Nat Neurosci: Inhibiting AHR receptors can reduce Zika virus replication and prevent microcephaly in mice.

!--:pagetitle"--2,2020 --Upi 2020 (UPI) --- -- Researchers from Harvard Medical School in the United States, the University of Sao Paulo in Brazil and the University of Buenos Aires in Argentina found that inhibiting aromatic hydrocarbon receptors (aryl hydrocarbon receptor, AHR) --- a protein that regulates immunity, stem cell maintenance, and cell differentiation--- allows the immune system to fight the Zika virus more effectively in replication in the body.
in experiments conducted in the biomedical science sainscience synodatily at the University of Sao Paulo in Brazil, the antiviral therapy has been shown to prevent microcephaly and other malformations in the fetuses of infected female rats during pregnancy.
the results of the study, recently published in the journal Nature Neuroscience, are entitled "AHR is a Zika virus host factor and a candidate target for antiviral therapy".
the authors of the paper are Jean Pierre Schatzmann Peron of the Institute of Biomedical Sciences at the University of Sao Paulo in Brazil, Cybele C. Garcia, a virologist at the University of Buenos Aires, and Francisco J. Quintana, professor of neurology at Harvard Medical School.
images from Nature Neuroscience, 2020, doi:10.1038/s41593-020-0664-0. "In the experiment, we used an experimental drug that inhibits AHR and observed a decrease in replication of both the Zika and dengue viruses,"
Peron said.
We now plan to test the effectiveness of the drug against the new coronavirus SARS-CoV-2.
" the experimental model used in this study is the same as that used by Peron's team in 2016 to confirm a causal link between the Zika virus and microcephaly."
in experiments at the time, female mice with the SJL lineage were more susceptible to The Zika virus than other experimental animals, and they were infected between the tenth and twelfth days of pregnancy.
when young mice were born, they found a significant reduction in the thickness of their cortex and a change in the number and morphology of cortical and other brain cells.
they also found that the virus replicates much faster in the brains of the placenta and in young mice than other organs. "We repeat the experiment, but there are differences,"
Peron said.
shortly before we infected pregnant mice with the Zika virus, we started having them take this AHR inhibitor orally.
treatment continues until the end of pregnancy.
the brains and weight of the young mice were normal, and the viral load was much lower than in the untreated control group.
the viral load of the placenta and central nervous system is almost undetectable.
, histopathological analysis showed that the thickness of the cortex did not decrease and that the number of nervous system cells killed by the virus was much smaller.
" according to Peron, mice treated with this AHR inhibitor did not have any adverse reactions, but the test must be repeated in monkeys before the drug could be tested in human volunteers.
launch edified Quintana Laboratory is one of the world's leading centres for the study of AHR proteins.
Quintana says his team discovered several years ago that interferons, the proteins produced by immune cells in response to the inflammatory response to infection, control the activation of AHR. "Given that interferon is at the heart of the antiviral immune response, we worked with the Garcia team to speculate that AHR may have been involved in the suppression of antiviral immunity,"
Quintana said.
we have designed anti-AHR therapies and developed nanoparticles and inhibitors for experiments.
" tests in laboratories and animals confirmed that the Zika virus activates AHR to suppress the host's immune response.
this can happen when the pathogen infects the liver, triggering the release of the tryptophan metabolite, kynurenine. "This metabolite activates AHR, which inhibits the expression of another protein called PML (promyelocytic leukemia protein, early granulocytic leukemia protein) --- is important for an antiviral immune response -- allowing the Zika virus to replicate more freely in cells,"
Peron said.
" at the University of Buenos Aires, Garcia led experiments on a variety of cell lines, including liver cells and neurogenic cells, stem cells that can differentiate into neurons and glial cells. "We treated these cell lines with The AHR agonists ( amplified the effects of this protein ) and AHR antagonists , " said
Garcia .
in this way, we confirmed that negative regulation of this receptor inhibits replication of the Zika virus.
in the same way, we have shown that positive regulation of this receptor promotes the replication of the virus in cells.
" Environmental Factor Garcia said the impact of the 2015 Zika outbreak was highly asymmetric.
in some regions and cities, the incidence of congenital syndrome and microcephaly caused by the virus is much higher than elsewhere.
in her view, this may be because environmental factors are conducive to infection in the hard-hit areas, or because residents there are more vulnerable to infection.
both factors may also contribute to the effects of the Zika virus. "Coincidentally, AHR can be activated by environmental contaminants, specific diets, or endogenous microbiomes,"
Garcia said.
our next challenge is to exclude or confirm a link between AHR, contaminated or socio-degraded environments, and increased toxicity to the Zika virus.
" (bioon.com) References: 1. Federico Giovannoni et al. AHR is a zika virus virus factor and a candidate target for antiviral. Nature Neuroscience, 2020, doi: 10.1038/s41593-020-0664-0.2. The Brazilian Zika virus strain strain strain strain sons synth defects in the models. Nature, 2016, doi:10.1038/nature18296.4. Zika virus brain cells bouts intra uterine growth of mice mice sydd sydd title """"!--/ewebeditor:page-.