For example, Do we know if this virus is neurotrophic or not? What is the route of entry in to the nervous system and neurons?

Thanks Lawrance,

I like to hear interesting and thought-provoking answers like yours. I am still puzzled though once in the blood, how the virus passing the blood-brain barrier (BBB) and  ending in neurons. Endocytosis? Axonal retrograde transport? And why causing such drastic effects in the fetus but only mild-symptoms in the adult? Why adult nervous system/neurons/BBB resistant to significant damage? What makes fetal neurons so vulnerable? What are the mechanisms of microcephaly? Reduced cell division? Increased premature neuronal death? Is the developemnt of spinal cord normal? Since they are surviving, I presume brainstem cardio-respiratory generators must be OK.

thanks, Refik

I am very interested, because I work with cultured iPS-derived human cortical neurons equivalent of fetal neurons. One of the properies I observe is the extensive gap junctional coupling at that early age-group (see below), which mostly disappears with maturation. I wonder if those gap-juctional intercellular communication assisting with the fast spread of virus/virus-like bacteria among cells. Gap junctions are basically large connections between neighbouring cells to allow fast exchange of materials. When I fill a single cell with a dye, the dye spreads from cell to cell into hundreds/thousands of cells within minutes.

best wishes, Refik

Conference Paper Extensive heterogeneous dye-coupling among cells derived fro...

Data Kanjhan-14-AuPS Poster-Extensive heterogeneous dye-coupling ...

No dye can not under normal conditions spread without a gap junction. Unless there is a specific membrane transporter or a specific endocytotic uptake pathway or a hole in the membrane. Healthy cell membranes are normally only conductive to small ions such as K, Cl, Na and Ca, and even that occurs via specific ion channels. However, some bacteria and viruses, so is some antibiotics, are able to make pores on membranes.

As discussed by Lawrence above, there are evidences that Zika virus has crossed placental barrier and in December 2015, the European Centre for Disease Control published a probable association of Zika Virus with congenital microcephaly. The data showed the an increase risk of microcephaly among the infants born to mothers who has zika virus infection during the first trimester.

regards

Rathish

OK that makes sense that capillary rich tissues such as sexual organs and fetus are particularly prone for the transmission. In that case I would not be surprised if you had a cut/injury in your mouth/tongue then also it is likely that you will get the virus in your system.

Yes I think it could also be a threat in Australia. There have already been a number of infections reported in travellers arriving in Australia from the Cook Islands and Indonesia. Aedes aegypti, the Yellow Fever Mosquito, which is only found in north Queensland (I am in South East Queensland). There is great potential that Aedes albopictus, better known as the Asian Tiger Mosquito, could become established in southern cities. Keeping this mosquito out of our cities is critical. Long sleeved shirts and long pants may soon become fashionable in high risk regions.

There are also reports of more serious consequences of Zika virus infections, including post-viral Guillain-Barré Syndrome (GBS), an autoimmune condition where person’s nerves are attacked by their own body. I guess epidemiologists are (will be) on the watch to see the trends in GBS cases.

Dear Alexander,

The answer to my question is actually NOONE KNOWS THE ANSWER! I did a search and there is no researh to answer the question.

cheers, Refik

Dear Refik,

I just read your question. I asked one relative question on Zika. I should not do that if I knew that you already did. Sorry for that.

Any way, I think Zika or this "Exotic virus" ! as posted by the CDC web site (Centers for Disease Control and Prevention)  is a very interesting and dangerous case. Two elements are critical 1) to confirm that the host- mosquitos were genetically modified and 2) to make the link of Zika and microcephaly.

The microcephaly is not yet absolutely linked to Zika, but if this is the case. then we have to do with a severe post-genomic effect which is tansmitted. This is my opinion.

I am very interested as I am working on a  paper on brain development. Keep updated.

Best, Vassilis

Thanks Vassilis,

Yes you are right. It is an interesting case but lot more research needed. What a coincidence that me and my friend are also working on a paper on that subject. I will check your site out and try to answer your question.

best wishes,

Refik

Dear Refik,

Nice to hear from you. Keep updated!

Best,

Vassilis

Dear Vassilis,

You are a virologist and I am intrigued by your first possibility in your previous comment on "to confirm that the host- mosquitos were genetically modified"

Is this a real possibility or just a rumor? Because if it is this would be a very big snap shot.

kind regards, Refik

Dear Refik, I really do not know. Is what I read. Would be great to know the details before make any conclusion. This is why I posted the question.  If, the microcepahly is linked to Zika then we likely should talk about post-genomic events - my feeling.

If, this is the case then the "modification" of the virus in the host should be critical. We need to get the scientific data before make any conclusion.

But by sure I feel that Zika targets PML-NBs and thus epigenetic machinery.

This should be key in brain and the phenotype.

Keep in touch.

Vassilis

PS. What I did not like is the definition "exotic virus" in the official web site of CDC (Centers for Disease Control and Prevention) !

Are we not supposed to be on a scientist community site? Not a conspirationist one... To say that DDT could do the work, you cant' be a MD and say that it was banned for no reason. It as permanent effects on the environment, does not discriminate between mosquitoes and other (beneficial) insects and accumulates in birds, leading to decrease in bird populations.

OK let's return back to the original question:

Any ideas about how mosquito-born Zika virus may be effecting central nervous system of fetuses/unborn babies?

