Secretion of Nonstructural Protein 1 of Dengue Virus from Infected Mosquito Cells: Facts and Speculations

Alcalá, Ana C.; Palomares, Laura A.; Ludert, Juan E.

doi:10.1128/jvi.00275-18

Cited by 26 publications

(21 citation statements)

References 40 publications

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“…The detailed understanding of this critical virus-cell interaction could open novel avenues for the development of better infection control strategies. We focus our discussion mainly on virion trafficking, as the mechanisms involved in secretion of the flavivirus protein NS1 have been recently reviewed in References [ 26 , 27 ]. Table 1 provides a succinct summary of the current state of knowledge of the involvement of cellular secretory pathway factors in the flavivirus life cycle.…”

Section: Introductionmentioning

confidence: 99%

Role of Host Cell Secretory Machinery in Zika Virus Life Cycle

Sager

Gabaglio

Sztul

et al. 2018

Viruses

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The high human cost of Zika virus infections and the rapid establishment of virus circulation in novel areas, including the United States, present an urgent need for countermeasures against this emerging threat. The development of an effective vaccine against Zika virus may be problematic because of the cross reactivity of the antibodies with other flaviviruses leading to antibody-dependent enhancement of infection. Moreover, rapidly replicating positive strand RNA viruses, including Zika virus, generate large spectrum of mutant genomes (quasi species) every replication round, allowing rapid selection of variants resistant to drugs targeting virus-specific proteins. On the other hand, viruses are ultimate cellular parasites and rely on the host metabolism for every step of their life cycle, thus presenting an opportunity to manipulate host processes as an alternative approach to suppress virus replication and spread. Zika and other flaviviruses critically depend on the cellular secretory pathway, which transfers proteins and membranes from the ER through the Golgi to the plasma membrane, for virion assembly, maturation and release. In this review, we summarize the current knowledge of interactions of Zika and similar arthropod-borne flaviviruses with the cellular secretory machinery with a special emphasis on virus-specific changes of the secretory pathway. Identification of the regulatory networks and effector proteins required to accommodate the trafficking of virions, which represent a highly unusual cargo for the secretory pathway, may open an attractive and virtually untapped reservoir of alternative targets for the development of superior anti-viral drugs.

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Section: Introductionmentioning

confidence: 99%

Role of Host Cell Secretory Machinery in Zika Virus Life Cycle

Sager

Gabaglio

Sztul

et al. 2018

Viruses

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“…The NS1 secretion of C6/36HT cells is not significantly inhibited when the cis and trans cisternae of the Golgi network are disrupted [ 28 , 29 ], or if the assembly of the coat protein II (COPII) complex is blocked, which is required for vesicle transport from the ER to the Golgi [ 28 , 29 ]. The secretion of NS1 by mosquito cells (C6/36HT) may be related to the caveolin-1 (CAV-1)-dependent pathway, which is associated with and relies on the caveolin chaperone complex (CCC) [ 28 , 29 , 30 , 31 ]. The efficiency of the CCC-based transport system in terms of NS1 secretion may be limited, because (i) it may not be used only for secretion, or (ii) this secretory route may depend on CCC complex formation.…”

Section: Discussionmentioning

confidence: 99%

Releasing Intracellular NS1 from Mosquito Cells for the Detection of Dengue Virus-Infected Mosquitoes

Cheng

Liu

et al. 2020

Viruses

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Dengue virus (DENV), the pathogen that causes dengue fever, is mainly transmitted by Aedes aegypti. Surveillance of infected mosquitoes is a major component of integrated mosquito control methods for reducing the risk of vector-born disease outbreaks. However, a specialized rapid test for DENV detection in mosquitoes is not currently available. Utilizing immunoblotting, we found that the secretion of NS1 from both a DENV-infected mosquito cell line and mosquito bodies was below the detection threshold. However, when Triton X-100 was used to lyse infected mosquitoes, intracellular NS1 was released, and could then be effectively detected by the NS1 rapid test. The distribution of DENV NS1 in intrathoracically infected mosquitoes was different from that of orally infected mosquitoes. Next, we performed sensitivity tests by bisecting mosquitoes longitudinally; one half of each mosquito was subjected to the NS1 rapid test while the other half was used for qPCR confirmation. This modified test had a sensitivity of nearly 90% from five days post-infection onwards, while DENV had escaped from the midgut barrier. This adapted test offers a valuable, easy-to-use tool for mosquito surveillance, which is a crucial component of DENV disease control.

