Global Impact of Mosquito-borne Alphaviruses on Humans: Their Spread and Rehabilitation
Abstract
Alphaviruses of the family Togaviridae are mostly arboviruses with worldwide distribution and are maintained in nature by reservoir hosts and mosquitoes in an enzootic cycle. Spillover events occur in the form of local outbreaks or epidemics involving human beings. These may cause arthritis or encephalitis which might be fatal. We have comprehensively reviewed the structure of the human pathogenic alphaviruses with the functions of individual proteins, and the life cycle events of alphaviruses with a special emphasis on the difference in
these events in the case of vectors and hosts, and diseases produced by them along with the pathogenesis. Molecular-level studies of these viruses, the phylogenetic evolutionary events, and various measures
being taken to prevent or control the infections caused by these viruses in humans are also discussed in this review article. The recent outbreaks of alphaviral infections demand in-depth knowledge of virus-host interaction at the molecular level and the development of better drugs to control the infections.
How to cite this article:
Sharma M, Sharma NR, Bansal A, Khan MA,Guleria J, Roy A, Kaushik S, Singh G. Global Impact of Mosquito-borne Alphaviruses on Humans: Their Spr ead and Rehabilitation. J Commun Dis. 2023;55(3):93-110.
DOI: https://doi.org/10.24321/0019.5138.202330
References
Woolhouse M, Scott F, Hudson Z, Howey R, Chase-Topping M. Human viruses: discovery and emergence.
Philos Trans R Soc Lond B Biol Sci. 2012;367(1064):2864-71. [PubMed] [Google Scholar]
Classification and nomenclature of viruses. Fourth report of the International Committee on Taxonomy of
Viruses. Intervirology. 1982;17(1-3):1-199. [PubMed]
Strauss JH, Strauss EG. The alphaviruses: gene expression, replication, and evolution. Microbiol Rev.
;58(3):491-562. [PubMed] [Google Scholar]
Garmashova N, Gorchakov R, Volkova E, Paessler S, Frolova E, Frolov I. The old world and new world alphaviruses use different virus-specific proteins for induction of transcriptional shutoff. J Virol. 2007;81(5):2472-84. [PubMed] [Google Scholar]
Powers AM, Brault AC, Shirako Y, Strauss EG, Kang W, Strauss JH, Weaver SC. Evolutionary relationships
and systematics of the alphaviruses. J Virol. 2001;75(21):10118-31. [PubMed] [Google Scholar]
Chen R, Mukhopadhyay S, Merits A, Bolling B, Nasar F, Coffey LL, Powers A, Weaver SC; ICTV Report
Consortium. ICTV virus taxonomy profile: Togaviridae. J Gen Virol. 2018;99(6):761-2. [PubMed] [Google
Scholar]
Jose J, Snyder JE, Kuhn RJ. A structural and functional perspective of alphavirus replication and assembly.
Future Microbiol. 2009;4(7):837-56. [PubMed] [GoogleScholar]
Weaver SC, Winegar R, Manger ID, Forrester NL.Alphaviruses: population genetics and determinants of
emergence. Antiviral Res. 2012;94(3):242-57. [PubMed][Google Scholar]
Bakar FA, Ng LF. Nonstructural proteins of alphaviruspotential targets for drug development. Viruses.
;10(2):71. [PubMed] [Google Scholar]
Uyaniker S, van der Spek SJ, Reinders NR, Xiong H, Li KW, Bossers K, Smit AB, Verhaagen J, Kessels HW. The
effects of Sindbis viral vectors on neuronal function. Front Cell Neurosci. 2019;13:362. [PubMed] [Google
Scholar]
Netolitzky DJ, Schmaltz FL, Parker MD, Rayner GA, Fisher GR, Trent DW, Bader DE, Nagata LP. Complete
genomic RNA sequence of western equine encephalitis virus and expression of the structural genes. J Gen
Virol. 2000;81(Pt 1):151-9. [PubMed] [Google Scholar]
Simmons JD, White LJ, Morrison TE, Montgomery SA, Whitmore AC, Johnston RE, Heise MT. Venezuelan
equine encephalitis virus disrupts STAT1 signaling by distinct mechanisms independent of host shutoff.
