ImageSource=RCSB PDB; StructureID=5mrk; DOI=http://dx.doi.org/10.2210/pdb5mrk/pdb;

Structural basis of Zika virus methyltransferase inhibition by sinefungin

New high resolution structure of ZIKV NS5 methyltransferase with the inhibitor sinefugin is available in Protein Data Bank (PDB ID: 5MRK).

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srep40920-f1

The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication

Zika virus (ZIKV) is a member of the Flaviviridae family, along with other agents of clinical significance such as dengue (DENV) and hepatitis C (HCV) viruses. Since ZIKV causes neurological disorders during fetal development and in adulthood, antiviral drugs are necessary. Sofosbuvir is clinically approved for use against HCV and targets the protein that is most conserved among the members of the Flaviviridae family, the viral RNA polymerase. Indeed, we found that sofosbuvir inhibits ZIKV RNA polymerase, targeting conserved amino acid residues. Sofosbuvir inhibited ZIKV replication in different cellular systems, such as hepatoma (Huh-7) cells, neuroblastoma (SH-Sy5y) cells, neural stem cells (NSC) and brain organoids. In addition to the direct inhibition of the viral RNA polymerase, we observed that sofosbuvir also induced an increase in A-to-G mutations in the viral genome. Together, our data highlight a potential secondary use of sofosbuvir, an anti-HCV drug, against ZIKV.

Figure 1

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Potential use of saliva samples to diagnose Zika virus infection

Serological diagnosis of ZIKV in countries where dengue virus (DENV) is endemic is challenging, because antibodies elicited by a prior DENV infection may cross-react against ZIKV. Therefore, molecular techniques, such as conventional or real-time reverse transcriptase polymerase chain reaction (RT-PCR/qRT-PCR), remain the reference methods for the diagnosis of ZIKV. However, the sensitivity of ZIKV RT-PCR in serum samples is not optimal due to low and short viremia. Here, we describe findings from a case series of acute febrile illness patient’s whose saliva and blood samples were tested for ZIKV by qRT-PCR.

 

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1-s2.0-S1476945X1630112X-gr1

Mathematical model for Zika virus dynamics with sexual transmission route

Zika virus is a flavivirus transmitted to humans primarily through the bite of infected Aedes mosquitoes. In addition to vector-borne spread, however, the virus can also be transmitted through sexual contact. In this paper, we formulate and analyze a new system of ordinary differential equations which incorporates both vector and sexual transmission routes. Theoretical analysis of this model when there is no disease induced mortality shows that the disease-free equilibrium is locally and globally asymptotically stable whenever the associated reproduction number is less than unity and unstable otherwise. However, when we extend this same model to include Zika induced mortality, which have been documented in Latin America, we find that the model exhibits a backward bifurcation. Specifically, a stable disease-free equilibrium co-exists with a stable endemic equilibrium when the associated reproduction number is less than unity. To further explore model predictions, we use numerical simulations to assess the importance of sexual transmission to disease dynamics. This analysis shows that risky behavior involving multiple sexual partners, particularly among male populations, substantially increases the number of infected individuals in the population, contributing significantly to the disease burden in the community.

Flow diagram of the Zika virus model (2.5) with sexual transmission route.

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ImageSource=RCSB PDB; StructureID=5mfx; DOI=http://dx.doi.org/10.2210/pdb5mfx/pdb;

Zika NS3 helicase:RNA complex

New high resolution structure of ZIKV NS3 helicase is available in Protein Data Bank (PDB ID: 5MFX)

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F2.medium

Vulnerability of primitive human placental trophoblast to Zika virus

Infection of pregnant women by Asian lineage strains of Zika virus (ZIKV) has been linked to brain abnormalities in their infants, yet it is uncertain when during pregnancy the human conceptus is most vulnerable to the virus. We have examined two models to study susceptibility of human placental trophoblast to ZIKV: cytotrophoblast and syncytiotrophoblast derived from placental villi at term and colonies of trophoblast differentiated from embryonic stem cells (ESC). The latter appear to be analogous to the primitive placenta formed during implantation. The cells from term placentas, which resist infection, do not express genes encoding most attachment factors implicated in ZIKV entry but do express many genes associated with antiviral defense. By contrast, the ESC-derived trophoblasts possess a wide range of attachment factors for ZIKV entry and lack components of a robust antiviral response system. These cells, particularly areas of syncytiotrophoblast within the colonies, quickly become infected, produce infectious virus and undergo lysis within 48 h after exposure to low titers (multiplicity of infection > 0.07) of an African lineage strain (MR766 Uganda: ZIKVU) considered to be benign with regards to effects on fetal development. Unexpectedly, lytic effects required significantly higher titers of the presumed more virulent FSS13025 Cambodia (ZIKVC). Our data suggest that the developing fetus might be most vulnerable to ZIKV early in the first trimester before a protective zone of mature villous trophoblast has been established. Additionally, MR766 is highly trophic toward primitive trophoblast, which may put the early conceptus of an infected mother at high risk for destruction.

