Organometallic Complex Strongly Impairs Chikungunya Virus Entry to the Host Cells

Chikungunya fever is a disease caused by the Chikungunya virus (CHIKV) that is transmitted by the bite of the female of Aedes sp. mosquito. The symptoms include fever, muscle aches, skin rash, and severe joint pains. The disease may develop into a chronic condition and joint pain for months or years. Currently, there is no effective antiviral treatment against CHIKV infection. Treatments based on natural compounds have been widely studied, as many drugs were produced by using natural molecules and their derivatives. Alpha-phellandrene (α-Phe) is a naturally occurring organic compound that is a ligand for ruthenium, forming the organometallic complex [Ru2Cl4(p-cymene)2] (RcP). Organometallic complexes have shown promising as candidate molecules to a new generation of compounds that presented relevant biological properties, however, there is a lack of knowledge concerning the anti-CHIKV activity of these complexes. The present work evaluated the effects of the RcP and its precursors, the hydrate ruthenium(III) chloride salt (RuCl3⋅xH2O) (Ru) and α-Phe, on CHIKV infection in vitro. To this, BHK-21 cells were infected with CHIKV-nanoluciferase (CHIKV-nanoluc), a viral construct harboring the nanoluciferase reporter gene, at the presence or absence of the compounds for 16 h. Cytotoxicity and impact on infectivity were analyzed. The results demonstrated that RcP exhibited a strong therapeutic potential judged by the selective index > 40. Antiviral effects of RcP on different stages of the CHIKV replicative cycle were investigated; the results showed that it affected early stages of virus infection reducing virus replication by 77% at non-cytotoxic concentrations. Further assays demonstrated the virucidal activity of the compound that completely blocked virus infectivity. In silico molecular docking calculations suggested different binding interactions between aromatic rings of RcP and the loop of amino acids of the E2 envelope CHIKV glycoprotein mainly through hydrophobic interactions. Additionally, infrared spectroscopy spectral analysis indicated interactions of RcP with CHIKV glycoproteins. These data suggest that RcP may act on CHIKV particles, disrupting virus entry to the host cells. Therefore, RcP may represent a strong candidate for the development of anti-CHIKV drugs.

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Chikungunya virus entry is strongly inhibited by phospholipase A2 isolated from the venom of Crotalus durissus terrificus

Scientific Reports ◽

10.1038/s41598-021-88039-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Igor Andrade Santos ◽

Jacqueline Farinha Shimizu ◽

Débora Moraes de Oliveira ◽

Daniel Oliveira Silva Martins ◽

Léia Cardoso-Sousa ◽

...

Keyword(s):

Phospholipase A2 ◽

Chikungunya Virus ◽

Hydrophobic Interactions ◽

Virus Entry ◽

Etiologic Agent ◽

Host Cells ◽

Significant Activity ◽

Crotalus Durissus Terrificus ◽

Crotalus Durissus ◽

Replicative Cycle

AbstractChikungunya virus (CHIKV) is the etiologic agent of Chikungunya fever, a globally spreading mosquito-borne disease. There is no approved antiviral or vaccine against CHIKV, highlighting an urgent need for novel therapies. In this context, snake venom proteins have demonstrated antiviral activity against several viruses, including arboviruses which are relevant to public health. In particular, the phospholipase A2CB (PLA2CB), a protein isolated from the venom of Crotalus durissus terrificus was previously shown to possess anti-inflammatory, antiparasitic, antibacterial and antiviral activities. In this study, we investigated the multiple effects of PLA2CB on the CHIKV replicative cycle in BHK-21 cells using CHIKV-nanoluc, a marker virus carrying nanoluciferase reporter. The results demonstrated that PLA2CB possess a strong anti-CHIKV activity with a selectivity index of 128. We identified that PLA2CB treatment protected cells against CHIKV infection, strongly impairing virus entry by reducing adsorption and post-attachment stages. Moreover, PLA2CB presented a modest yet significant activity towards post-entry stages of CHIKV replicative cycle. Molecular docking calculations indicated that PLA2CB may interact with CHIKV glycoproteins, mainly with E1 through hydrophobic interactions. In addition, infrared spectroscopy measurements indicated interactions of PLA2CB and CHIKV glycoproteins, corroborating with data from in silico analyses. Collectively, this data demonstrated the multiple antiviral effects of PLA2CB on the CHIKV replicative cycle, and suggest that PLA2CB interacts with CHIKV glycoproteins and that this interaction blocks binding of CHIKV virions to the host cells.

