|Year : 2021 | Volume
| Issue : 1 | Page : 12-17
Lipids fluctuations in mosquitoes upon arboviral infections
Mayra A Melendez-Villanueva1, Laura M Trejo-Ávila1, Kame A Galán-Huerta2, Ana M Rivas-Estilla2
1 Laboratorio de inmunología y virología. Unidad de Virología y Cáncer. Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, Mexico
2 Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Mexico
|Date of Submission||04-Jun-2019|
|Date of Acceptance||04-Dec-2020|
|Date of Web Publication||18-Nov-2021|
Dr Ana M Rivas-Estilla
Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León
Source of Support: None, Conflict of Interest: None
Arboviruses are responsible for several emerging and re-emerging infectious diseases, with dengue, Zika virus disease and Chikungunya fever being the most important arboviral diseases nowadays. Infection of these viruses depends primarily on its ability to replicate and disseminate in mosquitoes. Since these viruses are enveloped, viral replication, assembly and release occurs in the cellular membranes, which depends on the manipulation of host lipid metabolism. Specifically in mammalian cells replication, they use host lipids to establish a compartment known as replication complex that contains the replicase complex. This complex includes viral RNA, proteins and host factors necessary for a successful replication in mammalian cells. Although little is known about extrinsic factor(s) needed for arbovirus replication in vectors,recent reports show that high lipid concentrations are related with increased viral replication in mosquito cells infected with dengue, Zika and Chikungunya viruses. Here, we present a review that focuses on the cellular mechanisms and the lipid environment alteration in mosquito vector after arbovirus infection and their relationship with arbovirus replication.
Keywords: arbovirus; lipids; mosquitoes
|How to cite this article:|
Melendez-Villanueva MA, Trejo-Ávila LM, Galán-Huerta KA, Rivas-Estilla AM. Lipids fluctuations in mosquitoes upon arboviral infections. J Vector Borne Dis 2021;58:12-7
|How to cite this URL:|
Melendez-Villanueva MA, Trejo-Ávila LM, Galán-Huerta KA, Rivas-Estilla AM. Lipids fluctuations in mosquitoes upon arboviral infections. J Vector Borne Dis [serial online] 2021 [cited 2021 Dec 4];58:12-7. Available from: https://www.jvbd.org/text.asp?2021/58/1/12/313961
| Introduction|| |
Arboviruses cause several diseases, like dengue, zika virus disease and Chikungunya fever. These viruses are transmitted by the bite from an infected female mosquito. It is well known that in mammalians, arboviruses use lipids in every step of the viral replication cycle. Previous reports suggest that host membranes are reorganised by positive-single-stranded RNA (+ssRNA) viruses to build their replication complexes, suggesting that it requires a significant metabolic cost to the host cell related to lipid metabolism activity. It is important to know which of these pathways, during mosquito infection, could be exploited as potential targets for breaking the transmission cycle. Here we present the first review about the molecular characteristics and mechanisms into the cellular mosquito lipid environment during the replication of clinically important arboviruses.
| Material & Methods|| |
We thoroughly review the publications concerning the participation of lipids or its changes in levels or lipid environment in arbovirus vectors, specifically mosquitoes or mosquitos’ in cell culture infected with dengue virus, zika virus or Chikungunya virus because of the relevance of these infections nowadays.
Viral infection in mosquitoes
Mosquitoes are considered the most important vectors of human pathogen transmission. Aedes aegypti, for example, is responsible for the transmission of an important variety of pathogenic viruses. This cycle starts when the mosquito takes the blood meal from an infected host, after the ingestion, the viral particles enter to the midgut. Inside the cell, the replication cycle begins with the attachment of viral and cellular receptors molecules [Figure 1]. Some viruses require more than one receptor to be taken up by the cell. The initial interaction between viral surface and cell occurs through attachment factors, and later becomes more specific. Receptors can either participate in the endocytosis of viruses, inducing cell changes, and viral membrane conformation, finally driving to a penetration event. After the virus enters the mosquito midgut it can pass into the hemolymph and infect the fat body cells, trachea, hemocytes, ovaries, nerve tissue, and salivary glands, spreading the infection to the entire insect,,,. Large amounts of viruses are not necessary to transmit the infection to a new host. Some researchers suggest that a minimum number of infective virions are necessary for A. aegypti to transmit viruses like DENVor ZIKV to a new host.