J Virol. 2009;83(20):10571-81. [PubMed] [Google Scholar]
Salonen A, Vasiljeva L, Merits A, Magden J, Jokitalo E, Kääriäinen L. Properly folded nonstructural polyprotein
directs the Semliki forest virus replication complex to the endosomal compartment. J Virol. 2003;77(3):1691-
[PubMed] [Google Scholar]
Myles KM, Pierro DJ, Olson KE. Deletions in the putative cell receptor-binding domain of Sindbis virus strain
MRE16 E2 glycoprotein reduce midgut infectivity in Aedes aegypti. J Virol. 2003;77(16):8872-81. [PubMed]
[Google Scholar]
Das PK, Merits A, Lulla A. Functional cross-talk between distant domains of chikungunya virus non-structural
protein 2 is decisive for its RNA-modulating activity. J Biol Chem. 2014;289(9):5635-53. [PubMed] [Google
Scholar]
Garmashova N, Gorchakov R, Frolova E, Frolov I. Sindbis virus nonstructural protein nsP2 is cytotoxic and inhibits cellular transcription. J Virol. 2006;80(12):5686-96. [PubMed] [Google Scholar]
Vihinen H, Ahola T, Tuittila M, Merits A, Kääriäinen L. Elimination of phosphorylation sites of Semliki
Forest virus replicase protein nsP3. J Biol Chem. 2001;276(8):5745-52. [PubMed] [Google Scholar]
Kamer G, Argos P. Primary structural comparison of RNA-dependent polymerases from plant, animal and
bacterial viruses. Nucleic Acids Res. 1984;12(18):7269- 82. [PubMed] [Google Scholar]
Hong EM, Perera R, Kuhn RJ. Alphavirus capsid protein helix I controls a checkpoint in nucleocapsid core
assembly. J Virol. 2006;80(18):8848-55. [PubMed] [Google Scholar]
Lusa S, Garoff H, Liueström P. Fate of the 6K membrane protein of Semliki Forest virus during virus assembly.
Virology. 1991;185(2):843-6. [PubMed] [Google Scholar]
Liljeström P, Lusa S, Huylebroeck D, Garoff H. In vitro mutagenesis of a full-length cDNA clone of Semliki
Forest virus: the small 6,000-molecular-weight membrane protein modulates virus release. J Virol.
;65(8):4107-13. [PubMed] [Google Scholar]
Dey D, Siddiqui SI, Mamidi P, Ghosh S, Kumar CS, Chattopadhyay S, Ghosh S, Banerjee M. The effect of amantadine on an ion channel protein from Chikungunya virus. PLoS Negl Trop Dis. 2019;13(7):e0007548.
[PubMed] [Google Scholar]
Pfeffer M, Foster JE, Edwards EA, Brown MB, Komar N, Brown CR. Phylogenetic analysis of Buggy Creek
virus: evidence for multiple clades in the Western Great Plains, United States of America. Appl Environ
Microbiol. 2006;72(11):6886-93. [PubMed] [Google Scholar]
Brummer-Korvenkontio M, Vapalahti O, Kuusisto P, Saikku P, Manni T, Koskela P, Nygren T, Brummer-Korvenkontio H, Vaheri A. Epidemiology of Sindbis Virus infections in Finland 1981-96: possible factors explaining a peculiar disease pattern. Epidemiol Infect. 2002;129(2):335-45. [PubMed] [Google Scholar]
Sim C, Hong YS, Tsetsarkin KA, Vanlandingham DL, Higgs S, Collins FH. Anopheles gambiae heat shock
protein cognate 70B impedes O’nyong-nyong virus replication. BMC Genomics. 2007;8:231. [PubMed] [Google Scholar]
La Linn M, Eble JA, Lübken C, Slade RW, Heino J, Davies J, Suhrbier A. An arthritogenic alphavirus uses the
alpha1beta1 integrin collagen receptor. Virology. 2005;336(2):229-39. [PubMed] [Google Scholar]
Rulli NE, Suhrbier A, Hueston L, Heise MT, Tupanceska D, Zaid A, Wilmes A, Gilmore K, Lidbury BA,
Mahalingam S. Ross River virus: molecular and cellular aspects of disease pathogenesis. Pharmacol Ther.
