MEPPitope: spatial, electrostatic and secondary structure perturbations in the post-fusion Dengue virus envelope protein highlights known epitopes and conserved residues in the Zika virus
Abstract:The dramatic transformation of the Zika virus (ZIKV) from a relatively unknown virus to a pathogen generating global-wide panic has exposed the dearth of detailed knowledge about this virus. Decades of research in the related Dengue virus (DENV), finally culminating in a vaccine registered for use in endemic regions (CYD-TDV), provides key insights in developing strategies for tackling ZIKV. The previously established MEPP methodology compares two conformations of the same protein and identifies residues with … Show more
“…The observed mutations in the 2011 Panamanian strains not previously described (A50T from E protein, V71I from NS2A, H249Y from NS3) need to be studied to determine if they are implicated in viral fitness or immune responses. Indeed A50 is one of the residues from the C chain of the E protein that interacts with a potent DENV antibody 49 , thus the A50T substitution could play a role in antibody recognition or other immune responses.…”
The circulation of the South-east Asian/American (AS/AM) dengue 2 virus (DENV-2) genotype in the Americas has been associated with a high rate of severe disease. From 1993, the year DENV was reintroduced in Panama, until 2011 there were 29 dengue-associated deaths, 17 of which occurred in 2011, the most severe outbreak with a case fatality rate (CFR) of 44% (17 deaths out of 38 severe dengue cases). During this outbreak DENV-2 was reintroduced into the country, whereas over the prior five years DENV-1 and −3 were predominant. Herein, we describe the 2011 Panama outbreak and genetically characterize the Panamanian DENV-2 strains, which were associated with severe dengue disease in Panama. Our results suggest that the DENV-2 isolates from this outbreak belonged to the AS/AM genotype sub-clade 2BI and were genetically close to viruses described in the outbreaks in Nicaragua, Honduras, Guatemala and Mexico from 2006–2011. Sub-clade 2BI has previously been associated with severe disease in Nicaragua during outbreaks from 2005–2007.
“…The observed mutations in the 2011 Panamanian strains not previously described (A50T from E protein, V71I from NS2A, H249Y from NS3) need to be studied to determine if they are implicated in viral fitness or immune responses. Indeed A50 is one of the residues from the C chain of the E protein that interacts with a potent DENV antibody 49 , thus the A50T substitution could play a role in antibody recognition or other immune responses.…”
The circulation of the South-east Asian/American (AS/AM) dengue 2 virus (DENV-2) genotype in the Americas has been associated with a high rate of severe disease. From 1993, the year DENV was reintroduced in Panama, until 2011 there were 29 dengue-associated deaths, 17 of which occurred in 2011, the most severe outbreak with a case fatality rate (CFR) of 44% (17 deaths out of 38 severe dengue cases). During this outbreak DENV-2 was reintroduced into the country, whereas over the prior five years DENV-1 and −3 were predominant. Herein, we describe the 2011 Panama outbreak and genetically characterize the Panamanian DENV-2 strains, which were associated with severe dengue disease in Panama. Our results suggest that the DENV-2 isolates from this outbreak belonged to the AS/AM genotype sub-clade 2BI and were genetically close to viruses described in the outbreaks in Nicaragua, Honduras, Guatemala and Mexico from 2006–2011. Sub-clade 2BI has previously been associated with severe disease in Nicaragua during outbreaks from 2005–2007.
“…Flavivirus E proteins belong to the class-II fusion protein, which has a unique structure with a double membrane spanning the C-terminal anchor. Following the EDI/EDII/EDIII domains is a stem region that contains two cationic amphipathic helix-transmembrane domains (TMDs, TM1, and TM2) [ 5 ]. TM1 is the stop transfer sequence, and TM2 is the internal signal sequence ( Figure 2 ) that directs the proper processing and localization of the NS1 protein [ 35 ].…”
“…Most flaviviruses are zoonotic, meaning that infections may spread between animals and humans [ 2 , 3 ]. Many flaviviruses are associated with human diseases [ 4 , 5 ]. Presently, the yellow fever virus (YFV), Dengue virus (DENV), West Nile virus (WNV), tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV) [ 6 , 7 , 8 ], Tembusu virus (TMUV) [ 9 ], and Zika virus (ZIKV) [ 10 , 11 ] are the most important arboviruses that threaten humans and animals in certain regions of the world, causing public health burdens and veterinary concerns.…”
Flaviviruses are enveloped, single-stranded RNA viruses that widely infect many animal species. The envelope protein, a structural protein of flavivirus, plays an important role in host cell viral infections. It is composed of three separate structural envelope domains I, II, and III (EDI, EDII, and EDIII). EDI is a structurally central domain of the envelope protein which stabilizes the overall orientation of the protein, and the glycosylation sites in EDI are related to virus production, pH sensitivity, and neuroinvasiveness. EDII plays an important role in membrane fusion because of the immunodominance of the fusion loop epitope and the envelope dimer epitope. Additionally, EDIII is the major target of neutralization antibodies. The envelope protein is an important target for research to develop vaccine candidates and antiviral therapeutics. This review summarizes the structures and functions of ED I/II/III, and provides practical applications for the three domains, with the ultimate goal of implementing strategies to utilize the envelope protein against flavivirus infections, thus achieving better diagnostics and developing potential flavivirus therapeutics and vaccines.
“…Now, the sequences and in some cases the crystal structure of different important Zika virus proteins are available and they can be targeted through computational drug designing techniques [114][115][116][117]. Similarly, the already available data on the closely related viruses like dengue virus enzymes can be exploited for novel drug design [118]. In mouse model, it was noted that 25-hydroxycholesterol prevents the entry of virus particles inside the cell and is the first line of defense molecule [119].…”
Zika virus is an arbovirus that is spreading at an alarming state in the American continents and now in Asian countries. The Aedes mosquitoes are the vectors for the spread of this virus beside other ways of transmission. Currently, there are no vaccines or drugs available for its treatment. The Zika virus-related microcephaly cases are reported in fetuses of pregnant women who got this viral infection. However, the exact mechanism of Zika virus and microcephaly is still not established. Here we review Zika virus epidemiology, its unusual relationship with microcephaly in fetuses and current scientific research progress on it.not favorable for Aedes mosquitos [35]. In such areas, blood and semen donations should be properly checked for the presence of Zika virus, and further, people coming from affected areas should take care when they donate blood and semen in unaffected areas [36].
Relation between Zika virus and microcephalyMicrocephaly is one of the associated medical effects of Zika virus infection in mothers with their new born babies [36][37][38][39][40]. In the past, cases of Zika virus with microcephaly were not that common, but in Brazil, it was observed that the rate of microcephaly is twenty times more, which is quite alarming and new cases are still emerging [41]. Zika virus has the capacity to cross the placental barrier and infect the fetus [42,43]. The infected mothers of these babies have rashes in the first and second trimesters [44]. Beside microcephaly, brain calcifications, cataracts and intraocular calcifications of eyes in fetuses are also reported [45]. In other cases, agyria, hydrocephalus and associated cortical displacement and mild focal inflammation are also present [46][47][48]. Similarly in another case in addition to the above-mentioned symptoms,
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