairment in mice following infection with specific types (H3N2 & H7N7) of influenza viruses but not in others (H1N1).

Luckily, the Society for Neuroscience has provided a brief summary (below), and following that I have a link to the the study's abstract which is available on the University's website.

Flu may impact brain health
February 26, 2018, Society for Neuroscience
Long-term effect of influenza A virus infection on glial cell density and activation status within the hippocampal subregions. The neurotropic H7N7 IAV infection induced an increased microglia density in all hippocampal subregions at 30 days pi. Credit: Hosseini et al., JNeurosci (2018)

Female mice infected with two different strains of the flu exhibit changes to the structure and function of the hippocampus that persist for one month after infection, according to new research published in JNeurosci.
Although influenza is considered to be a respiratory disease, it has been associated with neurological symptoms in some cases. However, the long-term effects of flu on the brain have not been studied.

Martin Korte and colleagues investigated three different flu strains (H1N1, H3N2, H7N7) in mice. Two of these strains, H3N2 and H7N7, caused memory impairments that were associated with structural changes to neurons in the hippocampus. The infections also activated the brain's immune cells in this region for an extended period and altered the expression of genes implicated in disorders including depression, autism and schizophrenia. These findings suggest that some strains of the flu may pose a threat to healthy brain function.
More information: Long-term neuroinflammation induced by influenza A virus infection and the impact on hippocampal neuron morphology and function, JNeurosci (2018). DOI: 10.1523/JNEUROSCI.1740-17.2018

Obviously bad news if you are a mouse, but how predictive these results will turn out to be for humans is unknown at this time.  The abstract can be found at.

Long-term neuroinflammation induced by influenza A virus infection and the impact on hippocampal neuron morphology and function

Hosseini, Shirin

Influenza A viruses (IAV) as a major threat to human and animal health today are still a leading cause of worldwide severe pandemics. Although the primary target of these viruses in mammals is the lung, an influenza infection can be associated with neurological complications. However, the long-term consequences of an IAV infection for the central nervous system remain largely elusive.
In the first part of this study, two months old female mice were infected intranasally with non-neurotropic (H1N1 and H3N2) as well as neurotropic (H7N7) IAV subtypes in order to investigate possible long-term effects on hippocampal structure and function.

(Continue . . . )

Whenever we talk about long-term sequelae from influenza, the mysterious decade-long epidemic of Encephalitis Lethargica (EL) that followed the 1918 pandemic always comes to mind.

More than a million people were affected with severe Parkinson's-like symptoms, and while some scientists have suggested it may have been linked to the pandemic virus, others have pointed to a post-streptococcal immune response, or believe it was an aberrant autoimmune response, and dismiss the link with the 1918 pandemic.
The cause remains a mystery.
In 2008's The relationship between encephalitis lethargica and influenza: A critical analysis Sherman McCall, Joel A Vilensky and Jeffery K Taubenberger looked at both sides of this longstanding debate.Quite interestingly, they conclude:
Empirical studies provide little evidence of influenza causation; but, as we have demonstrated, technical limitations and the shortage of appropriate material for testing limit the degree of confidence. Therefore, unless another cause of classical EL is positively identified, its return in the context of another influenza pandemic remains formally possible. Such a recurrence would provide an opportunity to establish the etiology of EL using modern methods.
While the jury is still out on the long-term neurological impact of severe (or multiple) influenza infections - and more research is needed - these studies should at least provide us with some additional motivation to avoid the flu whenever possible.

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