|Figure 1: Arbovirus replication cycle in mosquito. A) Mosquito takes the blood meal from an infected host. Immune host cell (monocytes, macrophages and dendritic cells) are the first target during the infection in mammals. B) The viral particles enter to the midgut and replicate. C) Later, pass into the hemolymph and infect the fat body cells, trachea, hemocytes, ovaries, nerve tissue, and salivary glands, spreading the infection to the entire insect. D) Finally, the infection is spread through the saliva to another naive host. This figure was created with BioRender.com.|
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Viruses have evolved strategies to accomplish their complicated viral cycle in mosquitoes. They regulate multiple immune systems into the infected organisms. Four major signaling pathways have been elucidated that involve modulation of protein expression of Toll, IMD, JAK-STAT and RNA interference (RNAi). Hemocytes are the principal effector cells and regulate different mechanism like phagocytes is, encapsulation, formation of nodules, melanization and tissue repair to limit viral infection, and consequently, the infection has no important impact in the mosquito survival. Viruses successfully exploit either host or vector factors to achieve their efficient replication for a successful transmission to another naive host. The knowledge about the interactions among mosquitoes, viruses and hosts is poorly understood. There is an important challenge to understand the mechanisms that regulate the permissiveness of mosquitoes to viral infection.
Dengue virus (DENV) is a group of enveloped viruses belonging to the family Flaviviridae, genus flavivirus, which are classified into four serotypes that are antigenically different but closely molecularly related (DENV-1, DENV-2, DENV-3 and DENV-4). The genome of DENV is composed by a (+)ssRNA of ~11 kb. The genome encodes a polyprotein that is cleaved into seven non-structural proteins, (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5), and three structural proteinsthe capsid (C), the pre-membrane (prM) and the envelope. This virus is associated with febrile diseases outbreaks since 1980’s. According to the World Health Organization there are ~400 million of infected patients with DENV, making this virus the most hazardous arbovirus in the world.
Enzyme regulation during DENV replication
Little is known about the regulation of enzymes involved in lipid metabolism during DENV infection. It was demonstrated that Acyl CoA transferase and 4-hydroxybutyrate CoA transferase were up-regulated by DENV-2. These enzymes are involved in mitochondrial fatty acid oxidation, which are an important source of energy for the cell. On the other hand, it has been shown that infection by DENV increases the number of lipid droplets per cell. Because viruses lack the ability to synthesize lipids, they can hijack the machinery responsible for this process. They use this lipid storage organelle for viral replication. Blocking lipid droplet formation by inhibiting fatty acid synthesis with C75 (fatty acid synthase inhibitor) reduces the formation of viral particles by over 1000-fold. This suggest that the modulation of fatty acid metabolism could play a crucial role in virus production.
Relation of host lipids and dengue virus infection in mosquito vector
Host lipids play an important role during DENV replication in both human and mosquito cells,,,,. During replication in mammalian cells, DENV incorporates host-derived membranes compartments into a lipid envelope that surrounds the viral RNA and the capsid protein. These host-derived compartments facilitate and enhance viral release from infected cells grouping many viral particles into these structures, built into the endoplasmic reticulum, these structures could be transported to the apical membrane (exosome like) causing lysis and contributing to the virions entry into uninfected cells,,. Previous studies on DENV-infected mosquito cells have shown, by electron microscopy, that membranous structures are built similar to those found in human cells,. Membranes are used for support, protection and viral particle assembly in human and mosquitoes. Specifically, positive strand RNA viruses (eg. Arbovirus group) have developed a unique ability to exploit pre-existing membranes to build a novel RNA replication factory. The factory contains the replication complex, (viral RNA, proteins and host factors),. Furthermore, these compartments protect the virus from host immune defences. Previous reports indicate that RNA viruses could reorganize the endoplasmic reticulum (ER), Golgi complex, mitochondria and endosome membranes to shape the replication complex. This suggests that important changes may exist in the composition of lipids on infected cells for the construction of these replication complexes.