Now I think there is one thing standing out that there is alot chat/talk/discussion in the media with next to nothing scientific/hard evidence that actually connects Zika with microcephaly. A few observations may be regarded as "case report" instead of a major emergency. You can do a pubmed search and see how many results you will get for "Zika and microencephaly"? Only 9, and mostly reports/reviews only 3-4 of those are actually have some research. Every TV channel and every newspaper/magazine talking about Zika right now all around the world. Where are they getting these information from? Now everyone can intrepret this differently, but one thing comes to my mind is that IS THE MEDIA IS ALSO TAKEN CONTROL OVER SCIENTIFIC MATTERS? as they have done with politics, economics etc.

kind regards, Refik

I just read a nature news talking about Zika virus and there are some researchers in Brazil questioning the size of an apparent surge in the number of Brazilian children born with 'microcephaly" due to misdiagnoses.

"a high rate of misdiagnoses among reported cases is likely because the diagnostic criteria being used for microcephaly are broad"

I have not read any research paper directly stating the linkage between Zika and Microcephaly. Do you think this high concern about the virus is real? Or maybe it is just exaggerated by the media? Perhaps the microcephaly increased appearance is because of something else happening in Pernanbuco region (Brazil) and the media is mocking it by overstating Zika virus. Or maybe the diagnoses are not real at all.

What do you think?

Dear Raphael,

I have the exact questions in my mind. As I have indicated above there is alot of talk in the media but there very little/next to no scientific data to back the connection between the microcephaly and Zika. Why this was not a problem until now or why did not Zika cause microcephaly in Uganda/Africa? Noone knows>

best wishes, Refik

Dear all,

The numbers are so sketchy, but they will keep being repeated by the scare-mongering media until we all swear that there were 4,000 cases of zika-induced microcephaly.

Meanwhile, in Nature:

«Researchers at the body responsible for monitoring birth defects in Latin America are questioning the size of an apparent surge in the number of Brazilian children born with 'microcephaly' — abnormally small heads and brains.»

http://www.nature.com/news/zika-virus-brazil-s-surge-in-small-headed-babies-questioned-by-report-1.19259

Not to mention that even the Brazilian government has admitted that it can only confirm six-6-six cases of Zika association. Not nice for the six families, but a far cry from the thousands announced everyday in the press and repeated ad nauseam (in PT):

http://combateaedes.saude.gov.br/noticias/244-ministerio-da-saude-investiga-3-448-casos-suspeitos-de-microcefalia

What other opportunistic infections may be further affecting the development of malnourished babies' in that part of the world is anybody's guess.

Yes unfortunately increasingly it is looking like a Media-Induced Zika Emergency (MIZE) tied to possibly billions of dollars. Zika may well be a terrible virus causing microencephaly, but the scientific evidence to back that claim is next to nothing. Only six cases of possible Zika involvement, along with many other factors viruses/bacteria not ruled out. Really, only in six cases of microcephalie, Zika virus been found in the victims, but are the other potentials ruled out? No. As long as you have backing from MIZE, smaller/independent media and even many scientistis are getting sucked into a story that is no further than a story. If MIZE turns out to be wrong/fake, there will be noone to blame, because then they will say we are not scientists and we are only reporters. But there is potential to make lots and lots of money of this story.

best wishes, Refik

Dear All, Thank you for your contributions. Lawrence and I are put together a review based on this question. If you like you can read it from the following link.

best wishes, Refik

Working Paper The Zika Virus and Microcephaly

One of the two papers of  1952 that describes the virus, mentioned not just the discover of the virus but also its efect in rats, it is described in this paper that: "It was shown that with early passage virus mice of 7 days and under were susceptible to inoculations of virus by the intraperitoneal route, but that mice of 2 weeks of age and over could only rarely be infected by that route even when large doses of virus were used."

• Having in mind that , it is possible to say that at least in rats the virus is more dangerous in early stages, ¿is this happening in humans also?
• ¿can we use an animal model to study the effect of Zika virus in pregnancy?

http://trstmh.oxfordjournals.org/content/46/5/521.full.pdf+html?sid=7e623118-9570-44c7-938b-b30894df4ad9

Thanks Lina, Good point.

Refik

I agree that in Pernambuco is something special because there is more incidence of microcephaly that in other states with exposition to Zika, however I think that Zika is related, please take a look of this data: http://combateaedes.saude.gov.br/images/pdf/informe_microcefalia_epidemiologico15.pdf

The CDC announced today that it is more dangerous than thought, in addition to microcephaly in newborns and Guillain-Barre, the American Academy of Neurology announced late yesterday that it is the cause of Acute Disseminated Encephalomyelitis.

Here is a link to an article on 3 studies showing the microcephaly link to zika infections.

http://www.medpagetoday.com/InfectiousDisease/GeneralInfectiousDisease/57862?xid=nl_mpt_DHE_2016-05-13&eun=g637873d0r

Dear Robert,

Thank you for the media link interpreting those 3 recent scientific papers just came out this week.I will have to read the original papers and see if there are any flaws in their methodology, as the media link you have provided mentioned that "Normally, mice do not develop Zika infections, so each of the research teams developed different ways to cause pregnant mice to pass the virus to their offspring". I worked with mice for many years and I know many examples that we can not directly translate everything discovered in mice to humans. People have discovered drugs to cure diseases but such drugs had no significant effect in humans. 

By the way our paper also published this week, check it out.

best wishes, Refik

Article Does Zika Really Have the Capacity to Affect the Nervous Sys...

Thanks for the article.  I have printed it and will read it this weekend.  I know you are correct about the questions of mouse models.  While most drug studies have a correlation, I do believe that infection questions are more complex.  But, it is hard to do studies in humans, though postmortem examinations should provide clues.

Dear Robert,

Surely we still need animal studies to have idea and I am sure that the science will benefit from those studies. My only concern and caution is that we should not immediately reach conclusions and make decisions that may harm us. There are significant differences between mice and humans, such as human and mice placenta structurally are very different. Mice are also far more flexible and resilient than humans, for example, the mice changed their genes rapidly after the Chernobyl nuclear disaster and survived the nuclear blast that humans could have not. 

Thanks again,

best wishes, Refik

Refik,

I agree that continuing studies will help clarify the issues around zika and that we should be careful not to cause harm as we search for the answers.  Your article (scanned the abstract) seems to raise some good questions and I look forward to reading it.  I do want to warn you though, that since you published in a journal of a 'Predatory Publisher' you may find it difficult to have your article widely accepted, or even read by some researchers.  These publishers have made it difficult for proper scientific debates to occur in a proper manner (without immediate dismissal of some concerns or researchers).

Refik,

The article below just came into my inbox, and it discusses an article showing the inflammatory response in mice differs from that of humans and raises the issue of whether mice are a good model in inflammatory studies.  Hope this adds to what you need for your discussions.

http://www.biotechniques.com/news/biotechniquesNews/biotechniques-364387.html

Thanks Robert,

Since it is a review/critique type of article I am not really worried about the journal quality. It is good to keep the discussion going, let different ideas flourish and question everything. Scientific progress thrives in versatile ideas. At the end this is the world that we are living in at the moment. It is like British PM calling some other countries as corrupt, while it is likely more widespread in disguise, and perhaps in much bigger magnitudes where it is least expected. I don't think it is scientific at all to judge or credit any publication solely based on the journal name. Sometimes the best ideas and advances come from the most unexpected.

best wishes, Refik

Here is an interview with a researcher, short, but does deal a little with the mouse models.

http://www.laboratoryequipment.com/news/2016/05/q-michael-diamond-and-development-zika-fetuses?et_cid=5293636&et_rid=272645636&type=cta&et_cid=5293636&et_rid=272645636&linkid=http%3a%2f%2fwww.laboratoryequipment.com%2fnews%2f2016%2f05%2fq-michael-diamond-and-development-zika-fetuses%3fet_cid%3d5293636%26et_rid%3d%%subscriberid%%%26type%3dcta

Hi Robert,

Thanks for the interesting Q and A. By the way, a friend of mine told me that our mate Mr Beall is a librarian with a masters degree, powering himself to to call 700-800 scientific journals as predatory. I leave the judgement to you and the followers.

best wishes, Refik

Refik - your mate is not fully informed about Jeffrey Beall, see the Wikipedia article linked below.  The article is pretty good, but is not clear on the difference of a person who does "critical analysis of" vs is a "critic of."  Beall has two Master's degrees and has earned a full professorship in a high quality university.  He has published extensively and is an expert in journal and web based literature.  He is the very best at helping to protect the scientific enterprise by making researchers awarae of the problems with Predatory Publishing.  Please read a good part of his website before you begin to criticize him in an open forum such as this (second hand info that is uninformed is not what you want others to see, from your University or if you are seeking employment).  If you even check here on RG you will find a lot of discussion of the problems he is exposing (link below to one).  A good quality journal will always provide good peer review.  The Predatory journals do not.  For instance, with your paper, did you receive at least two extensive reviews where they asked you to tighten your arguments, to help improve them?  Did you get very good suggestions for improving your writing quality, grammar, clarity?  If you did not get many suggestions for improvements, you paid for poor quality publishing.  And of course, as these publishers take more money from unsuspecting researchers, they also have more to spend doing things like hijacking proper journals, holding high priced/low quality conferences, and causing science to not be trusted because of the poor quality research that is published.  Science is in a battle for funding all the time, and these predators hurt science, academia, personal reputations, collegiality in science, etc......

https://en.wikipedia.org/wiki/Jeffrey_Beall

https://www.researchgate.net/post/What_would_happen_if_WE_ALL_consult_Bealls_list_of_predatory_journals_and_refrain_from_the_possible_probable_or_potential_predators

Refik - I do want to add that my strong concerns about the Predatory Publishers is not a reflection on you.  We need good, and critical analysis, of what is happening in important research fields as Zika currently is.  I have looked through your contributions here, and I can say I feel that you are one researcher who does deserve their high score as your answers to questions are helpful, on point, show expertise, and are not just filler answers as so many RG members try to give to improve their scores.

Just a quick update. Recent reserach has shown that the Zika Virus interrupts human stem cells and inhibits human organoids. After infection, Zika virus NS4A and NS4B Proteins deregulate Akt- mTOR Signaling in Human Fetal Neural Stem Cells to distrupt/Inhibit Neurogenesis and Induce Autophagy (Liang et al 2016, Cell Stem Cell).

Best wishes, Refik

Dear Refik,

Zika is a virus (at least what is known as far).  The recent data on tears and eyes ‘Zika virus may persist in eyes: Disease may spread from infected eyes” ‘https://www.sciencedaily.com/releases/2016/09/160906130949.htm

and related data might reveal new information on transmission of Zika-related diseases suggesting additional info related to the exclusive viral origin as responsible of disease development.

Any virus has acquired a strategy allow to affect cell-host signal control.  A virus is a hijacker.  Stem cells and Akt- mTOR Signaling are central in host development but I think they are secondary effects of Zika infection.

Best, Vassilis

Dear Vassilis,

Thank you for your comment and the link, yes you are right. These are just expeimental model using human stem cells and or stem cell derived cells. Although these studies are allowing studying effects of Zika virus in isolation, a scenario that would be impossible to do. The cell culture conditions are different than the natural fetal development in placenta. For example, under natural conditions mother and fetuses are continuously challenged by multiple and different pathogens (viruses and bacteria) and there is blood brain barrier and an active immune system, antibodies and hormonal influences. Such differences may explain why every fetus does not get microcephaly if mother is infected with Zika?

best wishes,

Refik

Dear Refik,

If, one risk factor (any origin) is responsible for the microcephaly then a simple explanation is the quantity, every fetus is exposed differentially to the “risk” factors.  A second possibility is the genetic background of fetus and a third one is that any fetus is positive to Zika but not positive to the diseases’ phenotype (a possibility that should be already known but I do not know the answer).  A last possibility is that other risk factors of bacterial or human origin after Zika infection are co-responsible for disease development in addition to Zika.