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Phosphatidylserine within the Viral Membrane Enhances Chikungunya Virus Infectivity in a Cell-type Dependent Manner

10.1101/2022.01.14.476428 ◽

2022 ◽

Author(s):

Kerri L Miazgowicz ◽

Judith Mary Reyes Ballista ◽

Marissa D Acciani ◽

Ariana R Jimenez ◽

Ryan S Belloli ◽

...

Keyword(s):

Chikungunya Virus ◽

Intervention Strategy ◽

Host Cells ◽

Virus Infectivity ◽

Dependent Manner ◽

Cell Type ◽

Enveloped Viruses ◽

Outer Leaflet ◽

Viral Particles ◽

In Cells

Chikungunya virus (CHIKV), an alphavirus of the Togaviridae family, is the causative agent of the human disease chikungunya fever (CHIKF), which is characterized by debilitating acute and chronic arthralgia. No licensed vaccines or antivirals exist for CHIKV. Preventing the attachment of viral particles to host cells is an attractive intervention strategy. Viral entry of enveloped viruses from diverse families including Filoviridae and Flaviviridae is mediated or enhanced by phosphatidylserine receptors (PSRs). PSRs facilitate the attachment of enveloped viruses to cells by binding to exposed phosphatidylserine (PS) in the viral lipid membrane - a process termed viral apoptotic mimicry. To investigate the role of viral apoptotic mimicry during CHIKV infection, we produced viral particles with discrete amounts of exposed PS on the virion envelope by exploiting the cellular distribution of phospholipids at the plasma membrane. We found that CHIKV particles containing high outer leaflet PS (produced in cells lacking flippase activity) were more infectious in Vero cells than particles containing low levels of outer leaflet PS (produced in cells lacking scramblase activity). However, the same viral particles were similarly infectious in NIH3T3 and HAP1 cells, suggesting PS levels can influence infectivity only in cells with high levels of PSRs. Interestingly, PS-dependent CHIKV entry was observed in mosquito Aag2 cells, but not C6/36 cells. These data demonstrate that CHIKV entry via viral apoptotic mimicry is cell-type dependent. Furthermore, viral apoptotic mimicry has a mechanistic basis to influence viral dynamics in vivo in both the human and mosquito host.

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The degree of polymerization and sulfation patterns in heparan sulfate are critical determinants of cytomegalovirus entry into host cells

PLoS Pathogens ◽

10.1371/journal.ppat.1009803 ◽

2021 ◽

Vol 17 (8) ◽

pp. e1009803

Author(s):

Dipanwita Mitra ◽

Mohammad H. Hasan ◽

John T. Bates ◽

Michael A. Bierdeman ◽

Dallas R. Ederer ◽

...

Keyword(s):

Cell Surface ◽

Heparan Sulfate ◽

Virus Entry ◽

Degree Of Polymerization ◽

Host Cells ◽

Virus Infectivity ◽

Wild Type ◽

Enveloped Viruses ◽

Host Membrane ◽

Mutant Cells

Several enveloped viruses, including herpesviruses attach to host cells by initially interacting with cell surface heparan sulfate (HS) proteoglycans followed by specific coreceptor engagement which culminates in virus-host membrane fusion and virus entry. Interfering with HS-herpesvirus interactions has long been known to result in significant reduction in virus infectivity indicating that HS play important roles in initiating virus entry. In this study, we provide a series of evidence to prove that specific sulfations as well as the degree of polymerization (dp) of HS govern human cytomegalovirus (CMV) binding and infection. First, purified CMV extracellular virions preferentially bind to sulfated longer chain HS on a glycoarray compared to a variety of unsulfated glycosaminoglycans including unsulfated shorter chain HS. Second, the fraction of glycosaminoglycans (GAG) displaying higher dp and sulfation has a larger impact on CMV titers compared to other fractions. Third, cell lines deficient in specific glucosaminyl sulfotransferases produce significantly reduced CMV titers compared to wild-type cells and virus entry is compromised in these mutant cells. Finally, purified glycoprotein B shows strong binding to heparin, and desulfated heparin analogs compete poorly with heparin for gB binding. Taken together, these results highlight the significance of HS chain length and sulfation patterns in CMV attachment and infectivity.

