Abstract
Chikungunya virus (CHIKV) is a re-emerging alphavirus that is transmitted to humans by mosquito bites and causes musculoskeletal and joint pain1,2. Despite intensive investigations, the human cellular factors that are critical for CHIKV infection remain unknown, hampering the understanding of viral pathogenesis and the development of anti-CHIKV therapies. Here we identified the four-and-a-half LIM domain protein 1 (FHL1)3 as a host factor that is required for CHIKV permissiveness and pathogenesis in humans and mice. Ablation of FHL1 expression results in the inhibition of infection by several CHIKV strains and o’nyong-nyong virus, but not by other alphaviruses and flaviviruses. Conversely, expression of FHL1 promotes CHIKV infection in cells that do not normally express it. FHL1 interacts directly with the hypervariable domain of the nsP3 protein of CHIKV and is essential for the replication of viral RNA. FHL1 is highly expressed in CHIKV-target cells and is particularly abundant in muscles3,4. Dermal fibroblasts and muscle cells derived from patients with Emery–Dreifuss muscular dystrophy that lack functional FHL15 are resistant to CHIKV infection. Furthermore, CHIKV infection is undetectable in Fhl1-knockout mice. Overall, this study shows that FHL1 is a key factor expressed by the host that enables CHIKV infection and identifies the interaction between nsP3 and FHL1 as a promising target for the development of anti-CHIKV therapies.
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Data availability
The authors declare that the data supporting the findings are available within the paper and its Supplementary Information. Source Data for Figs. 1–4 are provided with the paper. All other data are available from the corresponding authors upon request.
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Acknowledgements
This study received funding from the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (ANR-10-LABX-62-IBEID), the ‘Investissements d’Avenir’ program (ANR-10-IHUB-0002, ANR-15-CE15-00029 ZIKAHOST and the INCEPTION program ANR-16-CONV-0005), Institut Pasteur, Inserm and European Research Council. Viruses were provided by the Europe and Virus Archive, which has received funding from the EU Horizon 2020 research and innovation program under grant agreement 653316. The authors thank the EA7310, Laboratoire de Virologie, Université de Corse-Inserm for funding the doctoral position of L.P. We thank F. Rey, O. Schwartz, N. Manel, H. de Thé, Y. Gaudin, J. Hellert, M.-L. Chaix, S. Marot, S. Chawki, A. Canat, A. Zamborlini, A. Saïb, F. Sigaux, S. Emiliani and F. Bachelerie for reading the manuscript and discussions; P. Thouvenot and D. Hardy for technical assistance; J. Chen and J. Bogomolovas for providing Fhl1−/− mice; M. Diamond and J. Fox, A. Merit and F. Tangy for providing the CHIKV 265 monoclonal antibody, the nsP3 antibodies and the alphavirus nsP1-4 constructs, respectively; and MGX-Montpellier facility for sequencing.
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Contributions
L.M. and A.A. conceived the study. L.M., M.L.H., T.C., V.K., A.B., L.B.-M., C. Delaugerre, M.L. and A.A. designed the experiments. L.M. performed the CRISPR–Cas9 screening and infection studies with L.B.-M. M.L.H. characterized the FHL1 and nsP3 interactions and performed the immunoprecipitation and western blot studies with help of V.K. A.L. validated the gRNA targeting human and mouse FHL1 and generated the FHL1-knockout cells described in this study and performed infection studies. A.B. performed the immunofluorescence microscopy experiments and some infection studies. L.M. and E.S.-L. analysed the gRNA sequencing studies and identified the hits. J.B.-G. and P.R. performed the electron microscopy experiments. C. Doyen and M.B. performed the GST pull-down experiments. B.M.K. generated the CHIKV molecular clones described in this study and P.-O.V. provided key CHIKV reagents. L.P. and X.d.L. provided the alphavirus strains and performed infection studies. T.C. and M.L. conceived and performed the in vivo studies and provided expertise in the design of CHIKV experiments. S.R. performed virus titration assays and mice genotyping. T.G. performed immunofluorescence experiments in mouse tissues with T.C. A.B.-L., R.B.Y., L.G., R.J.-M. and G.B. provided myoblasts and fibroblasts from patients with EDMD and the description of a new FHL1 mutation in EDMD disease. L.M. and A.A. wrote the initial manuscript draft, M.L. edited the draft and the other authors contributed to editing it in its final form.
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Extended data figures and tables
Extended Data Fig. 1 CRISPR–Cas9 genetic screen identifies essential host factors of CHIKV infection.
a, Schematic of CRISPR–Cas9 genome-wide screen in HAP1 haploid cells. b, Ranked list of the top 30 genes identified using the MAGeCK algorithm and their corresponding rank in RIGER analysis. c, Venn diagram comparing the top 200 hits from our screen and previously published CRISPR and haploid screens8,9 for CHIKV host factors.