;107(3):329-42. [PubMed] [Google Scholar]
Caly L, Horwood PF, Vijaykrishna D, Lynch S, Greenhill AR, Pomat W, Rai G, Kisa D, Bande G, Druce J, Abdad
MY. Divergent Barmah Forest virus from Papua New Guinea. Emerg Infect Dis. 2019;25(12):2266-9.
[PubMed] [Google Scholar]
Boyd AM, Kay BH. Experimental infection and transmission of Barmah Forest virus by Aedes vigilax (Diptera: Culicidae). J Med Entomol. 1999;36(2):186-9. [PubMed] [Google Scholar]
Ferreira PG, Ferraz AC, Figueiredo JE, Lima CF, Rodrigues VG, Taranto AG, Ferreira JM, Brandão GC, Vieira-Filho
SA, Duarte LP, Magalhaes CL, Magalhaes JC. Detection of the antiviral activity of epicatechin isolated from Salacia crassifolia (Celastraceae) against Mayaro virus based on protein C homology modelling and virtual
screening. Arch Virol. 2018;163(6):1567-76. [PubMed] [Google Scholar]
Ngoagouni C, Kamgang B, Kazanji M, Paupy C, Nakouné E. Potential of Aedes aegypti and Aedes albopictus
populations in the Central African Republic to transmit enzootic chikungunya virus strains. Parasit Vectors.
;10(1):164. [PubMed] [Google Scholar]
Howard JJ, Wallis RC. Infection and transmission of eastern equine encephalomyelitis virus with colonized
Culiseta melanura (Coquillett). Am J Trop Med Hyg.1974;23(3):522-5. [PubMed] [Google Scholar]
Hoch AL, Peterson NE, LeDuc JW, Pinheiro FP. An outbreak of Mayaro virus disease in Belterra, Brazil. III.
Entomological and ecological studies. Am J Trop Med Hyg. 1981;30(3):689-98. [PubMed] [Google Scholar]
Ali R, Jayaraj J, Mohammed A, Chinnaraja C, Carrington CV, Severson DW, Ramsubhag A. Characterization of
the virome associated with haemagogus mosquitoes in Trinidad, West Indies. Sci Rep. 2021;11(1):16584.
[PubMed] [Google Scholar]
Rezza G, Chen R, Weaver SC. O’nyong-nyong fever: a neglected mosquito-borne viral disease. Pathog Glob
Health. 2017;111(6):271-5. [PubMed] [Google Scholar]
Michie A, Dhanasekaran V, Lindsay MD, Neville PJ, Nicholson J, Jardine A, Mackenzie JS, Smith DW, Imrie
A. Genome-scale phylogeny and evolutionary analysis of Ross River virus reveals periodic sweeps of lineage
dominance in Western Australia, 1977-2014. J Virol. 2020;94(2):e01234-19. [PubMed] [Google Scholar]
Hubálek Z, Rudolf I, Nowotny N. Arboviruses pathogenic for domestic and wild animals. Adv Virus Res.