Fig. 2.

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f1-medium

Characterization of cytopathic factors through genome-wide analysis of the Zika viral proteins in fission yeast

The Zika virus (ZIKV) causes various neurologic defects including microcephaly and the Guillain-Barré syndrome. However, little is known about how ZIKV causes those diseases or which viral protein(s) is responsible for the observed cytopathic effects involved in restricted neuronal cellular growth, dysregulation of the cell cycle, and induction of cell hypertrophy or cell death. A genome-wide analysis of ZIKV proteins and peptides was conducted using fission yeast as a surrogate host. Seven ZIKV proteins conferred various cytopathic effects in which NS4A-induced cellular hypertrophy and growth restriction were mediated through the target of rapamycin (TOR) cellular stress-response pathway. These findings provide a foundation for identifying viral pathogenicity factors associated with the ZIKV diseases.

Fig. 1.

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1-zikavirus

Researchers identify key proteins that may make Zika so deadly

Until it burst onto the scene earlier this year, Zika was an obscure, little-known virus. As a result, scientists know little about how it works. Over the past year, they have learned that it can cause a range of dangerous health problems, including birth defects such as microcephaly and neurological problems such as Guillain-Barré syndrome. But they don’t know which Zika protein or proteins are causing harm, or exactly how these proteins cause damage.

Now, a new study by scientists at the University of Maryland School of Medicine (UM SOM) has for the first time identified seven key proteins in the virus that may be the culprits behind this damage. The study is the first comprehensive description of the Zika virus genome. The study was published today in the journal Proceedings of the National Academy of Sciences.

Zika virus

nsmb.3352-F2

Structure of the immature Zika virus at 9 Å resolution

The current Zika virus (ZIKV) epidemic is characterized by severe pathogenicity in both children and adults. Sequence changes in ZIKV since its first isolation are apparent when pre-epidemic strains are compared with those causing the current epidemic. However, the residues that are responsible for ZIKV pathogenicity are largely unknown. Here we report the cryo-electron microscopy (cryo-EM) structure of the immature ZIKV at 9-Å resolution. The cryo-EM map was fitted with the crystal structures of the precursor membrane and envelope glycoproteins and was shown to be similar to the structures of other known immature flaviviruses. However, the immature ZIKV contains a partially ordered capsid protein shell that is less prominent in other immature flaviviruses. Furthermore, six amino acids near the interface between pr domains at the top of the spikes were found to be different between the pre-epidemic and epidemic ZIKV, possibly influencing the composition and structure of the resulting viruses.

Cross-section of the immature ZIKV contoured to show the inner capsid shell.

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who

Fifth meeting of the Emergency Committee under the International Health Regulations (2005) regarding microcephaly, other neurological disorders and Zika virus

The Public Health Emergency of International Concern (PHEIC) declared by the Director-General of WHO has led the world to an urgent and coordinated response, providing the understanding that Zika virus infection and associated consequences represent a highly significant long-term problem that must be managed by WHO, States Parties and other partners in a way that other infectious disease threats are managed.

The EC originally recommended a PHEIC in February 2016 on the basis of an extraordinary cluster of microcephaly and other neurological disorders reported in Brazil, following a similar cluster in French Polynesia and geographic and temporal association with Zika virus infection which required urgent and coordinated and research. Because research has now demonstrated the link between Zika virus infection and microcephaly, the EC felt that a robust longer-term technical mechanism was now required to manage the global response.

As a result, the EC felt that Zika virus and associated consequences remain a significant enduring public health challenge requiring intense action but no longer represent a PHEIC as defined under the IHR. Many aspects of this disease and associated consequences still remain to be understood, but this can best be done through sustained research. The EC recommended that this should be escalated into a sustained programme of work with dedicated resources to address the long-term nature of the disease and its associated consequences.

The Committee reviewed the recommendations made at its previous meetings and agreed that WHO and partners had systematically addressed their advice. Furthermore, the EC reviewed and agreed to the WHO Zika transition plan outlined to establish the longer-term response mechanism which delivers the strategic objectives already identified in the Zika Strategic Response Plan.

Based on this advice, the Director-General declared the end of the Public Health Emergency of International Concern (PHEIC). The Director-General reissued the Temporary Recommendations from the previous meetings of the Committee which will be incorporated into the longer-term response mechanism. The Director-General thanked the Committee Members and Advisors for their advice over the past year.

who

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