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“…Although NS1 lacks a signal secretion in the N-terminal sequence, in vertebrate cells it follows a classical secretion pathway through Golgi to reach the extracellular space. In mosquito cells, an unconventional traffic route for secretion of DENV and ZIKV NS1 was observed, while in contrast, YFV NS1 seems to be secreted following the classical secretion route (11, 13). Given the presence of a conserved CBD in DENV and ZIKV NS1, but not in YFV NS1, a role for the CBD, as a molecular determinant, to direct the secretion fate within the Aedes endoplasmic reticulum architecture was proposed (13).…”

Section: Discussionmentioning

confidence: 99%

“…Secretion of YFV NS1 have been observed in mosquito cells albeit a higher concentration was maintained as cell-associated rather than secreted into the extracellular milieu (28); moreover, no NS1 secretion is observed in WNV or JEV infected mosquito cells (29, 30). Thus, the presence of an active CBD and the recognition of NS1 by the mosquito caveolin may be crucial for NS1 secretion in the mosquito, and suggest unique roles for the DENV and ZIKV soluble NS1 in the mosquito (11, 21).…”

Section: Discussionmentioning

confidence: 99%

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The secretory fate of flavivirus NS1 in mosquito cells is influenced by the caveolin binding domain

Ramirez

Ludert

2019

Preprint

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14Flaviviruses of major medical importance worldwide such as dengue (DENV), Zika (ZIKV), and 15 yellow fever (YFV) viruses are transmitted by mosquitoes Aedes sp. The non-structural protein 16 1 (NS1) of these flaviviruses is secreted from the infected cells using different secretion routes 17 depending on the cell and virus nature. The NS1 of DENV and ZIKV contain in the hydrophobic 18 region a conserved caveolin binding domain (CBD) (XXXXXX), which is not conserved in 19 YFV NS1. To ascertain the role of the CBD in the secretory route followed by flavivirus NS1, 20 expression vectors for the NS1 of DENV2, ZIKV and YFV were constructed. Using site-directed 21 mutagenesis, substitutions were made in the aromatic residues within CBD; in addition, the full 22 domain was replaced by those of other flaviviruses, creating chimeras in the CBD of NS1. 23 Substitutions of the aromatic residues to Ala or Thr, or CBD chimeras, results in increased 24 sensitivity of NS1 secretion to brefeldin A treatment, indicating a change to a classical secretion 25 pathway. Likewise, the insertion of the DENV/ZIKV CBD into the recombinant Gaussia-26 130 Gaussia Luc in DENV2-NS1. This insertion was introduced only in the DENV2-NS1 construct. 5.131 General experimental strategy with constructs. All mutations, insertions and chimera constructions 132 were transfected in C6/36 cells and NS1 secretion to the supernatants in cells treated or not with BFA 133 determined by ELISA. 134 135 136 441 2015-1 254461 to JEL. Authors declare no conflict of interest. 442 443 444

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Secretion of Nonstructural Protein 1 of Dengue Virus from Infected Mosquito Cells: Facts and Speculations

Cited by 26 publications

References 40 publications

Role of Host Cell Secretory Machinery in Zika Virus Life Cycle

Role of Host Cell Secretory Machinery in Zika Virus Life Cycle

Releasing Intracellular NS1 from Mosquito Cells for the Detection of Dengue Virus-Infected Mosquitoes

The secretory fate of flavivirus NS1 in mosquito cells is influenced by the caveolin binding domain

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