;89:201-75. [PubMed] [Google Scholar]
Mathiot CC, Grimaud G, Garry P, Bouquety JC, Mada A, Daguisy AM, Georges AJ. An outbreak of human Semliki Forest virus infections in Central African Republic. Am J Trop Med Hyg. 1990;42(4):386-93. [PubMed]
[Google Scholar]
Lundström JO, Hesson JC, Schäfer ML, Östman Ö, Semmler T, Bekaert M, Weidmann M, Lundkvist Å, Pfeffer M. Sindbis virus polyarthritis outbreak signalled by virus prevalence in the mosquito vectors. PLoS Negl
Trop Dis. 2019;13(8):e0007702. [PubMed] [Google Scholar]
Deardorff ER, Weaver SC. Vector competence of Culex (Melanoconion) taeniopus for equine-virulent subtype
IE strains of Venezuelan equine encephalitis virus. Am J Trop Med Hyg. 2010;82(6):1047-52. [PubMed] [Google Scholar]
Mahmood F, Chiles RE, Fang Y, Reisen WK. Methods for studying the vector competence of Culex tarsalis
for western equine encephalomyelitis virus. J Am Mosq Control Assoc. 2004;20(3):277-82. [PubMed]
[Google Scholar]
Myles KM, Kelly CL, Ledermann JP, Powers AM. Effects of an opal termination codon preceding the
nsP4 gene sequence in the O’Nyong-Nyong virus genome on Anopheles gambiae infectivity. J Virol. 2006;80(10):4992-7. [PubMed] [Google Scholar]
Lim EX, Lee WS, Madzokere ET, Herrero LJ. Mosquitoes as suitable vectors for alphaviruses. Viruses. 2018;10(2):84. [PubMed] [Google Scholar]
Forrester NL, Coffey LL, Weaver SC. Arboviral bottlenecks and challenges to maintaining diversity
and fitness during mosquito transmission. Viruses.2014;6(10):3991-4004. [PubMed] [Google Scholar]
Pingen M, Bryden SR, Pondeville E, Schnettler E, Kohl
A, Merits A, Fazakerley JK, Graham GJ, McKimmie CS. Host inflammatory response to mosquito bites
enhances the severity of arbovirus infection. Immunity. 2016;44(6):1455-69. [PubMed] [Google Scholar]
Smith AL, Tignor GH. Host cell receptors for two strains
of Sindbis virus. Arch Virol. 1980;66(1):11-26. [PubMed] [Google Scholar]
Rose PP, Hanna SL, Spiridigliozzi A, Wannissorn N, Beiting DP, Ross SR, Hardy RW, Bambina SA, Heise MT,
Cherry S. Natural resistance-associated macrophage protein is a cellular receptor for Sindbis virus in both
insect and mammalian hosts. Cell Host Microbe. 2011;10(2):97-104. [PubMed] [Google Scholar]
Wang KS, Kuhn RJ, Strauss EG, Ou S, Strauss JH. Highaffinity laminin receptor is a receptor for Sindbis virus
in mammalian cells. J Virol. 1992;66(8):4992-5001. [PubMed] [Google Scholar]
Byrnes AP, Griffin DE. Binding of Sindbis virus to cell surface heparan sulfate. J Virol. 1998;72(9):7349-56.[PubMed] [Google Scholar]
Knight RL, Schultz KL, Kent RJ, Venkatesan M, Griffin DE. Role of N-linked glycosylation for Sindbis virus infection and replication in vertebrate and invertebrate systems. J Virol. 2009;83(11):5640-7. [PubMed] [Google Scholar]
Klimstra WB, Nangle EM, Smith MS, Yurochko AD, Ryman KD. DC-SIGN and L-SIGN can act as attachment
receptors for alphaviruses and distinguish between mosquito cell- and mammalian cell-derived viruses.
J Virol. 2003;77(22):12022-32. [PubMed] [Google Scholar]
Marsh M, Bolzau E, Helenius A. Penetration of Semliki Forest virus from acidic prelysosomal vacuoles. Cell.
;32(3):931-40. [PubMed] [Google Scholar]
Carvalho CA, Silva JL, Oliveira AC, Gomes AM. On the entry of an emerging arbovirus into host cells: Mayaro
virus takes the highway to the cytoplasm through fusion with early endosomes and caveolae-derived vesicles.
