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Chikungunya and Zika Viruses: Comparison
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Please note this is a comparison between Version 2 by Vicky Zhou and Version 1 by Sineewanlaya Wichit.

Chikungunya and Zika viruses, both transmitted by mosquito vectors, have globally re-emerged over for the last 60 years and resulted in crucial social and economic concerns. Presently, there is no specific antiviral agent or vaccine against these debilitating viruses. Understanding viral–host interactions is needed to develop targeted therapeutics.

  • Chikungunya virus
  • Zika virus
  • antiviral
  • arbovirus
  • arbovirus–host interactions

1. Introduction

Chikungunya virus (CHIKV) and Zika virus (ZIKV) are arboviruses that have globally re-emerged and increased the global burden for public health. The viruses are mainly transmitted by the same mosquito vectors: Aedes aegypti and Ae. albopictus. However, ZIKV can also be transmitted by blood transfusion and sexual intercourse [1]. Arbovirus infections occur when mosquitoes blood-feed via human skin. During the meals, the mosquito inserts its mouthpiece into the skin and transmits infectious viral particles into both the epidermis and dermis, where inhabitant and migratory cells confront them [2]. People infected by CHIKV usually (up to 90%) develop clinical symptoms characterized by headache, high fever, maculopapular rash, myalgia, arthralgia, and severe asthenia that might last for months or years [3]. In contrast, only 20–25% of ZIKV-infected patients manifest symptoms, usually a “dengue-like” syndrome with a wide range of symptoms (headaches, fever, maculopapular rashes, arthralgia, conjunctivitis, and swelling at the extremities). However, of concern in ZIKV-infected patients are increasing reports of neurological complications (Guillain-Barré syndrome) and neurological birth defects (microcephaly) [4]. Despite the known healthcare threats caused by these viruses, there is still a lack of specific vaccines and therapeutics [5][6]. Normally, patients infected by CHIKV and ZIKV are given anesthetics, anti-inflammatory medications, and supportive care for relieving symptoms.

Antiviral drugs tend to use one of two main approaches, i.e., direct-acting antivirals (DAAs) and host-targeting antivirals (HTAs). DAAs directly target viral proteins and have proven to be successful. However, DAA compounds often display narrow-spectrum activity, and their development is time-consuming and costly [7]. HTAs are a promising approach that target host factors hijacked by viruses. This strategy demonstrates broad-spectrum activity and is developd using either newly discovered compounds or repurposing existing drugs [8]. Nevertheless, further knowledge of the virology, replication cycles, and host/virus interaction processes of these viruses is needed to help speed antiviral discovery.

2. Geographic Distribution of Chikungunya and Zika Viruses

CHIKV was first reported in southern Tanzania in 1952

[9]

, followed by occasional reports of CHIKV-infected cases in Africa

[10][11][12]

and Asia

[13][14][15][16]

. The first epidemic in Asia was documented in Bangkok, Thailand, in 1958

[14]

. Since then, CHIKV has rapidly spread worldwide. An outbreak in Kenya in 2004, which subsequently caused infections in most islands of the Indian Ocean over the next two years

[17][18][19][20]

. CHIKV from the Indian Ocean spread to many countries in Asia such as India

[21][22]

, Sri Lanka, Myanmar

[23]

, and Thailand

[24]

, as well as to northern Italy in 2007 (the first report in Europe)

[25]

. In 2010, the first autochthonous case was reported in Europe

[26]

, and, in the same year, CHIKV was also reported in several countries in Asia

[27][28][29]

. In the Americas, the first autochthonous case was identified in Saint Martin in 2013

[30]

. CHIKV subsequently caused viral infections through the North, Central, and South Americas

[31][32]. As of 2021, 115 countries/territories have been affected by CHIKV (Figure 3).

. As of 2021, 115 countries/territories have been affected by CHIKV (Figure 1).

Figure 31.

Geographic distribution of Chikungunya and Zika viruses. Information retrieved from the U.S. CDC website, last accessed in February 2021

[33][34]

. Map was created with mapchart.net.

ZIKV was first identified in 1947 from a sentinel rhesus monkey during a yellow fever project in the Zika forest near Entebbe in Uganda

[35]

. The first human cases were reported in 1952 from Uganda and the United Republic of Tanzania

[36]

. Since then, ZIKV-infected cases have occurred sporadically in Africa

[37][38][39][40][41][42]

and Asia

[16][43][44][45][46]

. A large outbreak of ZIKV occurred outside Africa and Asia in 2007 in the Pacific Ocean country of the Federated States of Micronesia (on “Yap Island”), thus causing infection of approximately 73% of residents

[47]

.

In 2013–2014, ZIKV caused an outbreak in French Polynesia and was subsequently transmitted to other Pacific islands including Easter Island, New Caledonia, and the Cook Islands

[48][49][50][51]

. A year later, in 2015, the first outbreak of ZIKV in the Americas took place in Brazil and rapidly spread through many countries in the region

[52][53]. As of 2021, 86 countries/territories worldwide report having ZIKV-infected cases (Figure 3). CHIKV and ZIKV co-circulate in more than 80 of these countries/territories (Figure 3).

