Chikungunya virus (CHIKV) is an arthritogenic arbovirus from Togaviridae family and Alphavirus genus, which is responsible for recurring epidemics over the years worldwide (Mason and Haddow, 1957). CHIKV is considered an important public health problem because it is endemic in tropical and subtropical regions of the globe. Its transmission occurs by the bite of infected mosquitoes from genus Aedes spp., mainly Aedes aegypti and Aedes albopictus, which are highly domesticated and extremely adaptable to environment changes, respectively, thereby resulting in an efficient spread across the countries and continents (Azevedo et al., 2015; World Health Organization, 2017).

Chikungunya virus infection results in a disease known as Chikungunya fever (CHIKF), characterized by high fever, rash, myalgia, headache, and a prominent polyarthralgia (Burt et al., 2017). Indeed, the name “Chikungunya”, which means “to become contorted” in the Kimakonde language, reflects the most remarkable characteristic of this disease, which is the intense and persistent joint pain (Mavalankar et al., 2008). This symptom is present in more than 90% of the symptomatic cases and can last for weeks, months, or even years in some individuals after complete virus clearance, resulting in a notorious economic and social impact (Wahid et al., 2017; Suhrbier, 2019). Although CHIKF is known as a non-deadly disease, atypical and severe acute manifestations can evolve to multiple organ failure and death. Mortality rates can range from 0.024 up to 0.7% and seem to depend on both the virus genotype/strain and the commitment of neurological system (Jaffar-Bandjee et al., 2010; de Brito, 2017; Dorléans et al., 2018; Freitas et al., 2018; da Silva et al., 2018; Suhrbier, 2019).

Despite the relevance of CHIKV infection to public health, there is still no vaccine or an effective antiviral drug for either the prevention or treatment of CHIKF. In contrast to other arboviruses, such as Dengue (DENV) and Zika (ZIKV) viruses, in which validated and trustable experimental models are largely known and used, experimental models for studying CHIKV infection are diverse and not rarely reproduce just a piece of the pathogenesis observed in humans, which is a challenge for vaccine and drug development. Therefore, understanding the whole picture of this complex disease as well as the current laboratory limitations is vital to address the major issues involving CHIKV infection. In the present review, we outline the major points of CHIKV epidemiology, replication, and pathogenesis and also address the current in vitro and in vivo state-of-the-art experimental models of chikungunya.

The first cases of a chikungunya-like illness in humans were recorded in 1823, in Zanzibar, Africa, followed by the report of a similar epidemic in St. Thomas Island, in the Caribbean, during the years 1827 and 1828 (Halstead, 2015). Since then, no other report of a related disease was noticed until 1952, when episodes of a rheumatic fever affected several people in Tanzania, where, for the first time, CHIKV was isolated, identified, and characterized as an arbovirus. Thus, CHIKV caused sporadic and local outbreaks in Africa and Asia until 2004, when it has spread to approximately 60 countries all over the globe (Schwartz and Albert, 2010), causing large and relevant outbreaks. The most remarkable outbreak occurred between 2005 and 2006 in La Reunion Islands in the Indian Ocean. During this epidemic, over one-third of the island’s population was infected, around 260,000 people, with an average of 40,000 new cases per week and 284 deaths (Josseran et al., 2006). In addition, it was the first evidence that a new vector specie, the mosquito A. albopictus, actively contributed to virus propagation (Thiboutot et al., 2010). As this mosquito is highly adaptable to temperate zones, a reflect of this outbreak was the identification of the first autochthonous outbreak in Europe 2 years later (in Italy in 2007) (Halstead, 2015). Although the entrance of CHIKV in the Americas had probably occurred by the same time, CHIKF was only reported in the Americas in 2013 (Morens and Fauci, 2014), when the first CHIKV outbreak occurred in Saint Martin, with 658 confirmed cases and an infection rate of 1.76% (Henry et al., 2017). Since then, local transmission has been identified in approximately 45 countries and territories in the Americas, resulting in more than 3 million confirmed cases (Jain et al., 2008; Yactayo et al., 2016; da Cunha and Trinta, 2017; Wahid et al., 2017).

