Translational Medicine Reports 2019; volume 3:8156 Chikungunya virus: Update ronments. The origin of the term chikun- on molecular biology, gunya comes from the African word kun- Correspondence: Mariateresa Vitiello, gunyala, literarily meaning to be contorted, Department of Clinical Pathology, Virology epidemiology and current and it refers to the typical patients’ posture Unit, San Giovanni di Dio e Ruggi d’Aragona strategies resulting from severe muscular and joint Hospital, Salerno, Italy. E-mail: [email protected] pain.3,4 CHIKV was first isolated during an Debora Stelitano,1 Annalisa Chianese,1 epidemic in Tanzania, in 1952-1953. Key words: Chikungunya virus; Life cycle; Roberta Astorri,1 Enrica Serretiello,1 However, it has been suggested that Epidemiology; Vector; Clinical management. 1 1 CHIKV outbreaks had already happened in Carla Zannella, Veronica Folliero, Africa, Asia and America before this date Contributions: DS, data collecting and manu- Marilena Galdiero,1 Gianluigi Franci,1 and were generally mistaken for dengue script writing; AC, RA, ES, CZ, VF, MG, GF, Valeria Crudele,1 Mariateresa Vitiello2 epidemics.5,6 In fact, as these viruses can VC, data collecting, manuscript reviewing and 1 reference search; MTV, data collecting, fig- Department of Experimental Medicine, cause similar clinical syndromes, retrospec- ures preparation and manuscript writing. University of Campania Luigi Vanvitelli, tive studies suggested that they may have 2 Naples; Department of Clinical been confused in the past, especially in the Conflict of interest: the authors declare no Pathology, Virology Unit, San Giovanni regions in which they are both endemic. potential conflict of interest. di Dio e Ruggi d’Aragona Hospital, Since its discovery, the virus has spread, Salerno, Italy from Africa and Asia, where it caused spo- Funding: VALEREplus program. radic outbreaks, particularly to the islands of the Indian Ocean and to Southeastern Received for publication: 8 March 2019. Accepted for publication: 28 March 2019. Asia, until it reached Europe (Italy, France Abstract 7 and Spain) and the American continent, as This work is licensed under a Creative Chikungunya virus (CHIKV), an shown in Figure 1. Commons Attribution 4.0 License (by-nc 4.0). arthropod-borne virus, is the aetiological In 1999-2000, a large Chikungunya epi- 8 agent of a disease characterized by several demic occurred in Congo. In 2005, an epi- ©Copyright D. Stelitano et al., 2019 aspecific symptoms including fever, myal- demic event interested the islands of the Licensee PAGEPress, Italy Indian Ocean, such as La Réunion. During Translational Medicine Reports 2019; 3:8156 gia and arthralgia. The virus is primarily doi:10.4081/tmr.8156 transmitted to humans through the bite of an the same period, numerous cases in Europe infected mosquito of Aedes genus. This have been reported as imported cases and virus was first isolated in Tanzania in 1953, associated with this outbreak. Another out- from which it spread to other African coun- break interested Gabon in 2007; while 1.5 viralgenome: i) East/Central/South African 9 tries, Asia, Northern and Southern America, million cases occurred in India. (ECSA); ii) Indian Ocean Lineage (IOL); Europe and Oceania. Today, many human To date, millions of human CHIKV iii) West African and iv) Asian.33 cases of CHIKV infection have been identi- infections have been recorded all over the Two vectors, Aedes aegypti and Aedes fied. The diffusion of CHIKV across the world.10 In recent years, an ever more tangi- albopictus, have been reported to be world, including Italy, is due to multiple ble threat to human health is represented by involved in CHIKV spread in large epidem- factors amongst which the wide distribution the re-emergence of infections caused by ic events. The first one is more common in of its vectors and high transmission effi- arboviruses, including Chikungunya. tropical and subtropical regions, while A. ciency play a crucial role. Currently, there albopictus is widespread in Africa, Asia, are no specific treatments and effective vac- Classification America and Europe.7 CHIKV distribution cines against CHIKV; indeed, available Alphavirus and Rubivirus are the two corresponds to that of its specific mosquito therapies allow symptoms mitigation and genera constituing the Togaviridae family. vectors. some promising vaccines are undergoing The Alphavirus genus comprises 29 species distributed worldwide and able to cause dis- clinical trials. The purpose of this review is 11-32 to offer an updated picture of CHIKV ease in humans and animals. (Table 1). Virion structure and genomic The need of specific vectors and reser- molecular biology, epidemiology andNon-commercial vector usearchitecture only distribution, clinical