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The degree of polymerization and sulfation patterns in heparan sulfate are critical determinants of cytomegalovirus infectivity

10.1101/590463 ◽

2019 ◽

Cited By ~ 1

Author(s):

Mohammad H. Hasan ◽

Rinkuben Parmar ◽

Quntao Liang ◽

Hong Qiu ◽

Vaibhav Tiwari ◽

...

Keyword(s):

Cell Surface ◽

Heparan Sulfate ◽

Virus Entry ◽

Degree Of Polymerization ◽

Convincing Evidence ◽

Host Cells ◽

Virus Infectivity ◽

Cmv Infection ◽

Virus Binding ◽

Heparan Sulfates

AbstractHerpesviruses attach to host cells by interacting with cell surface heparan sulfate (HS) proteoglycans prior to specific coreceptor engagement which culminates in virus-host membrane fusion and virus entry. Interfering with HS-herpesvirus interactions results in significant reduction in virus infectivity indicating that HS play important roles in initiating virus entry. In this study, we provide convincing evidence that specific sulfations as well as the degree of polymerization (dp) of HS govern human cytomegalovirus (CMV) infection and binding by following line of evidences. First, purified CMV extracellular virions preferentially bound to the sulfated longer chain of HS on a glycoarray compared to unsulfated glycosaminoglycans and shorter chain unsulfated HS. Second, the fraction of glycosaminoglycans (GAG) displaying higherdpand sulfation had a major impact on CMV infectivity and titers. Finally, cell lines knocked out for specific sulfotransferases Glucosaminyl 3-O-sulfotransferase (3-O-ST-1 and −4 and double −1/4) produced significantly reduced CMV titers compared to wild-type cells. Similarly, a peptide generated against sulfated-HS significantly reduced virus titers compared to the control peptide. Taken together, the above results highlight the significance of the chain length and sulfation patterns of HS in CMV binding and infectivity.ImportanceThe cell surface heparan sulfates (HS) are exploited by multiple viruses as they provide docking sites during cell entry and therefore are a promising target for the development of novel antivirals. In addition, the molecular diversity in HS chains generates unique binding sites for specific ligands and hence offers preferential binding for one virus over other. In the current study several HS mimics were analyzed for their ability to inhibit cytomegalovirus (CMV) infection. The results were corroborated by parallel studies in mutant mouse cells and virus binding to glycoarrays. Combined together, the data suggests that virus particles preferentially attach to specifically modified HS and thus the process is amenable to targeting by specifically designed HS mimics.

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Cathepsin B Protease Facilitates Chikungunya Virus Envelope Protein-Mediated Infection Via Endocytosis or Macropinocytosis

Viruses ◽

10.3390/v12070722 ◽

2020 ◽

Vol 12 (7) ◽

pp. 722

Author(s):

Mai Izumida ◽

Hideki Hayashi ◽

Atsushi Tanaka ◽

Yoshinao Kubo

Keyword(s):

Cathepsin B ◽

Chikungunya Virus ◽

Ebola Virus ◽

Leukemia Virus ◽

Host Cells ◽

Virus Envelope ◽

Chikv Infection ◽

Enveloped Virus ◽

Entry Pathway ◽

Virus Envelope Protein

Chikungunya virus (CHIKV) is an enveloped virus that enters host cells and transits within the endosomes before starting its replication cycle, the precise mechanism of which is yet to be elucidated. Endocytosis and endosome acidification inhibitors inhibit infection by CHIKV, murine leukemia virus (MLV), or SARS-coronavirus, indicating that these viral entries into host cells occur through endosomes and require endosome acidification. Although endosomal cathepsin B protease is necessary for MLV, Ebola virus, and SARS-CoV infections, its role in CHIKV infection is unknown. Our results revealed that endocytosis inhibitors attenuated CHIKV-pseudotyped MLV vector infection in 293T cells but not in TE671 cells. In contrast, macropinocytosis inhibitors attenuated CHIKV-pseudotyped MLV vector infection in TE671 cells but not in 293T cells, suggesting that CHIKV host cell entry occurs via endocytosis or macropinocytosis, depending on the cell lines used. Cathepsin B inhibitor and knockdown by an shRNA suppressed CHIKV-pseudotyped MLV vector infection both in 293T and TE671 cells. These results show that cathepsin B facilitates CHIKV infection regardless of the entry pathway.

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Genome-Wide Screening Uncovers the Significance of N-Sulfation of Heparan Sulfate as a Host Cell Factor for Chikungunya Virus Infection

Journal of Virology ◽

10.1128/jvi.00432-17 ◽

2017 ◽

Vol 91 (13) ◽

Cited By ~ 33

Author(s):

Atsushi Tanaka ◽

Uranan Tumkosit ◽

Shota Nakamura ◽

Daisuke Motooka ◽

Natsuko Kishishita ◽

...

Keyword(s):

Virus Infection ◽

Heparan Sulfate ◽

Chondroitin Sulfate ◽

Chikungunya Virus ◽

Yellow Fever Virus ◽

Host Cells ◽

Pseudotyped Virus ◽

Target Cells ◽

Chikv Infection ◽

Genome Wide

ABSTRACT The molecular mechanisms underlying chikungunya virus (CHIKV) infection are poorly characterized. In this study, we analyzed the host factors involved in CHIKV infection using genome-wide screening. Human haploid HAP1 cells, into which an exon-trapping vector was introduced, were challenged with a vesicular stomatitis virus pseudotype bearing the CHIKV E3 to E1 envelope proteins. Analysis of genes enriched in the cells resistant to the pseudotyped virus infection unveiled a critical role of N-sulfation of heparan sulfate (HS) for the infectivity of the clinically isolated CHIKV Thai#16856 strain to HAP1 cells. Knockout of NDST1 that catalyzes N-sulfation of HS greatly decreased the binding and infectivity of CHIKV Thai#16856 strain but not infectivity of Japanese encephalitis virus (JEV) and yellow fever virus (YFV). While glycosaminoglycans were commonly required for the efficient infectivity of CHIKV, JEV, and YFV, as shown by using B3GAT3 knockout cells, the tropism for N-sulfate was specific to CHIKV. Expression of chondroitin sulfate (CS) in NDST1-knockout HAP1 cells did not restore the binding of CHIKV Thai#16856 strain and the infectivity of its pseudotype but restored the infectivity of authentic CHIKV Thai#16856, suggesting that CS functions at later steps after CHIKV binding. Among the genes enriched in this screening, we found that TM9SF2 is critical for N-sulfation of HS and therefore for CHIKV infection because it is involved in the proper localization and stability of NDST1. Determination of the significance of and the relevant proteins to N-sulfation of HS may contribute to understanding mechanisms of CHIKV propagation, cell tropism, and pathogenesis. IMPORTANCE Recent outbreaks of chikungunya fever have increased its clinical importance. Chikungunya virus (CHIKV) utilizes host glycosaminoglycans to bind efficiently to its target cells. However, the substructure in glycosaminoglycans required for CHIKV infection have not been characterized. Here, we unveil that N-sulfate in heparan sulfate is essential for the efficient infection of a clinical CHIKV strain to HAP1 cells and that chondroitin sulfate does not help the CHIKV binding but does play roles at the later steps in HAP1 cells. We show, by comparing previous reports using Chinese hamster ovary cells, along with another observation that enhanced infectivity of CHIKV bearing Arg82 in envelope E2 does not depend on glycosaminoglycans in HAP1 cells, that the infection manner of CHIKV varies among host cells. We also show that TM9SF2 is required for CHIKV infection to HAP1 cells because it is involved in the N-sulfation of heparan sulfate through ensuring NDST1 activity.

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Cell-intrinsic Innate Immune Responses against Chikungunya Virus in a Human Ex Vivo Synovial Fibroblast Model

10.1101/2020.06.07.138610 ◽

2020 ◽

Author(s):

Fabian Pott ◽

Richard J. P. Brown ◽

Elena Neumann ◽

Thomas Pietschmann ◽

Christine Goffinet

Keyword(s):

Chikungunya Virus ◽

Cell Model ◽

Ex Vivo ◽

Antiviral Treatment ◽

Treatment Strategies ◽

Synovial Fibroblasts ◽

International Travel ◽

Type I ◽

Insect Vector ◽

Chikv Infection

AbstractIn recent years, newly and re-emerging arboviruses including Chikungunya virus (CHIKV), have caused growing concern due to expansion of insect vector ranges, mediated by the exponential increase in international travel and accelerating climate change. Due to the absence of specific antiviral treatment strategies and a protective vaccine, over 2 million CHIKV cases have been reported since 2005. Long-term morbidity after CHIKV infection includes debilitating chronic joint pain, which has associated health, social, individual, and economic impact. Here, we analyzed the early cell-intrinsic response to CHIKV infection in primary human synovial fibroblasts. This cell type represents a potential source of polyarthralgia induced by CHIKV infection. Synovial fibroblasts from healthy donors and osteoarthritic patients were similarly permissive to CHIKV infection. We observed a CHIKV infection-induced transcriptional profile that consisted in upregulation of several hundred interferon-stimulated genes, in addition to transcription factor-encoding genes and effector genes of proinflammatory pathways. In contrast, IL-6, which mediates chronic synovitis by stimulating neutrophil and macrophage infiltration into the joints, was barely secreted by CHIKV-infected fibroblasts. Finally, the cell-intrinsic response to interferon type I and III treatment of synovial fibroblasts differed from that of immortalized model cell lines. In synovial fibroblasts, CHIKV replication was impaired by IFN-α administered post-infection. In summary, primary human synovial fibroblasts serve as bona-fide ex vivo primary cell model of CHIKV infection and provide a valuable platform for studies of joint tissue-associated aspects of CHIKV immunopathogenesis.

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Tomatidine reduces Chikungunya virus progeny release by controlling viral protein expression

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0009916 ◽

2021 ◽

Vol 15 (11) ◽

pp. e0009916

Author(s):

Berit Troost-Kind ◽

Martijn J. van Hemert ◽

Denise van de Pol ◽

Heidi van der Ende-Metselaar ◽

Andres Merits ◽

...

Keyword(s):

Protein Expression ◽

Viral Protein ◽

Chikungunya Virus ◽

Antiviral Treatment ◽

Antiviral Effect ◽

Virus Infectivity ◽

Expression Levels ◽

Viral Protein Expression ◽

Huh7 Cells

Tomatidine, a natural steroidal alkaloid from unripe green tomatoes has been shown to exhibit many health benefits. We recently provided in vitro evidence that tomatidine reduces the infectivity of Dengue virus (DENV) and Chikungunya virus (CHIKV), two medically important arthropod-borne human infections for which no treatment options are available. We observed a potent antiviral effect with EC50 values of 0.82 μM for DENV-2 and 1.3 μM for CHIKV-LR. In this study, we investigated how tomatidine controls CHIKV infectivity. Using mass spectrometry, we identified that tomatidine induces the expression of p62, CD98, metallothionein and thioredoxin-related transmembrane protein 2 in Huh7 cells. The hits p62 and CD98 were validated, yet subsequent analysis revealed that they are not responsible for the observed antiviral effect. In parallel, we sought to identify at which step of the virus replication cycle tomatidine controls virus infectivity. A strong antiviral effect was seen when in vitro transcribed CHIKV RNA was transfected into Huh7 cells treated with tomatidine, thereby excluding a role for tomatidine during CHIKV cell entry. Subsequent determination of the number of intracellular viral RNA copies and viral protein expression levels during natural infection revealed that tomatidine reduces the RNA copy number and viral protein expression levels in infected cells. Once cells are infected, tomatidine is not able to interfere with active RNA replication yet it can reduce viral protein expression. Collectively, the results delineate that tomatidine controls viral protein expression to exert its antiviral activity. Lastly, sequential passaging of CHIKV in presence of tomatidine did not lead to viral resistance. Collectively, these results further emphasize the potential of tomatidine as an antiviral treatment towards CHIKV infection.