Different CHIKV genotypes have been identified since its discovery: Asian, the East Indian (IOL), the West Africa (WA), and the East/Central/South Africa (ECSA) (Nunes et al., 2015). The ECSA and WA genotypes are endemic in sub-Saharan Africa causing intermittent outbreaks, whereas the Asian genotypes are more restricted to Southeast Asia (da Cunha and Trinta, 2017). The IOL was first identified in 2004 as a descendant lineage from ECSA, and it was responsible for the epidemics that occurred in the Indian Ocean islands and Asia between 2005 and 2011 (Nunes et al., 2015).

At least two CHIKV interconnected transmission pathways take place: the sylvatic and the urban cycles. In the first, CHIKV is maintained in a sylvatic transmission cycle between forest dwelling Aedes mosquitoes and non-human primates resulting in sporadic human cases and small outbreaks (Diallo et al., 1999; Petersen et al., 2010). The other is the most relevant to public health and occurs by cyclic transmission of CHIKV from infected to non-infected individuals by the aid of A. aegypti and A. albopictus mosquitoes, the most relevant vectors of the urban cycle (Jain et al., 2008; Wahid et al., 2017). In this scenario, an adaptive Ala-Val mutation at position 226 in the E1 protein gene (E1:A226V) of an ECSA lineage strain abolished virus dependence on cholesterol to replicate, enhancing not only its infectivity but also CHIKV transmission by A. albopictus, which was crucial for virus spread to different continents (Kumar et al., 2008; Azevedo et al., 2015; Madariaga et al., 2016).

In addition to the classical sylvatic and urban transmission cycles, CHIKV infection can also occur by vertical transmission during pregnancy and blood transfusion. Despite not being the most relevant transmission paths, it comes to attention the ability of CHIKV to explore new routes, which is, by itself, a signal of alert for uncontrolled transmission and potential risk of pandemics (Madariaga et al., 2016). Vertical transmission was observed all over the pregnancy stages, but the effects of CHIKV infection in neonates are diverse, varying from asymptomatic to severe, in which myocarditis and/or meningoencephalitis are the most relevant signs of severity (Cardona-Correa et al., 2017). The literature indicates an increased risk for development of severe symptoms in neonates if mother is under viremia period during the childbirth but this risk softens if the infection occurs at least 4 weeks prior to birth (Robillard et al., 2006; Farias et al., 2019). Appassakij et al. (2020) reported that individuals infected with CHIKV can also be potential disease spreaders through blood transfusions or transplants, especially during an outbreak period. This event was observed during the outbreaks occurred in La Reunion, Italy, Thailand, and Puerto Rico. The prevalence of CHIKV RNA in blood donations ranged from approximately 0.4–2.1% during the epidemics. Therefore, an extra care should be taken during the transfusion processes in places where CHIKV is endemic or when outbreaks are ongoing (Petersen et al., 2010; Appassakij et al., 2013, 2020; Petersen and Epstein, 2014; Stanley et al., 2021).

Incubation of CHIKV in humans varies from 1 to 12 days (Panning et al., 2008; Kam et al., 2009; Burt et al., 2012), and viremia can reach up to 3.3 x 10⁹ copies/ml in the first week of infection (Parola et al., 2006; Simon et al., 2007; Panning et al., 2008; Appassakij et al., 2013). It notably contrasts to other arboviruses, mainly from Flaviviridae family, such as DENV and ZIKV, from which highest viremia levels varies between 10⁴ and 10⁶ copies/ml in the same period of infection (Srikiatkhachorn et al., 2012; Valiant et al., 2019). Despite most of CHIKV-infected individuals are symptomatic, less than 15% of infected population do not develop any symptoms (Burt et al., 2017).

Chikungunya fever is a spectrum of disease characterized by high, persistent, and self-limited fever, headache, myalgia, and moderate to severe polyarthralgia (da Cunha and Trinta, 2017). Serological exams from CHIKF patients indicate lymphopenia and/or moderate thrombocytopenia and high levels of alanine transaminase (ALT), aspartate aminotransferase (AST), creatinine, and creatinine kinase, which demonstrate the commitment of the liver and kidneys in the infection. In some individuals, calcium deficiency might also happen, which could be related with the cases in which bone absorption occurs (Thiberville et al., 2013; Bedoui et al., 2018). The symptoms usually disappear between the first- and second-week post-infection, occurring together with the restoration of serological parameters. Nevertheless, 30–40% of the cases evolve to a chronic phase, in which debilitating arthralgia persists for months or even years (Borgherini et al., 2008; Schwartz and Albert, 2010; Marimoutou et al., 2012; Schilte et al., 2013). The genetic and immunological factors that drive the chronicity of arthritic symptoms are still not understood. Dermatological manifestations can also occur in 40–50% of the infected population, usually appearing after the beginning of classical symptoms, between the second and the fifth days, and persist for at least 2 days (Borgherini et al., 2007; Inamadar et al., 2008). These manifestations are characterized by skin rashes in the face and the limbs, facial edema, and oral mucosa bleeding (Burt et al., 2012; Caglioti et al., 2013). In adults, the incidence of atypical and severe cases, which are usually associated to hospitalization, increases with age and elderly people are more prone to develop severe manifestations. Respiratory complications, high blood pressure, and cardiac problems are one of the main complications associated to CHIKF severity. Notwithstanding, newborns are the most susceptible to it. Transmission from mother to fetus occurs at the time of birth in the case of intrapartum maternal viremia. Infected neonates usually develop pain, prostration, fever, and thrombocytopenia within few days after birth, and some of them may even have encephalopathy and intracranial bleeding with persistent sequelae (Gérardin et al., 2008; Ramful et al., 2014). In addition to age, personal lifestyle is also correlated to a poorest prognosis of the disease, as previously demonstrated that excessive alcohol ingestion increases mortality rates by CHIKV (da Cunha and Trinta, 2017).

Although CHIKV is markedly an arthritogenic virus, it can also infect the nervous system. Among neurological complications, the most prevalent symptoms seem to be abnormal mental status, headache, focal deficits, and seizures. Other symptoms such as meningoencephalitis, meningoencephalomyeloradiculitis, myeloradiculitis, myelitis, myeloneuropathy, external ophthalmoplegia, facial palsy, sensorineural deafness, and optic neuritis were described during the recent epidemics (Pinheiro et al., 2016). In addition, it was detected the virus RNA in the eye tissue, which correlates to the manifestation of papillitis, retrobulbar neuritis, and neuroretinitis (Mahendradas et al., 2010; Couderc et al., 2012). Encephalitis occurs either simultaneously or within a few days after the onset of systemic symptoms, during the viremia period (Caglioti et al., 2013; Madariaga et al., 2016; Pinheiro et al., 2016). Guillain-Barre syndrome as well as mild hemorrhage, myocarditis, and hepatitis were also reported and are usually observed in both the elderly population and individuals with comorbidities (Lemant et al., 2008; Lebrun et al., 2009; Agarwal et al., 2017; Silva and Dermody, 2017). Alves-Leon and colleagues demonstrated that CHIKV patients with inflammatory demyelinating disease have genotypic resemblance with neurological autoimmune diseases patients, as multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) (Alves-Leon et al., 2021).

Chikungunya virus is usually considered a non-life-threatening disease, but fatal cases have been described. In addition to the most relevant CHIKV outbreak which occurred in La Reunion islands that resulted in 284 deaths (Josseran et al., 2006), an outbreak in Brazil led to 68 fatal cases from which CHIKV RNA was detected in cerebrospinal fluid of at least 92.3% of them, according to the Brazilian Ministry of Health. These data clearly bring an important conclusion that CHIKV neurological commitment is a severity factor directly correlated to the mortality rate. In addition, virus lineage also correlates with mortality being the ECSA lineage the most relevant as it was detected in most of the fatal cases (de Lima et al., 2020).

Chikungunya virus is a spherical and enveloped virus with an approximately 70 nm of diameter (Silva and Dermody, 2017). Its genome consists of a single-strand positive-sense 12 kb-long RNA with two open reading frames (ORFs) separated by a non-codifying junction and two non-translated regions named 5′UTR and 3′UTR. The 5′ORF is translated from the genomic RNA (gRNA) and codifies the non-structural polyprotein (P1234) that will be further cleaved in individual non-structural proteins nsP1 to 4. The 3′ORF is translated from a positive-sense subgenomic mRNA (sgRNA) and codifies the structural proteins: capsid (C), envelope 3 (E3), envelope 2 (E2), 6K, and envelope 1 (E1) (Strauss and Strauss, 1994; Khan et al., 2002; Solignat et al., 2009; Silva and Dermody, 2017). The role of each of the CHIKV proteins is summarized in Table 1.