features and strategies voirs and particular ecological conditions for infection prevention and treatment. influence the geographic distribution of the CHIKV is an enveloped virus with an single species. icosahedral nucleocapsid enclosing the viral Alphaviruses are typically transmitted genome. Mature viral particles have a diam- to susceptible hosts by an arthropod vector. eter of about 700Å.34 CHIKV presents a Introduction In certain cases, virus-vector interactions positive single-stranded RNA genome may be highly specific, with only one vec- [(+)ssRNA] of about 11.8Kb.35 The viral Chikungunya virus (CHIKV) is an tor type being capable of viral transmission. genome is capped and polyadenylated and arthropod-borne virus (arbovirus) included Among Alphaviruses, nine are of medi- includes two open reading frames encoding in the Alphavirus genus of the Togaviridae cal and economic interest: CHIKV, structural and non-structural proteins,36 as family.1 It is well estabilished that CHIKV O’nyong-nyong virus, Sindbis virus, shown in Figure 2. The large 5’ Open is the aetiological agent of a disease charac- Semliki Forest virus, Venezuelan Equine Reading Frame 1 (ORF1), that extends over terized by fever, myalgia, arthralgia, Encephalitis virus, Eastern Equine two-thirds of the viral genome, encodes for headaches, skin rash and joint swelling.2 Encephalitis virus, Western Equine four non-structural proteins (nsP1, nsP2, The virus is transmitted to humans by Encephalitis virus and Ross River virus.32 nsP3 and nsP4) playing a crucial role in dif- mosquito vectors belonging to Aedes genus; The available classification includes ferent functions including RNA capping, the high transmission efficiency promotes four distinct CHIKV genotypes, according- replication and protein cleavage.37 ORF1 is disease outbreaks even across urban envi- ly to the E1 gene sequence and translated into a single polyprotein which is [page 22] [Translational Medicine Reports 2019; 3:8156] Review then cleaved to produce the mature proteins. about 240 copies of the capsid protein C1 cleavage in E2 and E3 proteins occurs dur- The nsP1 presents RNA capping activi- associated with the viral genome to form an ing the transition from the progressively ty, nsP2 acts as an helicase and protease organized icosahedral nucleocapsid of more acidic Golgi network to the early enzyme, nsP3 is crucial for genome synthe- about 400 Å in diameter.39 endosome, characterized by acidic pH, to sis and nsP4 is a RNA-dependent RNA The nucleocapsid core is surrounded by the plasma membrane with neutral pH.39 polymerase.36 a lipid envelope rich in viral spikes, whose E1 glycoprotein is a 442 aa protein An untranslated junction-region links packing differs between immature and organized in three β-sheet-rich domains the ORF1 with the ORF2. The ORF2, mature particles.39 These membrane- respectively named I, II and III. Thanks to a placed at the 3’ end of the viral genome, anchored structures are triplets of E1/E2 fusion-loop located at the tip of the domain encodes for the viral structural proteins C1, heterodimer organized in T=4 quasi-sym- II, this glycoprotein plays a fundamental E1, E2, E3 and 6K;37 these proteins are metry.39 role in membrane fusion.39,40 translated as a large precursor polyprotein The E2 and E3 proteins originate from a E2 is a 423 aa glycoprotein composed that is subsequently cleaved by proteases common precursor named p62. Together by three immunoglobulin-like domains into the different proteins.38 with E1, this protein is able to form the viral called A, B and C, connected by a β-ribbon. The central core of the virus consist of spikes in the endoplasmic reticulum. P62 This CHIKV protein plays a major role in Table 1. Alphaviruses: abbreviations, vectors, vertebrate hosts and main clinical features. Virus Arthropod vector Vertebrate host Geographical distribution Disease* Source 1 BFV Culex annulirostris Human Australia (Queensland, Victoria, Arthralgia, rash Flexman et al. (1998),26 New South Wales) Jacups et al. (2008)18 2 CHIKV Aedes spp. Human Africa (including Southern Tanzania), Arthalgia, arthritis, Schwartz et al. (2010)27 (A. albopictus, America, India, Europe encephalitis A. aegypti) (including North- Eastern Italy) 3 EEEV Culis etamelanura, Horse, Human Eastern USA (including North Carolina), Encephalitis Del Piero et al. (2001),14 occasionally Caribbean, South America Beckwith et al. (2002)12 Coquillettidia perturbans and Aedes canadensis 4 EVEV Culex cedecei Human USA (Florida) Encephalitis Coffey et al. (2006)13 5 GETV Culex gelidus Human, Pig, Horse Asia (including Malaysia), Rash Nemoto et al. (2015)22 Northern Australia 6 HJV Culis etamelanura Equine, Human North and South America Encephalitis Allison et al. (2009)11 7 MAYV