. As of 2021, 86 countries/territories worldwide report having ZIKV-infected cases (Figure 1). CHIKV and ZIKV co-circulate in more than 80 of these countries/territories (Figure 1).

3. Interplay of Virus Proteins and Host Factors

To develop antiviral agents, a greater understanding of virus–host interaction is required. Summaries of the viral protein–host factor interactions of CHIKV and ZIKV are shown in Table 1 and Table 2, respectively.

Table 1.

Summary of known host factors that interact with Chikungunya virus proteins. NLS: nuclear localization signal; NES: nuclear exportation signals; E: envelope; nsP: non-structural protein; GAGs: glycosaminoglycans; hTIM: human T cell immunoglobulin mucin; AXL: Axl receptor tyrosine kinase; Mxra8: matrix remodeling-associated protein 8; DC-SIGN: dendritic-cell-specific ICAM-grabbing non-integrin; ER: endoplasmic reticulum.

Viral Protein

(Binding Site)

Host Factor/Protein		 Host Factor/Protein Function Host Factor/Protein Involves in Viral Replication (Binding Site) Host Factor/Protein Host Factor/Protein FunctionReference
Host Factor/Protein Involves in Viral Replication Reference
Capsid

(NLS)		 Karα4/major binding site Molecule transportation between nucleus and cytoplasm. Allow for virus capsid for nuclear translocation. [54
Capsid

(Positively charged interface formed by α4 helix)		 Nucleotides (single-stranded and double-stranded RNAs or DNAs) DNA synthesis.
]
Mechanism unknown. [71]
Capsid (NES, aa 143–155)
Capsid

(pre-α1 loop)
CRM1 (XPO1)/NR RNA and protein exportation from the nucleus to cytoplasm. Exit virus capsid from the nucleus.
Lipid droplets
[54]
Not reported. Virus–host membrane fusion. [71]
E3 Furin Serine endoprotease with calcium-dependent favor cleaving the paired basic amino acids. Cleave E3 from pE2-E1 dimer. [55]
Capsid G3BP1 and Caprin-1 G3BP1: Essential in innate immune response.

Caprin-1: Regulates mRNAs transportation and translation and is involved in neuron synaptic and cell proliferation and migration.		 The interaction facilitates viral replication and also impairs stress granule formation. [72]
E2 PHB Various functions, with an especially critical role in proteins and lipids regulating mitochondrial metabolism. Attach and entry factors. [56]
Capsid UPF1 Essential for nonsense-mediated decay (NMD) pathway. Inhibits the antiviral effect of NMD pathway. [73]
E2 GAGs Cellular process regulation including cell signaling. Attach and entry factors. [57]
E2 hTIM1 Human immune response, apoptotic cell engulfment, and T cell proliferation regulation. Attach and entry factors. [58]
PrM/M (PrM) Furin Serine endoprotease with calcium-dependent favor cleaving the paired amino acids. Facilitate the viral maturation process. [74]
E (DII) Endoplasmic membrane Synthesis, folding, modification, and transport of proteins. Membrane fusion. [75]
E2 AXL Cellular process involvement and regulation. Attach and entry factors. [58]
E (DIII) Endosome Regulate the transportation of proteins and lipids among cellular compartments of the endocytic pathway. Membrane fusion. [75]
E2 Mxra8 Modulates the activity of various signaling pathways. Attach and entry factors. [59]
E DC-SIGN, HSP70, TIM-1 and TAM receptors (TYRO3, AXL, and MER) DC-SIGN: dendritic cell differentiation, cell adhesion, signaling, migration, and antigen recognition.

TIM-1: regulates human immune response, cell survival, and the clearance of apoptotic cells.

HSP70: involved in protein folding and unfolding regulation and protects the cell from oxidative stress.

TAM receptors: involved in many cellular processes including cell differentiation, cell survival, migration, and innate immune modulation.		 DC-SIGN and TIM-1: involved in viral entry.

HSP70: mediate viral entry, replication, and release.

TAM receptors: involved in viral entry and innate immune responses modulation.		 [76][77][78][79][80][81][82]
E2 DC-SIGN Involved in dendritic cell differentiation, cell adhesion, signaling, migration, and antigen recognition.
E Mfsd2a Support blood–brain barrier formation and function.
Attach and entry factors. [60]
Impaired brain development [83]
E2 PTPN2 A tyrosine phosphatase involved in numerous signaling events. Transport virus structural protein to host cell membrane. [61]
NS1 TBK1 Regulates inflammatory responses to foreign agents. Blocks IFN signaling [84]
E2 COL1A2 Type I collagen that strengthens and supports many tissues in the body. Mechanism unknown. [61]
nsP2
NS2A TBK1
E2 ACTG1 Part of cellular trafficking machinery. Transport virus structural protein to host cell membrane. [61]
6K/TF - - - -
Regulates inflammatory responses to foreign agents. Blocks IFN signaling. [85]
  IRF3 Transcriptional regulator of type I IFN-dependent immune responses. Inhibits the production of type I IFN induced by MDA5/RIG-I signaling pathway. [86]
UBQLN4, RCHY1, WWP1
NS2B TBK1 Regulates inflammatory responses to foreign agents Blocks IFN signaling. [85][84]
E1 COMMD1 Regulation of cellular protein degradation and ubiquitination. Transport virus structural protein to host cell membrane and regulate host immune responses. [61]
NS2B/3 SEPT2 Involved in actin cytoskeleton organization. Trigger cell death and stress in hNPC. [74]
E1 THBS1 Involved in dentinogenesis and ER stress responses. Involved in the regulation of host immune responses. [61]
Involved in protein degradation and autophagy.
  Jak1 Involved in interleukin-2 and interleukin-10 receptors.
E1 DYNC1H1 Transfer material such as neurons across cells and important in cell division. Transport virus structural proteins to host cell membrane and related to neurological manifestation. [61]
Suppress JAK–STAT signaling. [84]
NS4A MAVS Required for innate immune defense against viruses. Blocks the IFN signaling. [87][88]
E1 ATP1B3 Sodium/potassium-transporting ATPase. Fusion factors.
 