After CHIKV is inoculated to the host organism, E2 glycoprotein binds to the membrane receptor Mxra8 on the target cells, which activate an internal signaling pathway resulting in the commitment of clathrin molecules to the plasma membrane and CHIKV clathrin-mediated endocytosis (Sourisseau et al., 2007; Bernard et al., 2010; McMahon and Boucrot, 2011; van Duijl-Richter et al., 2015; Zhang et al., 2018; Basore et al., 2019; Song et al., 2019; Figure 1). Following this event, clathrin molecules are separated from the endocytic vesicle and the acidification of endosomal pH triggers the detachment of E1-E2 heterodimers. This protein rearrangement results in the exposition of the fusion loop, a small motif of 19 residues on E1 protein, that drives the fusion of the endosomal with the viral membranes (Voss et al., 2010; Fields and Kielian, 2013). In addition to the key role of E1 and E2 in the recognition of target cell and membrane fusion process, Ooi et al. (2013) identified two other membrane proteins, which are the fuzzy homologue protein (FUZ) and the tetraspanin membrane protein (TSPAN9), required for the proper infection process by using a genome-wide small interference RNA (siRNA). The FUZ is involved in the clathrin-mediated endocytosis pathway, and TSPAN9 helps viral entry by two possible mechanisms: (i) virus orientation to the early endosome and/or (ii) modulation of the endosome membrane to be more permissive to the fusion process (Ooi et al., 2013). Nevertheless, other molecules, such as glycosaminoglycans (GAGs), T-cell immunoglobulin and mucin (TIM) family, Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN), AXL receptor tyrosine kinase, and membrane protein complex CD147, have all been described to participate in CHIKV-target cell interaction and to act as alternative cell receptors for CHIKV (Silva et al., 2014; Acharya et al., 2015; van Duijl-Richter et al., 2015; Schnierle, 2019; McAllister et al., 2020; De Caluwé et al., 2021), although binding to them might not be sufficient to trigger virus internalization (Wang et al., 1992; Klimstra et al., 2003; La Linn et al., 2005; Kielian et al., 2010). Other infection routes occur in epidermal and muscle cells. In the first cell line, CHIKV enters the cell by epidermal growth factor receptor substrate 15 (Eps15)-dependent pathway, and in the second cell line, micropinocytosis seems to be the preferred path, which shows the adaptive evolution of CHIKV to infect host cells by several means other than clathrin-dependent endocytosis (Bernard et al., 2010; Lee et al., 2019).

After the membrane fusion, the virus nucleocapsid is released to the cytoplasm, where protein C quickly detaches from the gRNA, which is immediately translated into the non-structural polyprotein P1234. The polyprotein is further cleaved by the viral protease nsP2 at the nsP3/4 cleavage site, releasing the viral polymerase nsP4 and the polyprotein P123 (Shin et al., 2012). The nsP4 will thus synthesize the negative-strand RNA used as a template for new copies of positive-polarity RNA (Figure 1). It is believed that the synthesis of the positive-strand is connected to the processing of the P123, as its cleavage into individual proteins maintains the synthesis of the positive-strand RNA but interferes in the minus-strand RNA synthesis (Strauss and Strauss, 1994). Indeed, P123 processing is associated with the sgRNA formation, as this event redirects the replication complex toward vesicular cytoplasmic spherules that will host double strand viral RNA (dsvRNA), protecting it from degradation and/or recognition by intracellular dsRNA sensors (Silva and Dermody, 2017). The polyprotein P123 is then cleaved at nsP1/2 followed by processing the nsP2/3 site. Interestingly, some CHIKV isolates encode an opal stop codon located after nsP3, which can control the expression of nsP4, by a read-through mechanism (Solignat et al., 2009). After these events, all individual nsPs are produced and the synthesis of the structural proteins is initiated.

The 3′ORF of the sgRNA is translated into a structural polyprotein that is further cleaved into individual proteins by viral and host proteases. Structural proteins are required for many viral processes, including virus assembly, receptor binding, and membrane fusion (Jose et al., 2009). The first produced structural protein is the C, a multifunctional protein responsible for packaging viral RNA and drive virion budding process (Hong et al., 2006; Thomas et al., 2010). The C protein contains a serine-protease domain responsible for its self-cleavage from the rest of the structural polyprotein (Thomas et al., 2010). The ability to exert a proteolytic activity indicates the relevance of this protein for successful new virus production, as its cleavage does not depend on host machinery. In other words, the rate of C protein production is the determinant step for new virus assembly. Once produced, C protein oligomerizes and opsonizes the gRNA to form the nucleocapsid core (Sharma et al., 2018; Figure 1).