Extended Data Fig. 2 Validation of FHL1 gene edition by CRISPR–Cas9.
a–c, Schematic of the genomic organization of FHL1 (a), alternative splicing of the isoforms FHL1A, FHL1B and FHL1C (b) and their corresponding proteins (c). Initiation and stop codons are indicated in red and relative positions of the sequence targeted by the sgRNA are indicated in blue. d, Sanger sequencing of FHL1 in control and ∆FHL1 HAP1 cells. e, Genomic DNA was used for PCR amplification using primers flanking the sequence targeted by FHL1 sgRNA2. The absence of an amplification product of 3.9 kb (black arrow) in the HAP1 clone suggests that a large indel is responsible for the absence of FHL1 expression. Asterisks indicate unspecific PCR products. Data are representative of two experiments. f, Immunoblot of FHL1 in control and ∆FHL1 cells. One representative experiment of three experiments is shown. g, Control and ∆FHL1 cells were plated and viability was assessed over a 72-h period using the CellTiter-Glo assay. Data shown are mean ± s.e.m. n = 2 independent experiments were performed in quadruplicate. Two-way ANOVA with Dunnett’s multiple comparison test; P values are indicated.
Extended Data Fig. 3 FHL1 is an essential host factor for CHIKV and ONNV infection.
a, Immunofluorescence images of control and ∆FHL1 HAP1 cells inoculated with CHIKV21 (MOI of 10), fixed 48 h after infection and stained for E2 expression. NI, not infected. b, Immunofluorescence images of control and ∆FHL1 HAP1 cells inoculated with CHIKV expressing nsP3–mCherry (MOI of 10) and fixed 48 h after infection. a, b, Images were taken on a fluorescence microscope and are representative of three experiments. c, Control and ∆FHL1 HAP1 cells were inoculated with increasing MOIs of CHIKV21, and infection was quantified 48 h after infection by flow cytometry using the anti-E2 3E4 monoclonal antibody. Data are mean ± s.d. n = 3 independent experiments performed in duplicate. Two-way ANOVA with Tukey’s multiple comparison test. d, Multi-step growth curves with the CHIKV21 strain in control or ∆FHL1 cells. Data are mean ± s.e.m. n = 2 independent experiments performed in duplicate. Two-tailed multiple t-tests with Holm–Sidak correction. e, Control and ∆FHL1 HAP1 cells were inoculated with increasing MOIs of ONNV or MAYV, and infection was quantified 48 h later by flow cytometry using anti-E2 3E4 and 265 monoclonal antibodies. Data are mean ± s.e.m. n = 2 independent experiments performed in duplicate. Two-way ANOVA with Tukey’s multiple comparison test. f, Control and ∆FHL1 HAP1 cells were inoculated with increasing MOIs of DENV or ZIKV, and infection was quantified 48 h later by flow cytometry using the anti-E 4G2 monoclonal antibody. Data are mean ± s.e.m. n = 3 independent experiments performed in duplicate. Two-way ANOVA with Tukey’s multiple comparison test. ****P < 0.0001.
Extended Data Fig. 4 FHL1A and FHL2 expression in ∆FHL1 cells restores CHIKV infection.
a, Immunoblot (IB) of ectopic FHL1 expression in HAP1 cells stably transduced with an empty vector or FHL1A, FHL1B or FHL1C isoform. Data are representative of three experiments. b, Quantification in the supernatant of infected HAP1 cells of viral particles released by measuring the viral titre on Vero E6 cells. Data are representative of three experiments performed in duplicate. Data are mean ± s.e.m. c, ∆FHL1 HEK293T cells transfected with an empty vector or HA-tagged plasmids encoding FHL1A and FHL2 were infected with increasing MOIs of CHIKV21. Infection was quantified 24 h after infection by flow cytometry. Data are mean ± s.d. n = 3 experiments performed in duplicate. Two-way ANOVA with Dunnett’s multiple comparison test. ****P < 0.0001.
Extended Data Fig. 5 FHL1A overexpression in BeWo and HepG2 cells enhances CHIKV infection.
a, Expression of endogenous FHL1 in HAP1, HEK293T, BeWo and HepG2 cells. b, Immunoblot of ectopic FHL1 expression in Bewo and HepG2 cells stably transduced with an empty vector or HA-tagged FHL1A. a, b, Data are representative of three experiments. c, d, Bewo cells stably transduced with an empty vector or HA-tagged FHL1A were inoculated with increasing MOIs of CHIKV21. c, Infection was quantified 48 h after infection by flow cytometry using the anti-E2 3E4 monoclonal antibody. Data are mean ± s.e.m. n = 3 independent experiments performed in duplicate. Two-way ANOVA with Tukey’s multiple comparison test. d, Quantification of the viral particles released into the supernatants of infected cells, measured as the viral titre on Vero E6 cells. Data are mean ± s.d. n = 2 independent experiments performed in duplicate. