| Compass | Actuality | Patent View | Curiosity box |
BIOTEOMED.ORG
| Zika virus 2019 |
| PRECLINICAL
RESEARCH Zika Neurotropism: what is going on? Epidemiological
experience so far have taught us that approximately 80% of Zika virus (ZIKV)
infections go asymptomatic.
Those with the development of mild clinical symptoms, harbor the
infection with
an incubation period of 3 to 13 days usually followed by a one-week
course of the disease possibly including rash, minor fever,
conjunctivitis, arthralgia and myalgia, regardless of the age and sex
of the infected host1.
Like
other arboviruses, for cellular entry, ZIKV target
different tissue types of the host (by surface adhesion,
Zika surface ‘E’ proteins),
but its target cell preference and mechanism of damaging target
cells have shown some new attributes as of
the Central and Latin American epidemics in
2015-2018 (for
details see Actuality
2016, 2017,
2018). In
these outbreaks, unlike
the Zika-Africa and the Zika-Asia lines, the
Zika-America virus
strains circulating most
notably in Brazil, could
cause death in utero
and in newborn
and, could provoke congenital
Zika syndrome with the phenotypic manifestation of
microcephaly.
The
transplacenta neurotropic and teratogenic potential of ZIKV in
embryonic neurogenesis1,2,3;
the pathogenic potential of ZIKV in the development of adult
neurological (encephalopathy, encephalitis, meningitis,
myelitis ...) and autoimmune neurological, haematological
disorders (e.g. Guillain-Barré syndrome, immune
thrombocytopenia), its role in the exacerbation of
existing symptoms 4,5,6,
are now already
proven.
Having
exposed to intrauterine ZIKV infection, progenitor
cells of neural morphogenesis have been reported with
different susceptibility to ZKV virus in a review of studies
on concordant (affected-affected)
and discordant (affected-healthy) twin
pairs born with congenital Zika syndrome7.
A
total of 2 pairs of monozygotic and 7 pairs of dizygotic twins were
tested. Monozygotic twins were all affected. Among dizygotic twins 6
pairs were discordant for
congenital Zika syndrome, and 1 pair was concordant for it (both members of the pair were sick).
Among the results described in the communication, the following are to be highlighted.
*In neural progenitor cells
prepared from neonatal blood samples of twins discordant
for congenital Zika syndrome, the in vitro expression pattern of key
genes determining neural development, differs significantly (e.g. mTOR and Wnt
signaling pathways).
*In
neural progenitor cells prepared from neonatal blood samples
of twins discordant for congenital Zika syndrome, the in vitro susceptibility to additional ZIKV
infection (enhanced reproduction of virus, virus induced pathological disorders) in cells from affected twins is significantly higher compared to cells from healthy twins.
*The phenomena described
above seem not to be determined by major genes, so one
can assume that congenital Zika syndrome is a multifactorial
disease, the development of which is also significantly influenced
by molecular mechanisms regulating cellular metabolic events in
the host.
*The in vitro growth
pattern of neural progenitor cells prepared from affected and healthy
blood samples proved to be the same. A different in vitro growth pattern was induced by additional ZIKV infection in the cell cultures. *In
developing and regenerating biological systems, including
embryonal neurogenesis, multiple divisions of stem cells,
progenitor cells create cell mass essential for further
developmental steps. Due to cellular gene expression patterns
and the interactive and modulating intracellular-extracellular
morphogenic guides (e.g. metabolic and patterning signals, intracellular and extracellular signalizations)
the cell mass resulting from serial divisions get through a complex
highway with milestones of cell migration, cell adhesion, cell
determination,
differentiation, morphogenesis, and synaptogenesis.
The milestones in the process are as well criteria and
consequences of each other; crucial error(s) in any of them can
result in unbalanced growth, distorted differentiation, impaired
morphogenesis, or even teratogenesis. The same
stand for adult neural progenitor cell populations capable to divide in the adult (see hippocampus region GD-ZSG, zona
subventricularis neurogenic region) 8, 9, 10
.
The significant difference between the
in vitro expression pattern of key genes determining neural
development of progenitor cells of affected and healthy
twins, is in fact a prospective possibility for distorted neurogenesis provoked by intrauterine ZIKV infection.
From this prospective possibility the pathological realization will not come as a rule; additional in
vitro ZIKV infection as inducer was needed for the pathological "overwriting" of gene expression pattern when determining the distortion.
The above seem to be proven by life, since - fortunately - ZIKV-infected pregnancies do not end in congenital Zika syndrome, provided that infection occurs relatively late, after the 25th week of gestation 11. Increased susceptibility of neural progenitor cells to ZIKV infection has been confirmed in animal experiments and in vitro organoid cultures12. In
ZIKV-infected progenitor cells, cell cycle shifts were also
observed, i.e. cells were occasionally stopped in G1, S, or
G2 phases of the cycle, often lacking cell division (M phase).
Since other Flaviviruses were lacking this characteristic, it
was therefore assessed as a Zika-specific effect. 13.
Thus, in neural progenitor
cells, ZIKV infection interferes with the cell cycle; this
interference prevents the formation of the cell mass essential for
neurogenesis (corticogenesis), consequently it serves as a passport for
deformations (chromosome aberrations, mitochondrial defects, size changes ...) to occur
14.
1. Musso D.,Ko A.I.,Baud D. (2019): Zika Virus Infection - After the Pandemic N.Engl.J.Med. 381: 1444 - 1457. DOI: 10.1056/NEJMra1808246 2. Mlakar J. et al. (2016): Zika virus associated with microcephaly N.Engl.J.Med 374: 951-958. 3. Shapiro-Mendoza C.K. et al. (+51) (2017): Pregnancy Outcomes After Maternal Zika Virus Infection During Pregnancy - U.S. Territories, January 1, 2016 - April 25, 2017 MMWR Morb Mortal Wkly Rep. 66: 615-621. PMCID: PMC5657842 4. Dirlikov E. et al.(+16)(2018): Clinical Features of Guillain-Barré Syndrome With vs Without Zika Virus Infection, Puerto Rico, 2016 JAMA Neurol. 2018 Sep; 75(9): 1089–1097. PMCID: PMC6143122 5. Gorshkov K. et al.(+9)(2019): Zika Virus: Origins, Pathological Action, and Treatment Strategies Front. Microbiol. https://doi.org/10.3389/fmicb.2018.03252 6. Muñoz L.S., et al. (2017):
Neurological Implications of Zika Virus Infections in Adults J.Infect. Dis. 216 (Suppl.10): S897-S905.
7.
Caires-Júnior L.C. et al.(+41)(2018): Discordant congenital Zika
syndrome twins show differential in vitro viral susceptibility of
neural progenitor cells Nat.Commun. 9: 475 PMCID:
PMC5797251 doi: 10.1038/s41467-017-02790-9 8. Urbán
N., Guillemot F.(2014): Neurogenesis in the embryonic and adult brain:
same regulators, different roles Front.Cell.Neurosci. 8: 396.PMCID:
PMC4245909 doi: 10.3389/fncel.2014.00396
9. Alvarez-Buylla A., Garcia-Verdugo J.M.(2002): Neurogenesis in Adult Subventricular Zone J.Neurosci. 22: 629-634. DOI: https://doi.org/10.1523/JNEUROSCI.22-03-00629.2002 10. Cornell B., Toyo-oka K. (2017): Front.Mol.Neurosci. 10: 318. PMCID: PMC5643407 doi: 10.3389/fnmol.2017.00318 11. Lima G.P. et al.(2019): Factors associated with the development of Congenital Zika Syndrome: a case-control study BMC Infect.Dis. 19: 277. doi:10.1186/s12879-019-3908-4 12. Chen H.I. et al.(2019): Applications of Human Brain Organoids to Clinical Problems Developmental Dynamics 248: 53-64. https://doi.org/10.1002/dvdy.24662 13. Brault J.B. et al.(2016): Comparative analysis between flaviviruses reveals specific neural stem cell tropism for Zika virus in the mouse developing neocortex. EBioMedicine 10: 71–76. PMCID: PMC5006693 doi: 10.1016/j.ebiom.2016.07.018 14. Wen Z. et al.(2017): How does Zika virus cause microcephaly? Genes & Dev. 31: 849-861. doi: 10.1101/gad.298216.117 |
CLINICAL
TRIALS for
history:
Actuality 2017/Zika
virus/.....Zika
vaccine constructs ...
Actuality 2018 / Zika virus/ ..... Clinical trials ... Purified inactivated Zika virus: conventional active immunization
Plasmid DNA vaccine coding for virus surface structural proteins 'prM-E' or 'M-E'
messenger RNA (mRNA) Vaccine coding for virus surface structural proteins
2. NCT04064905 / situation on 08-12-2019: Recruiting Safety, Tolerability, and Immunogenicity of Zika Vaccine mRNA-1893 in Healthy Flavivirus Seropositive and Seronegative Adults Study Start Date: July 30, 2019 Estimated Study Completion Date: July, 2021 Location: US Nebraska, US Texas, Puerto Rico Sponsors and Collaborators: ModernaTX Inc., Biomedical Advanced Research and Development Authority
Recombinant measles vaccine coding for virus surface antigens
Source:
ClinicalTrials.gov
PubMed |
| Compass | Actuality | Patent View | Curiosity box |
| Copyright© www.bioteomed.org |
Contact:
btm(at)bioteomed(dot)org
nature,
science, research, invention, industry, biology, physics, chemistry,
agriculture, medicine, drugs, patents, technology, literature, arts,
education
|