Dear Refik,

I found important to share some personal ideas on microcephaly, Zika and risk factors/microcephaly,

On the basis of bibliography there 4 categories of risk factors that are linked to a microcephaly phenotype (excluding Zika):

a) Certain infections during pregnancy, such as rubella, toxoplasmosis, or cytomegalovirus

Vaccines against rubella are in general combined with measles and mumps vaccine (MMR vaccine) and measles, mumps and varicella vaccine (MMRV vaccine). 

I copy from medical sites: “Varicella (chickenpox) causes blister-like rash, itching, fever, and tiredness. Complications can include severe skin infection, scars, pneumonia, brain damage, or death.”

b) Severe malnutrition, meaning a lack of nutrients or not getting enough food

c) Exposure to harmful substances, such as alcohol, certain drugs, or toxic chemicals

d) Interruption of the blood supply to the baby’s brain during development

Both a-d cases should target common signaling pathways.  Of interest is the No a.  The presence of Zika in western countries with highly vaccinated populations might be a new reason for a new “risk” factor. Best Vassilis

Dear Vassilis,

Thank you for sharing your ideas here. You are absolutely right and indeed there are a number of factors, other than Zika, that are known to also cause microcephaly. Zika is the new kid in the block, with potential future surprises.

best wishes, Refik

Dear Refik:

APOLOGIES: Knowing my post is not connected to the initial question but:

Information added with regard to actuality (has been reported today in Austrian Newspaper for the first time):

MEYER SAUTEUR PM et al:

Research Article

Mycoplasma pneumoniae triggering the Guillain-Barré syndrome: A case-control study

Annals of Neurology, Volume 80, Issue 4 October 2016

Pages 566–580

First published: 26 August 2016   

DOI: 10.1002/ana.24755

http://onlinelibrary.wiley.com/doi/10.1002/ana.24755/abstract

For (your) convenience only:

Abstract

Objective

Guillain-Barré syndrome (GBS) is an acute postinfectious immune-mediated polyneuropathy. Although preceding respiratory tract infections with Mycoplasma pneumoniae have been reported in some cases, the role of M. pneumoniae in the pathogenesis of GBS remains unclear. We here cultured, for the first time, M. pneumoniae from a GBS patient with antibodies against galactocerebroside (GalC), which cross-reacted with the isolate. This case prompted us to unravel the role of M. pneumoniae in GBS in a case-control study.

Methods

We included 189 adults and 24 children with GBS and compared them to control cohorts for analysis of serum antibodies against M. pneumoniae (n = 479) and GalC (n = 198).

Results

Anti–M. pneumoniae immunoglobulin (Ig) M antibodies were detected in GBS patients and healthy controls in 3% and 0% of adults (p = 0.16) and 21% and 7% of children (p = 0.03), respectively. Anti-GalC antibodies (IgM and/or IgG) were found in 4% of adults and 25% of children with GBS (p = 0.001). Anti-GalC-positive patients showed more-frequent preceding respiratory symptoms, cranial nerve involvement, and a better outcome. Anti-GalC antibodies correlated with anti–M. pneumoniae antibodies (p < 0.001) and cross-reacted with different M. pneumoniae strains. Anti-GalC IgM antibodies were not only found in GBS patients with M. pneumoniae infection, but also in patients without neurological disease (8% vs 9%; p = 0.87), whereas anti-GalC IgG was exclusively found in patients with GBS (9% vs 0%; p = 0.006).

Interpretation

M. pneumoniae infection is associated with GBS, more frequently in children than adults, and elicits anti-GalC antibodies, of which specifically anti-GalC IgG may contribute to the pathogenesis of GBS. Ann Neurol 2016;80:566–580

Good news dear Wolfgang,

It confirms that Science to progress needs a model and a hypothesis. Molecular Chorobiology is such a discipline. Let’s see the next steps.

To my opinion there is an enormous confusion in the conception of many scientists, they think that 1 corresponds to the 2 and the 3 to the 4 in a biological system.

This is a major error. The 1 and 2, 3, 4 etc. are just observation moments or correctly spatial events.

In example, the host-cell configuration that is subdivided by the scientists according to the context of the virus (DNA-virus, RNA-virus etc.) is just another spatial event (Chorobiology). If, virus needs information from the environment so to “survive”, the selection system would provide such an information not only by the host but also by the environment. There comes the tremendous danger of bacteria, microbiome and evolution.

Thanks, Vassilis

PS. I still think that super-vaccination plays a major role in “zika” pathogenesis – I used “,” for zika as for me is unclear what the molecular context of a viral infraction is.

Dear Vassilis Doucas, thank you for your interesting comment.

I only wanted to add that today morning I twice had a reason to think over personal scientific education - and eventually information politics for the "normal" human not addicted to learn much from Natural life Sciences....

1st) in yesterday's Newspaper-article (=The Standard.at, which is a national newspaper) the information about the GBS-M.pneumoniae relationships was worth approximately 80 text lines..(cf.: http://derstandard.at/2000045290857/Ausloeser-fuer-Guillain-Barre-Syndrom-entschluesselt.   |  .apologize for not being able to present the English translation).

Today morning in the regional press / newspaper (SN.at, which also is read nationwide in Austria) the information given was condensed to approximately 9.5 lines (cf. http://www.salzburg.com/nachrichten/diverse/archivsuche/?q=Hustenbakterium&submit.x=0&submit.y=0).

2nd): Surprise:  had I ever heard or read from "Molecular Chorobiology"?  No...

Do I want to know about (at least whether the term had been "misspelled" or not...as this is the case if you try to search by google - at least for the first attempt I was told to search for / that the results displayed were for "Chronobiology"....)?    YES.

So I learned about your definition ( "Molecular Chorobiology" ) in: https://www.researchgate.net/post/Mathematical_Physics_proposes_the_existence_of_interrelated_spaces_Do_you_agree_that_entanglement_is_a_property_of_spaces, there especially: Reply # 016, 018, 020  .

There I found the hint on your publication in Nature [ "I have introduced a first idea of this model (Doucas, Nature Micr 2006 - ‘Many images to one structure” and the biological data of the model are mainly provided by virus-host cell interactions)" ], cf: https://www.ncbi.nlm.nih.gov/pubmed/17058349  and 'realiter' to be found at: http://www.nature.com/nrmicro/journal/v4/n4/full/nrmicro1398-c1.html. Unfortunately restricted access to subscribers....

=========================================================

NB: Edited 2017-09-21,21:15 Local time: some minute ago I found the following hint on "CORRESPONDENCE":

"Correspondence

Nature Reviews Microbiology 4, (April 2006) | doi:10.1038/nrmicro1398-c1

DNA and RNA viruses target a common subnuclear domain: many images to one structure?

Sirs,...."      , available free online @ http://www.nature.com/nrmicro/journal/v4/n4/full/nrmicro1398-c1.html (hopefully that page(s) is(are) accessible for all others too!), a pdf version to read /view via 'View interactive PDF in ReadCube' also is indicated.

W. M..Salzburg

===========================================================

so:  Would you mind to send me (if available) a pdf-copy of this your letter (Correspondence | Nature Reviews Microbiology 4, (April 2006) | doi:10.1038/nrmicro1398-c1) to my private e-mail address ( womuss'at'gmail.com ) ? I would like to learn more about your concept.

(Ialso found your publications as listed in PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=Doucas%20V%5BAuthor%5D&cauthor=true&cauthor_uid=17058349 )

Thank you really in advance, best wishes and regards, WM.

NB/PS:   'viral infraction' (in your PS above): did you mean 

-"infraction", - "infarction" or is it to be read as - "infection"

 Dear Wolfgang and Vassilis,

Thank you very much for your both comments. The findings in the paper introduced by Wolfgang is very interesting. Unfortunately I can not download the full paper, and if anyone can send me a copy I will appreciate it  very much. From the abstract it sounds very interesting and relevant/similar to our recent Zika paper where we have a section on Guillain-Barré syndrome (GBS). Lawrence and I argued for potential link between mycobacterium infections and GBS.

best wishes, Refik

Dear Refik,  

thank you....and you are assured that the idea for my posting was the fact that I knew 2 authors  "argueing for potential link between mycobacterium infections and GBS."

At least I tried to apply for the personal pdf-copy at the first author by e-mailing to him personally (in NL). But I guess the team might be 'frightened' by many requests for their article (;-))....  Best wishes and regards, WM

Thanks Wolfgang,

Now I have added this article as a comment to our publication in Modern Research in Inflammation-2016. kind regards, Refik

Dear Wolfgang,

Thanks for your interest in ChoroBiology.

Viral infraction.., in fact I was thinking of viral infection.  Very likely the flaviviruses as the DENV trigger cell apoptosis to favor viral dissemination.  We do not have a silent infection in the case of GB syndrome and/or microcephaly related to “Zika”. So, infraction or hijacking describes best Zika activities.  Infraction or hijacking of which cell property?

I have demonstrated that both HIV and Adeno5 share the property to target and reorganize a cellular 3D-domain (PML). This is true for many different viruses and distinct signaling pathways. A 3D-domain is just the mirror of the spatial organization of the cell. But the cell refers also to activity.

To explain my model, I created Molecular ChoroBiology, a novel discipline in Biology, that covers the role of Choros in controlling Signal transduction. In a simplified version Choros is the Space and the Activity.  It is like a dancing floor (3D) and the dancers (activity).  

Cell is organized in 3D: 1D:Transcription f(T), 2D:Translation f(t) and 3D:DNA/RNA processing- f(I). Both dimensions should be coordinated.  We can add more dimensions, of course.   

Our Euclidean 3D vision, is where these cell activities/dimensions are coordinated.

In mathematics, the Pythagorean theorem, is a fundamental relation in Euclidean geometry among the three sides of a right triangle. The theorem can be written as an equation relating the lengths of the sides a, b and c, called the Pythagorean equation a^{2}+b^{2}=c^{2}.

So, if a risk factor alters cell translation, could be possible to establish an equation so to measure Transcription and DNA processing and therefore establish if, a risk factor is pathogenic or not?

To my view, even though such an equation (spatial equation) is not yet valid, the conclusion is that the dimensional Space or Choros expresses regulatory properties at the cellular level.

Coming to Zika and GBS-M.pneumoniae relationships, I could say that DENV2 is known to target PML-NBs. Zika is likely similar.  What is the role of M. pneumoiniae and mainly IgG?  One possibility is that IgG increases affinity and so membrane fusion and so, alters the “spatial equation” rendering Zika more virulent.

There are other possibilities. 

The most intriguing is the link of microcephaly and Zika that indicates a teratogenic activity of this “virus” and therefore it cannot be excluded a horizontal “gene transfer” or an “activity transfer” mediated by “Zika infection” from mother to newborn.  This is my opinion. HGT activity is described for Bracoviruses in Lepidoptera.