PeerJ. 2017;5:e3245. [PubMed] [Google Scholar]
Gibbons DL, Erk I, Reilly B, Navaza J, Kielian M, Rey FA, Lepault J. Visualization of the target-membraneinserted
fusion protein of Semliki Forest virus by combined electron microscopy and crystallography. Cell.2003;114(5):573-83. [PubMed] [Google Scholar]
Kujala P, Ikäheimonen A, Ehsani N, Vihinen H, Auvinen P, Kääriäinen L. Biogenesis of the Semliki Forest virus
RNA replication complex. J Virol. 2001;75(8):3873-84. [PubMed] [Google Scholar]
Wengler G. The regulation of disassembly of alphavirus cores. Arch Virol. 2009;154(3):381-90. [PubMed]
[Google Scholar]
Barton DJ, Sawicki SG, Sawicki DL. Solubilization and immunoprecipitation of alphavirus replication
complexes. J Virol. 1991;65(3):1496-506. [PubMed] [Google Scholar]
Perera R, Owen KE, Tellinghuisen TL, Gorbalenya AE, Kuhn RJ. Alphavirus nucleocapsid protein contains
a putative coiled coil alpha-helix important for core assembly. J Virol. 2001;75(1):1-10. [PubMed] [Google
Scholar]
Lobigs M, Garoff H. Fusion function of the Semliki Forest virus spike is activated by proteolytic cleavage
of the envelope glycoprotein precursor p62. J Virol.1990;64(3):1233-40. [PubMed] [Google Scholar]
Sanz MA, Madan V, Carrasco L, Nieva JL. Interfacial domains in Sindbis virus 6K protein. Detection and functional characterization. J Biol Chem. 2003;278(3):2051-7. [PubMed] [Google Scholar]
Jose J, Taylor AB, Kuhn RJ. Spatial and temporal analysis of alphavirus replication and assembly in mammalian
and mosquito cells. mBio. 2017;8(1):e02294-16. [PubMed] [Google Scholar]
Zacks MA, Paessler S. Encephalitic alphaviruses. Vet Microbiol. 2010;140(3-4):281-6. [PubMed] [Google
Scholar]
Jonsson CB, Cao X, Lee J, Gabbard JD, Chu YK, Fitzpatrick EA, Julander J, Chung DH, Stabenow J, Golden JE.
Efficacy of a ML336 derivative against Venezuelan and eastern equine encephalitis viruses. Antiviral Res.
;167:25-34. [PubMed] [Google Scholar]
Miner JJ, Yeang HX, Fox JM, Taffner S, Malkova ON, Oh ST, Kim AH, Diamond MS, Lenschow DJ, Yokoyama
WM. Chikungunya viral Arthritis in the United States: a mimic of seronegative rheumatoid arthritis. Arthritis
Rheumatol. 2015;67(5):1214-20. [PubMed] [Google Scholar]
Willems WR, Kaluza G, Boschek CB, Bauer H, Hager H, Schütz HJ, Feistner H. Semliki Forest virus: cause
of a fatal case of human encephalitis. Science. 1979;203(4385):1127-9. [PubMed] [Google Scholar]
Fazakerley JK. Semliki Forest virus infection of laboratory mice: a model to study the pathogenesis
of viral encephalitis. Arch Virol Suppl. 2004;(18):179- 90. [PubMed] [Google Scholar]
Aaskov JG, Chen JY, Hanh NT, Dennington PM. Surveillance for Ross River virus infection using blood
donors. Am J Trop Med Hyg. 1998;58(6):726-30. [PubMed] [Google Scholar]
Flexman JP, Smith DW, Mackenzie JS, Fraser JR, Bass SP, Hueston L, Lindsay MD, Cunningham AL. A comparison of the diseases caused by Ross River virus and Barmah Forest virus. Med J Aust. 1998;169(3):159-63. [PubMed] [Google Scholar]
Soilu-Hänninen M, Erälinna JP, Hukkanen V, Röyttä M, Salmi AA, Salonen R. Semliki Forest virus infects
mouse brain endothelial cells and causes blood-brain barrier damage. J Virol. 1994;68(10):6291-8. [PubMed]
[Google Scholar]
Dubuisson J, Lustig S, Ruggli N, Akov Y, Rice CM. Genetic determinants of Sindbis virus neuroinvasiveness. J
Virol. 1997;71(4):2636-46. [PubMed] [Google Scholar]
