Abstract:Dengue virus (DENV), a member of Flaviviridae family, has become neurovirulent in humans after rapid geographical expansion. Host proteasomal machinery contains both ubiquitin ligases as well as deubiquitinases (DUBs), known to influence key cellular and biological functions. MicroRNA‐mediated modulations of DUBs in case of DENV infections have not been explored yet. DENV propagation, MiRNA overexpression, miRNA knockdown, transfection, RT‐PCR, luciferase assay, and western blotting have been used in this stud… Show more
“…We reported TRAF3 being regulated by miR-32 in human microglial cells upon the exposure of HIV-1 Tat protein [76]. Our recent finding of Dengue NS5-mediated perturbation of miR-590 and consequent suppression of a de-ubiquitinase protein, USP42 indicated that how microRNAs could play a critical role in DENV pathogenesis [77]. Figure 3.Exosomal microRNA cargo contributes to DENV pathogenesis.…”
Section: Role Of Micrornas In Denv Severitymentioning
Dengue fever is one of those unique diseases where host immune responses largely determine the pathogenesis and its severity. Earlier studies have established the fact that dengue virus (DENV) infection causes haemorrhagic fever and shock syndrome, but it is not directly responsible for exhibiting these clinical symptoms. It is noteworthy that clinically, vascular leakage syndrome does not develop for several days after infection despite a robust innate immune response that elicits the production of proinflammatory and proangiogenic cytokines. The onset of hyperpermeability in severe cases of dengue disease takes place around the time of defervescence and after clearance of viraemia. Extracellular vesicles are known to carry biological information (mRNA, miRNA, transcription factors) from their cells of origin and have emerged as a significant vehicle for horizontal transfer of stress signals. In dengue virus infection, the relevance of exosomes can be instrumental since the majority of the immune responses in severe dengue involve heavy secretion and circulation of pro-inflammatory cytokines and chemokines. Here, we present an updated review which will address the unique and puzzling features of hyperpermeability associated with DENV infection with a special focus on the role of secreted extracellular vesicles.
“…We reported TRAF3 being regulated by miR-32 in human microglial cells upon the exposure of HIV-1 Tat protein [76]. Our recent finding of Dengue NS5-mediated perturbation of miR-590 and consequent suppression of a de-ubiquitinase protein, USP42 indicated that how microRNAs could play a critical role in DENV pathogenesis [77]. Figure 3.Exosomal microRNA cargo contributes to DENV pathogenesis.…”
Section: Role Of Micrornas In Denv Severitymentioning
Dengue fever is one of those unique diseases where host immune responses largely determine the pathogenesis and its severity. Earlier studies have established the fact that dengue virus (DENV) infection causes haemorrhagic fever and shock syndrome, but it is not directly responsible for exhibiting these clinical symptoms. It is noteworthy that clinically, vascular leakage syndrome does not develop for several days after infection despite a robust innate immune response that elicits the production of proinflammatory and proangiogenic cytokines. The onset of hyperpermeability in severe cases of dengue disease takes place around the time of defervescence and after clearance of viraemia. Extracellular vesicles are known to carry biological information (mRNA, miRNA, transcription factors) from their cells of origin and have emerged as a significant vehicle for horizontal transfer of stress signals. In dengue virus infection, the relevance of exosomes can be instrumental since the majority of the immune responses in severe dengue involve heavy secretion and circulation of pro-inflammatory cytokines and chemokines. Here, we present an updated review which will address the unique and puzzling features of hyperpermeability associated with DENV infection with a special focus on the role of secreted extracellular vesicles.
“…MicroRNAs participate in regulation of almost all cellular and physiological processes of an organism namely developmental transitions, neuronal patterning/ functions, apoptosis, cell cycle, metabolism, immune responses, inflammation and host-pathogen interaction etc (34). Viral infections such as Dengue virus infection, ZIKV, JEV, HCV, HIV, herpesvirus, polyomavirus, retroviruses, pestivirus, and hepacivirus are extensively known to play with host microRNA machinery for their successful life cycle (29,(35)(36)(37). It have been reviewed in detail elsewhere (33,34,38).…”
SARS-CoV-2, the novel coronavirus infection has consistently shown an association with neurological anomalies in patients, in addition to its usual respiratory distress syndrome. Multi-organ dysfunctions including neurological sequelae during COVID-19 persist even after declining viral load. We propose that SARS-CoV-2 gene product, Spike, is able to modify the host exosomal cargo, which gets transported to distant uninfected tissues and organs and can initiate a catastrophic immune cascade within Central Nervous System (CNS). SARS-CoV-2 Spike transfected cells release a significant amount of exosomes loaded with microRNAs such as miR-148a and miR-590. microRNAs gets internalized by human microglia and suppress target gene expression of USP33 (Ubiquitin Specific peptidase 33) and downstream IRF9 levels. Cellular levels of USP33 regulate the turnover time of IRF9 via deubiquitylation. Our results also demonstrate that absorption of modified exosomes effectively regulate the major pro-inflammatory gene expression profile of TNFα, NF-κB and IFN-β. These results uncover a bystander pathway of SARS-CoV-2 mediated CNS damage through hyperactivation of human microglia. Our results also attempt to explain the extra-pulmonary dysfunctions observed in COVID-19 cases when active replication of virus is not supported. Since Spike gene and mRNAs have been extensively picked up for vaccine development; the knowledge of host immune response against spike gene and protein holds a great significance. Our study therefore provides novel and relevant insights regarding the impact of Spike gene on shuttling of host microRNAs via exosomes to trigger the neuroinflammation.
“…This indicates that NS5 may have a direct role in influencing lipid metabolism (Heaton and Randall, 2010;Carpp et al, 2014;Poyomtip et al, 2016). Further understanding of the role of NS5 in these pathways is important given that lipid metabolism is necessary for viral replication (Melo et al, 2018).…”
Section: Critical Comments On the Growing List Of Ns5-interacting Hummentioning
confidence: 99%
“…Some of the recent emerging studies are beginning to indicate that NS5 has a causal link in autophagy via influencing a host deubiquitinase protein, USP42 expression via increased microRNA, miR-590 ( Mishra et al., 2019 ) and TRAF-6 ( Pu et al., 2017 ). However, the interacting partners of NS5 involved in these processes are yet to be identified.…”
Section: Critical Comments On the Growing List Of Ns5-interacting Hummentioning
Dengue is emerging as one of the most prevalent mosquito-borne viral diseases of humans. The 11kb RNA genome of the dengue virus encodes three structural proteins (envelope, pre-membrane, capsid) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5), all of which are translated as a single polyprotein that is subsequently cleaved by viral and host cellular proteases at specific sites. Non-structural protein 5 (NS5) is the largest of the non-structural proteins, functioning as both an RNA-dependent RNA polymerase (RdRp) that replicates the viral RNA and an RNA methyltransferase enzyme (MTase) that protects the viral genome by RNA capping, facilitating polyprotein translation. Within the human host, NS5 interacts with several proteins such as those in the JAK-STAT pathway, thereby interfering with anti-viral interferon signalling. This mini-review presents annotated, consolidated lists of known and potential NS5 interactors in the human host as determined by experimental and computational approaches respectively. The most significant protein interactors and the biological pathways they participate in are also highlighted and their implications discussed, along with the specific serotype of dengue virus as appropriate. This information can potentially stimulate and inform further research efforts towards providing an integrative understanding of the mechanisms by which NS5 manipulates the human-virus interface in general and the innate and adaptive immune responses in particular.
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