Glycerophospholipids (GPs) are the major components of cellular membranes and take part in fluidity, nutrient exchange, trafficking and signalling,,,. In mosquitoes it has been demonstrated that GPs significantly increased on days 7 and 11 post-blood meal (pbm) when the midgut of Aedes aegypti was infected with DENV. It was also observed that there is a diverse signalling of phosphatidyl-inositol closely followed by phosphatidylglycerol, cardiolipin precursors in mitochondrial membranes. These membranes have a role in the replication complex assemble in eukaryotic cells infected with different (+)ssRNA viruses. The primary components of most cellular membranes: phosphatidyl-choline, phosphatidyl-ethanolamine and phosphatidyl-serine were also increased during day 7 pbm (when the viral replication has a significant increase) [Figure 2].
|Figure 2: Phospholipid alteration after dengue virus infection in Ae. Aegypti midgut. Red arrows represent increase in GPs. Abbreviations: FAS, fatty acid synthase; NS3, non-structural protein 3; CDP-DAG, cytidine diphosphate diacylglycerol; DAG, diacylglycerol; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PI, phosphatidylinositol; PS, phosphatidylserine; MAG, monoacylglycerol; TAG, triacylglycerol; DHCer, dihydroceramide; HexCer, hexosyl-ceramide; GPCer, glycerophospholipid-ceramide. This figure was created with BioRender.com.|
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Glycerolipids (GLs), including mono-, di- and triacylglycerols (MAG, DAG and TAG, respectively) are important effectors of energy in metabolism in mammals and mosquitoes. Recent report showed an important increase of MAG, DAG and TAG during days 3 and 7 pbm in DENV-infected midguts, using high mass spectrometry. It is thought that these GL sare transported to the fat body, ovaries and salivary glands and DAG is further used as precursor of GPs. These GPs work as a second messengers regulating cell proliferation and survival, and are required in the late time points (7 and 11 days pbm) as energy sourcefor supporting viral infection while it spreads through the whole insect, [Figure 2].
Sphingolipids (SPs) are bioactive molecules that play important roles in the structural composition of cellular membranes and numerous cell-signalling pathways,,,. The SP pathway has been studied in mosquito cells and its alteration has been demonstrated after flavivirus infection. For example, sphinganine, sphinganine-1-PC, sphingosine, ceramides, and hexosylceramides are accumulated in DENV-infected mosquito midguts in days 3, 7, and/or 11 pbm these fluctuations are represented in [Figure 2].
Fatty acids have structural roles in membranes when they are incorporated into complex lipids (GPs, SPs and GLs). On the other hand, they can have critical roles in signalling, energy homeostasis and insect immune response,,. C75, an inhibitor of Fatty Acid Synthetase (FAS), reduced DENV replication in C6/36 mosquito cells indicating that fatty acid biosynthesis is a key in human and mosquito DENV infection success. FAS was localized in the viral RNA replication sites during DENV infection. Subsequently, fatty acids are required and conserved during DENV infection in human and mosquito cells. In addition, it was observed that fatty acid derivatives were increased. This fatty acid derivatives were fatty amides, hydroxy fatty acids, free fatty acids, eicosanoids and leukotriene, fatty-amines, glycosides, dicarboxylic acids, keto-fatty acids, prostaglandin a2, prostaglandin d2, and PGD2-dihydroxypropanylamine and one thromboxane (dehydrodinor-TXB2). Eicosanoids are inflammatory mediator molecules that play several important roles in insect immunity. Finally, β-oxidation is also regulated during DENV infection. It has been reported that acyl-carnitines had a significant increase in mosquito DENV-infected cells.
Insects cannot synthesize cholesterol de novo but must take it from dietary sources and/or microflora,. It has been shown that flaviviruses can regulate cellular cholesterol homeostasis to improve genome replication in mammalian cells. They can use free cholesterol to transport the viral complex components. Cholesterol levels during DENV infection have been reported to increase 19%. It has been shown that cholesterol is critical for DENV replication in mammalian host,. It is interesting to consider what might happen in the mosquito where these lipids are limited. On the other hand, other kind of lipids could substitute the cholesterol functions of during DENV replication in the mosquitoes. The specific role of these molecules might play in the virus-vector interactions is still poorly explained and needs to be investigated.