Heise MT, Simpson DA, Johnston RE. A single amino acid change in nsP1 attenuates neurovirulence of
the Sindbis-group alphavirus S.A.AR86. J Virol.2000;74(9):4207-13. [PubMed] [Google Scholar]
Lidbury BA, Mahalingam S. Specific ablation of antiviral gene expression in macrophages by antibodydependent enhancement of Ross River virus infection. J Virol. 2000;74(18):8376-81. [PubMed] [Google Scholar]
Rulli NE, Guglielmotti A, Mangano G, Rolph MS, Apicella C, Zaid A, Suhrbier A, Mahalingam S. Amelioration of
alphavirus-induced arthritis and myositis in a mouse model by treatment with bindarit, an inhibitor of
monocyte chemotactic proteins. Arthritis Rheum. 2009;60(8):2513-23. [PubMed] [Google Scholar]
Deresiewicz RL, Thaler SJ, Hsu L, Zamani AA. Clinical and neuroradiographic manifestations of eastern equine
encephalitis. N Engl J Med. 1997;336(26):1867-74. [PubMed] [Google Scholar]
Houk EJ, Kramer LD, Hardy JL, Chiles RE. Western equine encephalomyelitis virus: in vivo infection and
morphogenesis in mosquito mesenteronal epithelial cells. Virus Res. 1985;2(2):123-38. [PubMed] [Google
Scholar]
Rupp JC, Sokoloski KJ, Gebhart NN, Hardy RW. Alphavirus RNA synthesis and non-structural protein
functions. J Gen Virol. 2015;96(9):2483-500. [PubMed] [Google Scholar]
Gliedman JB, Smith JF, Brown DT. Morphogenesis of Sindbis virus in cultured Aedes albopictus cells. J Virol.
;16(4):913-26. [PubMed] [Google Scholar]
Tooker P, Kennedy SI. Semliki Forest virus multiplication in clones of Aedes albopictus cells. J
Virol. 1981;37(2):589600. [PubMed] [Google Scholar]
Riedel B, Brown DT. Role of extracellular virus on the maintenance of the persistent infection induced in
Aedes albopictus (mosquito) cells by Sindbis virus. J Virol. 1977;23(3):554-61. [PubMed] [Google Scholar]
Russell DL, Dalrymple JM, Johnston RE. Sindbis virus mutations which coordinately affect glycoprotein
processing, penetration, and virulence in mice. J Virol. 1989;63(4):1619-29. [PubMed] [Google Scholar]
Tang J, Jose J, Chipman P, Zhang W, Kuhn RJ, Baker TS. Molecular links between the E2 envelope glycoprotein
and nucleocapsid core in Sindbis virus. J Mol Biol. 2011;414(3):442-59. [PubMed] [Google Scholar]
Snyder AJ, Mukhopadhyay S. The alphavirus E3 glycoprotein functions in a clade-specific manner.
J Virol. 2012;86(24):13609-20. [PubMed] [Google Scholar]
Saxton-Shaw KD, Ledermann JP, Borland EM, Stovall JL, Mossel EC, Singh AJ, Wilusz J, Powers AM. O’nyong
nyong virus molecular determinants of unique vector specificity reside in non-structural protein 3. PLoS Negl
Trop Dis. 2013;7(1):e1931. [PubMed] [Google Scholar]
Schuchman R, Kilianski A, Piper A, Vancini R, Ribeiro JM, Sprague TR, Nasar F, Boyd G, Hernandez R, Glaros
T. Comparative characterization of the Sindbis virus proteome from mammalian and invertebrate hosts
identifies nsP2 as a component of the virion and sorting nexin 5 as a significant host factor for alphavirus
replication. J Virol. 2018;92(14):e00694-18. [PubMed] [Google Scholar]
Gould EA, Coutard B, Malet H, Morin B, Jamal S, Weaver S, Gorbalenya A, Moureau G, Baronti C, Delogu I,
Forrester N, Khasnatinov M, Gritsun T, de Lamballerie X, Canard B. Understanding the alphaviruses:
recent research on important emerging pathogens and progress towards their control. Antiviral Res.
;87(2):111-24. [PubMed] [Google Scholar]
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