[61
IRF3
]
Transcriptional regulator of type I IFN-dependent immune responses. Inhibits the production of type I IFN induced by MDA5/RIG-I signaling pathway. [86]
E1 BST-2 Antiviral response by blocking mature virion budding from host cell. Budding factors. [62]
nsP1 BST-2 Antiviral response by blocking mature virion budding from host cell. Budding factors. [62]
nsP2 Rpb1 Catalyse RNA transcription. nsP2 induces Rpb1 degradation, leading to the inhibition of cellular transcription and antiviral responses. [63]
nsP2 SFRS3/SRp20 Involved in mRNA exportation from the nucleus and RNA splicing. Mechanism unknown. [64]
Promotes viral replication. [64]
nsP2 GFAP, PDK2, RBM12B, TPR GFAP: A cell-specific marker helps to differentiate astrocytes from other glial cells.

PDK2: Regulate glucose and fatty acid metabolism and homeostasis, cell proliferation, and delay apoptosis.

RBM12B: RNA-binding protein.
NS4B TBK1 Regulates inflammatory responses to foreign agents. Blocks IFN signaling. [85][84]
NS5 STAT1 Mediated cellular response to IFNs, cytokines, and growth factors. Blocks IFN signaling. [89]
nsP2 CCDC130, CPNE6, POLR2C, MAPK9, EIF4A2, EEF1A1, EIF3I
NS5

(MTase domain)		 STAT2 Mediated IFN-alpha and IFN-beta signaling. Blocks IFN signaling. [90] Putative interactors with nsP2 and mainly involved in apoptosis, transcription, and translation mechanism. Mechanism unknown. [65]
nsP2 CEP55, KLC4, TACC3, VIM Component of cytoskeleton. Support the formation of replication complex and help to transport in the infected cells. [64]
nsP2 HNRNPK Important role in mRNA metabolism, DNA damaging, and activating and controlling the transcription process. Promotes viral replication. [64]
nsP2 TTC7B Regulate and localize phosphatidylinositol 4-kinase to the cell membrane. Support nsP2 for shutting off the cellular processing of host cells. [64]
nsP2 ASCC2, EWSR1, IKZF1, TRIM27, ZBTB43, MRFAP1L1(MRG15) ASCC2: Support gene transcription and repairing.

EWSR1: Involved in cell signaling, gene expression. and RNA processing and transport.

IKZF1: A transcription factor.

TRIM27: Control gene transcription.

MRFAP1L1(MRG15): Regulate transcription by the binding with retinoblastoma tumor suppressor (Rb) and MORF4/MRG nuclear protein PAM14.

ZBTB43: Suppress Blimp1 transcription process.		 Mechanism unknown. [64]

TPR: Support protein and mRNA transportation from the nucleus.		 Mechanism unknown. [64]
nsP2 NDP52/CALCOCO2 Involved in autophagy, inhibit pathogen proliferation. Support the replication complexes formation. [64]
nsP3 PI3K-Akt-mTOR pathway Involved in cellular proliferation and regulate cell cycle. Support the replication complexes internalization. [66]
nsP3 G3BP1 and G3BP2 G3BP1: Can be used as stress granule marker and to facilitate stress granule assembly.

G3BP2: Could transport mRNA.		 Mediate viral replication. [67]
nsP3 SK2 Involved in cell proliferation, differentiation, and host cell immunity. Mediate viral replication. [68]
nsP3 Hsp90β Maintain cellular homeostasis by modulating cellular processes. Mechanism unclear. [69]
nsP4 LCP1 Involved in T cell activation mechanisms. Mechanism unknown. [64]
nsP4 Hsp90α Maintains cellular homeostasis by modulating cellular processes. Support replication complex formation. [69]
nsP4 eIF2α Important for translation process. Mediate the viral replication. [70]
Table 2.

Summary of known host factors which interact with Zika virus proteins. TBK: TANK binding kinase 1; IRF: interferon regulator factor; MAVS: mitochondrial antiviral-signaling; NS: non-structural protein; MTase: methyltransferase; IFN: interferon; MDA5: melanoma differentiation-associated protein 5; RIG-1: retinoic acid-inducible gene-I.

Viral Protein

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