During CHIKV replication, the ratio of gRNA:sgRNAs can vary between 1:3.5 to 1:5.5 (Scholte et al., 2013). Therefore, the success of virus assembly depends on the ability of C protein to distinguish between them and also other host’s small RNAs. It was believed that the presence of a packaging signal (PS) composed by structural RNA elements located in the nsP2 gene was the key element responsible for it (Kim et al., 2011). However, it was recently discovered that both CHIKV and Semliki Forest virus (SFV) do not exclusively depend on the PS at nsP2 to assertively package the gRNA. In fact, the first 2/3 of gRNA contains several binding sites for C protein, and its interaction in these regions drives proper RNA selection and nucleocapsid assembly (Brown et al., 2020).

Following this event, the structural polyprotein pE2-6K-E1 is conducted to the endoplasmic reticulum (ER) and Golgi apparatus, on account of a signal peptide sequence present in its N-terminal region (Firth et al., 2008; Snyder et al., 2013), where they will be processed and post-translational modifications, such as glycosylation, will take place. Host proteases, such as furin, cleave the structural polyprotein into individual E1, E2, E3, and 6K, which are further used for building the new virion particles (Yap et al., 2017). A ribosomal frameshift in the translation of the 6K gene might happen resulting in the production of the Transframe protein (TF) that shares the same N-terminal domain of 6K but different C-terminal and is involved in viral production, pathogenesis, and virus budding processes (Snyder et al., 2013; De Caluwé et al., 2021). During the exocytic pathway, post-translational modifications on E1 and E2 glycoproteins allow their association in heterodimers complexes, composing the virus envelope (Yap et al., 2017). Succeeding these events, the nucleocapsid core moves to membrane regions rich in E1-E2 dimers and mature virion is released by budding process from the infected cell (Figure 1). The complete budding mechanism is still not completely understood, but some interesting studies have reported the dependence of optimal temperature and pH conditions, as well as the presence of host cell membrane cholesterol to occur (Marquardt et al., 1993; Lu and Kielian, 2000; Lu et al., 2001). In addition, viral release is intensified by the presence of 6K and TF proteins, since the deletion or mutation in their genes negatively modulates the rate and the efficiency of virion budding, indicating their relevance to the process (Gaedigk-Nitschko and Schlesinger, 1991; Lu and Kielian, 2000; Ramsey and Mukhopadhyay, 2017).

Chikungunya virus can bind to several cellular receptors and undergo different internalization pathways. It exhibits wide cell, tissue, organ, and organism tropism, and the understanding of where and how the infection occurs in each site of active replication is the first step in the fight against this virus.

In invertebrate hosts, several tissues are susceptible to CHIKV and infection occurs very quickly. The midgut epithelium appears to be the first site of viral replication (Monteiro et al., 2019) followed by propagation to secondary organs, such as the salivary glands (Wong et al., 2016). By the way, infection of this tissue is the key step to make the mosquito a competent vector, since the transmission occurs when it salivates during blood feeding and the released saliva contains infectious CHIKV particles. The time between feeding with infected blood and the ability to transmit to vertebrate hosts, known as extrinsic incubation period (EIP), is a valuable parameter to estimate transmission rate and viral load during feeding. In case of CHIKV, the EIP can be as short as 2 days and quantification of viral RNA can be as high as 10^4.8 PFU in salivary gland and 10^3.3 PFU in extracted saliva (Dubrulle et al., 2009).