Other clinically important arbovirus and its vector-lipids content relation
Zika virus (ZIKV) is an emerging arbovirus that is transmitted by mosquitoes of the genus Aedes. This virus belongs to Flaviviridae family which includes several other arboviruses of clinical importance (e.g., DENV, West Nile virus, and Yellow Fever virus) and possess a genome (+)ssRNA. Recent outbreaks of ZIKV in South Pacific and Latin America have evidenced the potential to cause severe neurological damage complications such as Guillain-Barré syndrome and microcephaly in new-borns. The information about ZIKV and its relationship with host lipids is limited, but it is thought that this virus can use and exploit host lipids due to similarity to DENV replication cycle.
A metabolomic analysis on Aedes albopictus C6/36 cells infected with the Brazilian ZIKV strain showed that 13 lipids species were identified in ZIKV-infected mosquito cells [Table 1]. Twelve participate directly in the intracellular metabolism of glycerophospholipid in the host cellsduring mammalian infection. Eight are acyl-glycerophospholipids, (six acylglycerophosphoserines and two acylglycerophosphocholines), three species are diacylglycerophospholipids, (two diacylglycerophosphocholines and one diacylglycerophosphoserine) and one is a sphingolipid. These results were corroborated performing a semi-quantitative analysis of the lipids confirmed in ZIKV-infected cells that showed significant higher levels. They obtained an increase upto 2.15-fold higher concentration of metabolites in ZIKV-infected cells compared to noninfected controls. However, when they performed a quantitative comparison between the elected markers for control and ZIKV-infected cells there was no statistically significant difference. These results suggest that both, control and ZIKV-infected cells, use the same glycerophospholipid metabolic pathway. This may be explained by the fact that both, ZIKV-infected and uninfected cells, have essentially the same metabolic profile,but some specific changes could be induced during the viral infection in the cells during,. It is also important to mention that the glycerophospholipid metabolism,remains at lower levels when the cell is in homeostasis.
|Table 1: Lipid markers elucidated by MS/MS for Aedes albopictus ZIKV- infected C6/36 cells (adapted from Melo et al.)|
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Chikungunya virus (CHIKV) is a member of the Alphavirus genus in the Togaviridae family. Chikungunya fever is a viral disease transmitted by this agent through a bite of infected Aedes mosquitoes (Aedes aegypti and Aedes albopictus). Little is known about modulation of lipids during CHIKV infection in mosquitoes. Concerning enzymes involved in lipid metabolism, it has been demonstrated that Acyl CoA and 3-hydroxyacylco A dehydrogenase transferase were up-regulated by CHIKV.
Researchers evaluated the modulation of expression of different proteins in CHIKV-infected salivary glands of Aedes aegypti. They reported its level was increased ~5 folds 3 days post infection in salivary glands extracts. Another protein involved in fatty acid metabolism is Cyclohex-1-ene-1-carboxyl-CoA hydratase that display a catalytic activity. This protein has been reported to have an increase in level expression 3 days post-infection in salivary gland mosquito extracts, suggesting that blockage of this proteins can reduce the cytopathic effects of the virus due to the importance of this proteins in metabolism of fatty acids. This family of proteins plays a particularly important role in the metabolism of unsaturated fatty acids. It has been demonstrated that knocking-down the gene of mitochondrial short chain enoyl-CoA hydratase in a human glioblastoma cell line impairs virus replication in cells persistently infected with measles virus. This finding remarks the possible interaction between virus replication and lipid metabolism.
| Conclusion|| |
Although the informationavailable in this field is limited, there is an important relationship between the diverse arbovirus’ replication mechanismsand host lipids metabolism in mammalian cells. There are still many aspects to discover in order to explain the relationship between arboviruses and the dynamic of vector lipid metabolism, specifically mosquitoes of the genus Aedes. Arbovirusvectors interactions could be critical to facilitate virus replication. Arboviral infection specifically alters the lipid repertoire of the mosquito. The viruses alter metabolic pathways that may be critical for achieving optimal levels of replication in the vector required for successful dissemination and ultimately transmission. The virus sequesters lipidsto build the replication complex and improve the efficiency of its replication exploiting different lipid path-ways. Therefore, exploring vector metabolism is a powerful tool to identify metabolic crucial points that could be investigated to interfere with pathogen transmission or to implement vector control.
Conflict of interest: None
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[Figure 1], [Figure 2]