I agree with y colleagues

Recently Bardani et al reported in Science (14 Apr 2017: Vol. 356, Issue 6334, pp. 175-180, DOI: 10.1126/science.aal4365: Enhancement of Zika virus pathogenesis by preexisting antiflavivirus immunity

Antibodies against related flavi-viruses such as dengue (DENV) and West Nile (WNV) can cross-react with Zika virus (ZIKV) and could thereby increase disease severity. Using convalescent plasma from DENV- and WNV-infected individuals, they have found substantial enhancement of ZIKV infection in vitro that was mediated through immunoglobulin G engagement of Fcγ receptors. Administration of DENV- or WNV-convalescent plasma into ZIKV-susceptible mice resulted in increased morbidity—including fever, viremia, and viral loads in spinal cord and testes—and increased mortality. Antibody-dependent enhancement may explain the severe disease manifestations associated with recent ZIKV outbreaks and highlights the need to exert great caution when designing flavivirus vaccines. Antibody-dependent enhancement (ADE) also led to high levels of virus in mouse testes and spinal cords, which may help explain sexual transmission of Zika in humans and central nervous system diseases like microcephaly in babies and Guillain-Barré Syndrome in adults.

Dear Refik, Good news this pp it goes to the good direction.   If you have reagents and time, it would be great to test in a Zika environment the PML-NBs integrity +/- IgG concentration (easy control). The data might provide a link between Zika and CNS and immunitry.  Very likely Zika attacks also AIRE domains / immune system.

I do not have time and the related reagents to do it. I am sure it will work. If, Zika and PML-NBs and related domains interact with ZIKA - 99% certain - then we can built the model of horizontal “gene transfer” in CNS. That would be great.

 Keep in touch. Best, Vassilis

Dear Vassilis,

Thank you for your comment. I wish I had the means too but I don't. Hopefully someone else with the means will be able to do it:)) I am still working on my review, while doing so I have come across this interesting article in Science that I have mentioned above. This latest research findings indicate the complexity of the Zika infections and also the interaction with prior viral/bacterial infections or vaccinations. If you are interested and have the time we can collaborate on that?

Best wishes, Refik

@Refik:  concerning the article I mentioned in my Re # 062  (and you were mentioning to be not able to download the article)

MEYER SAUTEUR PM et al:

Research Article

Mycoplasma pneumoniae triggering the Guillain-Barré syndrome: A case-control study

Annals of Neurology, Volume 80, Issue 4 October 2016

Pages 566–580

First published: 26 August 2016   

DOI: 10.1002/ana.24755

http://onlinelibrary.wiley.com/doi/10.1002/ana.24755/abstract

 I only can inform that I requested the article at the principal and corresponding author 3rd of October 2016 but unfortunately did not get any answer. a quick search in RG-Archive for "publications" finds the title and authors at:  https://www.researchgate.net/publication/305885211_Mycoplasma_pneumoniae_triggering_the_Guillain-Barre_syndrome_A_case-control_study_Mycoplasma_pneumoniae_in_Guillain-Barre_syndrome  (but only abstract is provided. But perhaps anybody will respond on the  "REQUEST full TEXT" - message.....

The matter - if I remember correctly -  was in the news (press) again most recently... but I'd have to dig in the daily editions...

Hope you are well, with my best wishes and regards,  yours sincerely, Wolfgang

Article Mycoplasma pneumoniae triggering the Guillain-Barré syndrome...

Dear Wolfgang,

Thank you very much for reminding me about this article. Yes I still don't have a copy of it and just sent a request at RG. It will certainly be a useful article to read and use as a reference.

Best wishes,

Refik

Clues from inherited microcephaly exposes how Zika virus targets fetuses and causes microcephaly

A recent paper came out in Science by Chavali et al. last week (7 July 2017) shows that a neural precursor protein, Musashi-1 (MSI1) also binds ZIKV RNA to amplify viral replication in cells.

Microcephaly has been the terrifying hallmark of the recent outbreak of Zika virus (ZIKV) in the Americas. How the virus damages brain development in the fetus is enigmatic. Chavali et al. found that in congenital microcephaly, mutations in a neural precursor protein, Musashi-1 (MSI1), impede RNA binding to neural stem cell targets, resulting in abnormal brain development. MSI1 also binds ZIKV RNA to amplify viral replication in cells. This interaction could put a pregnant woman at risk of giving birth to a microcephalic child. Furthermore, MSI1 is expressed at high levels in the mouse testis, which may explain the sexual transmission of this virus.

Zika virus, a flavivirus, shows a tropism for neural progenitor cells, but a detailed understanding of this tendency for infection is not yet well understood. Chavali et al. report that a specific region of Zika's RNA genome binds to an RNA-binding protein called Musashi-1, which is highly expressed in neural progenitor cells. These progenitors are precursors for neurons and astrocytes, cells required for cortical development. The interaction between Zika viral RNA and MSI1 may explain why these precursor cells are targets for infection.Abstract: A recent outbreak of Zika virus in Brazil has led to a simultaneous increase in reports of neonatal microcephaly. Zika targets cerebral neural precursors, a cell population essential for cortical development, but the cause of this neurotropism remains obscure. Here we report that the neural RNA-binding protein Musashi-1 interacts with the Zika genome and enables viral replication. Zika infection disrupts the binding of MSI1 to its endogenous targets, thereby deregulating expression of factors implicated in neural stem cell function. We further show that MSI1 is highly expressed in neural progenitors of the human embryonic brain and is mutated in individuals with autosomal recessive primary microcephaly. Selective MSI1 expression in neural precursors could therefore explain the exceptional vulnerability of these cells to Zika infection.

Musashi-1 an RNA binding protein plays a role in assymetry and cell fate. From abstract a question comes on speciifcity between flavivirus and MsI1, how to explain that major reports of microcephaly are concentrated in Brazil? Inactivation of MsI1 by ZIKA should be of interest ...to control MsI1 upregulation....Disruption of MsI1 function by ZIKA...as the cause of teratogenesis ...though might use ZIKA in anticancer therapy. Need to see the full data...