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Critical role for bone marrow stromal antigen 2 in acute Chikungunya virus infection

Journal of General Virology ◽

10.1099/vir.0.068643-0 ◽

2014 ◽

Vol 95 (11) ◽

pp. 2450-2461 ◽

Cited By ~ 29

Author(s):

Wadie D. Mahauad-Fernandez ◽

Philip H. Jones ◽

Chioma M. Okeoma

Keyword(s):

Bone Marrow ◽

Chikungunya Virus ◽

Critical Role ◽

Cd40 Ligand ◽

Host Cells ◽

Lymphoid Tissues ◽

Chikv Infection ◽

Retroviral Infection

Bone marrow stromal antigen 2 (BST-2; also known as tetherin or CD317) is an IFN-inducible gene that functions to block the release of a range of nascent enveloped virions from infected host cells. However, the role of BST-2 in viral pathogenesis remains poorly understood. BST-2 plays a multifaceted role in innate immunity, as it hinders retroviral infection and possibly promotes infection with some rhabdo- and orthomyxoviruses. This paradoxical role has probably hindered exploration of BST-2 antiviral function in vivo. We reported previously that BST-2 tethers Chikungunya virus (CHIKV)-like particles on the cell plasma membrane. To explore the role of BST-2 in CHIKV replication and host protection, we utilized CHIKV strain 181/25 to examine early events during CHIKV infection in a BST-2−/− mouse model. We observed an interesting dichotomy between WT and BST-2−/− mice. BST-2 deficiency increased inoculation site viral load, culminating in higher systemic viraemia and increased lymphoid tissues tropism. A suppressed inflammatory innate response demonstrated by impaired expression of IFN-α, IFN-γ and CD40 ligand was observed in BST-2−/− mice compared with the WT controls. These findings suggested that, in part, BST-2 protects lymphoid tissues from CHIKV infection and regulates CHIKV-induced inflammatory response by the host.

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Emerging chikungunya virus variants at the E1-E1 inter-glycoprotein spike interface impact virus attachment and Inflammation.

Journal of Virology ◽

10.1128/jvi.01586-21 ◽

2021 ◽

Author(s):

Margarita V. Rangel ◽

Nicole McAllister ◽

Kristen Dancel-Manning ◽

Maria G. Noval ◽

Laurie A. Silva ◽

...

Keyword(s):

Human Health ◽

Chikungunya Virus ◽

Molecular Mechanisms ◽

Cell Attachment ◽

Host Cells ◽

Chikv Infection ◽

Virus Attachment ◽

Pathogenic Variants ◽

Important Region

Chikungunya virus (CHIKV) is a re-emerging arthropod-borne alphavirus and a serious threat to human health. Therefore, efforts toward elucidating how this virus causes disease and the molecular mechanisms underlying steps of the viral replication cycle are crucial. Using an in vivo transmission system that allows intra-host evolution, we identified an emerging CHIKV variant carrying a mutation in the E1 glycoprotein (V156A) in the serum of mice and saliva of mosquitoes. E1 V156A has since emerged in humans during an outbreak in Brazil, co-occurring with a second mutation, E1 K211T, suggesting an important role for these residues in CHIKV biology. Given the emergence of these variants, we hypothesized that they function to promote CHIKV infectivity and subsequent disease. Here, we show that E1 V156A and E1 K211T modulate virus attachment and fusion and impact binding to heparin, a homolog of heparan sulfate, a key entry factor on host cells. These variants also exhibit differential neutralization by anti-glycoprotein monoclonal antibodies, suggesting structural impacts on the particle that may be responsible for altered interactions at the host membrane. Finally, E1 V156A and E1 K211T exhibit increased titers in an adult arthritic mouse model and induce increased foot-swelling at the site of injection. Taken together, this work has revealed new roles for E1 where discrete regions of the glycoprotein are able to modulate cell attachment and swelling within the host. IMPORTANCE Alphaviruses represent a growing threat to human health worldwide. The re-emerging alphavirus chikungunya virus (CHIKV) has rapidly spread to new geographic regions in the last several decades, causing overwhelming outbreaks of disease, yet there are no approved vaccines or therapeutics. The CHIKV glycoproteins are key determinants of CHIKV adaptation and virulence. In this study, we identify and characterize the emerging E1 glycoprotein variants, V156A and K211T, that have since emerged in nature. We demonstrate that E1 V156A and K211T function in virus attachment to cells, a role that until now has been only attributed to specific residues of the CHIKV E2 glycoprotein. We also demonstrate E1 V156A and K211T to increase foot-swelling of the ipsilateral foot in mice infected with these variants. Observing that these variants and other pathogenic variants occur at the E1-E1 inter-spike interface, we highlight this structurally important region as critical for multiple steps during CHIKV infection. Together, these studies further defines the function of E1 in CHIKV infection and can inform the development of therapeutic or preventative strategies.

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