In humans and non-human primates, CHIKV primarily targets epithelial tissue in the area of inoculation. Epithelial fibroblast, keratinocytes, and melanocytes are susceptible to CHIKV (Sourisseau et al., 2007; Puiprom et al., 2013; Ekchariyawat et al., 2015; Gasque and Jaffar-Bandjee, 2015; Wichit et al., 2017; Matusali et al., 2019). Indeed, infection of these cells is a key step for stablishing the disease since CHIKV titer is rapidly increased, which is essential to reach other targets without being completely neutralized by host immune system. However, it is still unknown whether infection of epithelial cells exert any other effect in the pathogenesis than just an internal virus reservoir. After reaching the bloodstream and lymphatic system, CHIKV will infect blood cells and other tropism organs, such as liver, joints, muscles, brain, and spleen (Ozden et al., 2007; Her et al., 2010; Ruiz Silva et al., 2016; Suhrbier, 2019; Tritsch et al., 2020). Blood monocytes, B lymphocytes, and plasmacytoid dendritic cells (pDCs) are susceptible to CHIKV infection (Hawman et al., 2016; Ruiz Silva et al., 2016; Webster et al., 2018). It can also enter and replicate in synovial and muscles fibroblasts, synovial macrophages, myoblasts, muscle satellite cells, chondrocytes, and osteoblast (Ozden et al., 2007; Hoarau et al., 2010; Chusri et al., 2011; Phuklia et al., 2013; Hussain et al., 2016; Lentscher et al., 2020; Pott et al., 2020). Infection of synovial macrophages is important to keep high viremia during the acute phase (Her et al., 2010; Ruiz Silva et al., 2016; Haist et al., 2017), and viral RNA was detected in these cells in both humans and non-human primates during the chronic phase of the disease, suggesting that persistent viral replication may be related to the maintenance of arthritic symptoms (Hoarau et al., 2010; Labadie et al., 2010; Hawman et al., 2013). It is well known that CHIKV might also infect the nervous system but the mechanism of how the virus cross the blood-brain barrier is still poorly characterized. Endothelial brain cells, neuroblastoma cells, astrocytes, microglial cells, neurons, oligodendrocytes, corneal endothelium, corneal fibroblasts, scleral stroma, ciliary body, iris, and ocular muscle fibers have been reported to be infected by CHIKV but further studies need to be performed to confirm the effect of their infection to CHIKF clinical outcome (Abere et al., 2012; Couderc et al., 2012; Dhanwani et al., 2012; Wikan et al., 2012; Abraham et al., 2013, 2017; Fraisier et al., 2014; Lim and Chu, 2014; Das et al., 2015; Wei Chiam et al., 2015).

Chikungunya virus infection is known to cause severe musculoskeletal disorder, but the molecular mechanism involved in this process is not fully understood (Maek-A-Nantawat and Silachamroon, 2009). Observational studies in human subjects revealed that CHIKV infection elicits immune mechanisms similar to autoimmune diseases, which might explain the similarity between the arthritic phenomenon that occurred during the infection with rheumatoid arthritis (RA) (Chirathaworn et al., 2020). We categorize below the innate and the adaptive immune responses during CHIKV infection.

Although cell lines are extremely useful and demonstrated to be a powerful tool to understand the replication and molecular aspects of CHIKV pathogenesis, they may not reflect whole infection scenario. Development of rodent and non-human primate animal models is essential to advance the knowledge on CHIKV pathogenicity as well as to serve as a nonclinical model for anti-CHIKV drug or vaccine development. Table 3 summarizes the state-of-the art animal models used in CHIKV studies.

Chikungunya virus have recently become an urgent problem to public health because of several reasons, such as (i) the large and important outbreaks occurred in the last decade resulting in thousands of hospital interventions and hundreds of deaths, (ii) its possible widespread all over the globe as the result of virus ability to propagate in different vector species, and (iii) the high rate of long-term debilitating arthralgia with direct and significant social and economic impact. Several contributions have been made to understand the mechanisms associated to virus replication and pathogenesis. We know now that a plethora of cell types are susceptible to CHIKV infection, some of them directly contributing to both the establishment and maintenance of the disease, some of them acting to prevent the evolution of viral infection, whereas others have a minor but not less import role, serving as virus reservoir. Understanding the most affected tissues and cell types allows the development of reproducible, validated, and robust cellular and animal models to study CHIKV infection in the pursuit of helping the development of therapeutic and vaccine options to manage CHIKF. In this regard, our current knowledge is that CHIKF is a very complex disease in which it is impossible to reproduce the full disease signature in a unique in vivo model. Instead, there are several approaches and transgenic models that reproduce pieces of the disease and together might contribute to disease comprehension and to serve in development of antiviral technologies.

LC, BR, PC, TS, and DA drafted, revised, and prepared the manuscript. TS and RM-B revised the manuscript. RM-B and DA conceptualized and made the final revision on the manuscript. DA finalized the manuscript for submission. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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