Hi Vassilis,

Thank you for your contributions. Indeed potential control of cancer, or stem cells turning into cancer cells, by Zika or similar flaviviruses acting on Musashi-1 may be a big hit in the future. I can't share the full paper here but I will forward it to you. Best wishes, Refik 

Hi Vassilis,

In aggrement with your previous suggestion: A recent study by Zhu et al "Zika virus has oncolytic activity against glioblastoma stem cells" published in JExpMed suggests that Zika virus may be used to treat aggressive brain cancers.

Abstract of the study: Glioblastoma is a highly lethal brain cancer that frequently recurs in proximity to the original resection cavity. We explored the use of oncolytic virus therapy against glioblastoma with Zika virus (ZIKV), a flavivirus that induces cell death and differentiation of neural precursor cells in the developing fetus. ZIKV preferentially infected and killed glioblastoma stem cells (GSCs) relative to differentiated tumor progeny or normal neuronal cells. The effects against GSCs were not a general property of neurotropic flaviviruses, as West Nile virus indiscriminately killed both tumor and normal neural cells. ZIKV potently depleted patient-derived GSCs grown in culture and in organoids. Moreover, mice with glioblastoma survived substantially longer and at greater rates when the tumor was inoculated with a mouse-adapted strain of ZIKV. Our results suggest that ZIKV is an oncolytic virus that can preferentially target GSCs; thus, genetically modified strains that further optimize safety could have therapeutic efficacy for adult glioblastoma patients.

For full paper use the following link (open access):)

http://jem.rupress.org/content/jem/early/2017/09/05/jem.20171093.full.pdf

Therefore, harmful Zika virus that can cause devastating brain damage in babies could offer up a surprising new treatment for adult brain cancer. This latest research shows thats the Zika virus can selectively infect and kill hard-to-treat cancerous cells in adult brains. Glioblastomas are the most common in adults and one of the trickiest to treat: fast growing and diffuse, meaning they spread through the brain, making it difficult to see the boundaries of the tumour and healthy tissue. Therefore treatment or removal with radiotherapy, chemotherapy and surgery is difficult. Idea of using viruses to fight cancer is not a new. Zika virus that targets cells that are very important for brain growth in babies, resulting in microcephalie. However, adult brains contains limited or a lot less stem cellsand therefore Zika virus infections are far less serious in adults. Therefore Zika virus could be used to target growing tumours such as glioblastoma stem cells continuously growing and dividing in adults.

After all having Zika infection in adults may help fight cancer???

Dear Refik, Nice data... We should run Biology without money and lab.........What we need is a model and a scientific hypothesis..  This is not in fact true, we need also the experimental part to prove and test models and hypothesis. 

What I keep from this pp is the link to INF signaling. As I have already told you, I am certain that Zika targets PML bodies. How Musashi-1 links to PML-NBs and to Zika and from Zika to cell fate is another question.

What is more comlex in this pp is their statement that "The effects against GSCs were not a general property of neurotropic flaviviruses, as West Nile virus indiscriminately killed both tumor and normal neural cells."  A tumor cell and a normal cell, what makes their differences?? We name cancer and normal cells upon our Observations but flaviviruses or any signaling do not use our ANALYTICAL system to differentiate between a cancer and a normal cell. I think this is a major confusion point in anti-cancer therapies.  Keep in touch, best Vassilis

Guys surely someone has done clinical study to determine in which month of pregnancy infection of mother causes most severe microcephaly . If you don't know when then how can you figure out which developmental protein of cytokine is active and so responsible?

This is very interesting article: Zika virus could be used to treat brain cancer, new study suggests!

The same mechanism that damages developing brains allows Zika virus to target cancer stem cells...

https://www.researchgate.net/blog/post/zika-virus-could-be-used-to-treat-brain-cancer-new-study-suggests

Dear Ljubomir,

Thank you very much for the above link. This is very interesting and exciting research that Zika virus may be used to treat brain cancers. Indeed that is what I and Vassilis were talking/discussing about earlier. It all makes good sense in theory, but we have to wait and see what will be the outcome of human trials. It is interesting how the Zika story is evolving-Who knows one day we may get genetically modified live Zika viral injections to treat nasty brain cancer.

Best wishes, Refik

@ Ljubomir and Refik, Virus or cancer, any signal should use the same "cell signal coordination pathway". What is common in a cell, is the "domains"; virtual/stem or differentiated", cellular domains illustrate topology and function; they play a key role in cell memories and cell signal response.

What a virus can do is to reactivate a differentiated "domain". Same, it is the process of cancer progression. If, virus function as cell hijacker, cancer is similar they both are “browser hijackers”. Cellular domains, Molecular Chorobiology. This is how I think that the signal is coordinated (any signal).

To remind that: "a domain, in the context of networking, refers to any group of users, workstations, devices, printers, computers and database servers that share different types of data via network resources. There are also many types of subdomains. ......"

Cell Signal coordination works in a similar conception.... We need only to visualize the virtual organization of "networking" at the molecular level....and, that implies that cell borders are infinite... if, infinite has a sense at the molecular life....

This question addressed by Refik on Zika is very intriguing.....He should finish his review. Finally, it will be a great introduction on cancer therapies…..best, vassilis

Dear Vassilis,

Thank you for your comments and contributions to this question. On another note, there is an interesting interaction between viruses and cancer: while some viruses can be oncolytic, others are oncogenic or oncoviruses. Indeed an estimated 15 percent of all human cancers worldwide may be attributed to viruses, often called Oncoviruses. Both DNA and RNA viruses have been shown to be capable of causing cancer in humans. Epstein-Barr virus, human papilloma virus, hepatitis B virus, and human herpes virus-8 are the DNA viruses, and Human T lymphotrophic virus type 1 and hepatitis C viruses are the two RNA viruses that are capable of causing or contributing factors to development of human cancers. On the other hand, a number of viruses have been identified as oncolytic, an oncolytic virus is a virus that preferentially infects and kills cancer cells.

Research into the potential of viruses as anti-cancer agents begin in the 1960s. A number of viruses including adenovirus, reovirus, measles, herpes simplex, senecavirus, Newcastle disease virus and vaccinia have been identified and/or clinically tested as oncolytic agents. Most recently Zika virus has been added to that list. A number of trials and applications have previously been approved with some of the oncolytic viruses. One of the potential problem with application of oncoviruses (virotherapy) is the development of an immune response, which can destroy the virus and thus prevent it from destroying the cancer. The early studies and trials had some setbacks and that was partly due to lack of technology to modify viruses. These technologies are now available and we have the Zika virus that is highly effective on brain cancer stem cells. I therefore think that there are exciting times ahead for Zika researchers.

Best wishes,

Refik

Finally we know the answer for why the Zika virus has become more virulent and increased incidence of microcephaly since 2013: A single serine to asparagine substitution (S139N) in the viral polyprotein substantially increased ZIKV infectivity in human neural progenitor cells.

Zika virus (ZIKV) has evolved into a global health threat due to its unexpected causal link to microcephaly. Phylogenetic analysis reveals that contemporary epidemic strains have accumulated multiple substitutions from their Asian ancestor. Here, we show that a single serine to asparagine substitution (S139N) in the viral polyprotein substantially increased ZIKV infectivity in both human and mouse neural progenitor cells (NPCs), led to more significant microcephaly in the mouse fetus, and higher mortality in neonatal mice. Evolutionary analysis indicates that the S139N substitution arose before the 2013 outbreak in French Polynesia and has been stably maintained during subsequent spread to the Americas. This functional adaption makes ZIKV more virulent to human NPCs, thus contributing to the increased incidence of microcephaly in recent ZIKV epidemics (L. Yuan et al., Science 10.1126/science.aam7120 (2017).

Dear followers,

A new study in December 2017 issue of Nature Neuroscience by Gladwyn-Ng et al is providing evidence how Zika virus at molecular level involved in congenital microcephaly. Stress-induced unfolded protein response contributes to Zika virus–associated microcephaly

The study shows that ZIKV triggers endoplasmic reticulum stress and unfolded protein response in the cerebral cortex of infected postmortem human fetuses as well as in cultured human neural stem cells. The study show that Zika infection triggers endoplasmic reticulum stress in embryonic brains in vivo. This perturbs a physiological unfolded protein response within cortical progenitors that controls neurogenesis. Thus, ZIKV-infected progenitors generate fewer projection neurons that eventually settle in the cerebral cortex, whereupon sustained endoplasmic reticulum stress leads to apoptosis. This is the first detailed explaination for how Zika may negatively effect development of cortex and cause microcephaly.

For details please follow the link below

Best wishes, Refik

Article Stress-induced unfolded protein response contributes to Zika...

Researchers need Zika data fast. This mobile app could deliver.

ZikaTracker is a mobile app developed by Alyson Kelvin and her colleagues in Brazil and at mWater. It gives patients and healthcare workers in communities affected by the Zika virus the opportunity to report the locations and symptoms of infections to the global research community...

https://www.researchgate.net/blog/post/researchers-need-zika-data-fast-this-mobile-app-could-deliver

Dear all, not knowing whether the following has been mentioned in this thread already, nevertheless honestly added:

article by MESCI P. et al, [unfortunately for me only PPV *) ]

'Modeling neuro-immune interactions during Zika virus infection'

Mesci P. et al.

Human Molecular Genetics, Volume 27, Issue 1, 1 January 2018, Pages 41–52,https://doi.org/10.1093/hmg/ddx382

Published: 17 October 2017

https://academic.oup.com/hmg/article-abstract/27/1/41/4557143?redirectedFrom=fulltext

Only for convenience here the Abstract:

"Although Zika virus (ZIKV) infection is often asymptomatic, in some cases, it can lead to birth defects in newborns or serious neurologic complications in adults. However, little is known about the interplay between immune and neural cells that could contribute to the ZIKV pathology. To understand the mechanisms at play during infection and the antiviral immune response, we focused on neural precursor cells (NPCs)-microglia interactions. Our data indicate that human microglia infected with the current circulating Brazilian ZIKV induces a similar pro-inflammatory response found in ZIKV-infected human tissues. Importantly, using our model, we show that microglia interact with ZIKV-infected NPCs and further spread the virus. Finally, we show that Sofosbuvir, an FDA-approved drug for Hepatitis C, blocked viral infection in NPCs and therefore the transmission of the virus from microglia to NPCs. Thus, our model provides a new tool for studying neuro-immune interactions and a platform to test new therapeutic drugs."

From this location (Salzburg) in Central Europe (today some hrs ago also was midwinter/winter solstice) I wish pleasant holidays, to anybody who celebrates: 'Merry Christmas' and either calm recreation or beautiful 'summer-event' -days (esp. for Refik!) best wishes and regards W. M.

*) NB: If there is anybody out there willing to share that article as a pdf only for personal learning (naturally respecting Copyright issues!) please remember '[email protected]' Thank you!

[some minutes after initial posting edited ONLY for some spelling errors in the text].

Dear Wolfgang,

Thank you very much the link for the paper indicating neuro-immune interactions in Zika virus infections involving microglia and neural precursor cells. This interaction increasingly seem to be the central part of the microcephaly resulting from Zika infections.

Thank you also for your good wishes for the festive season-yes indeed it is very hot here in Australia for Xmas-at the beach. I wish you also very best for the Xmas and the New year.

Refik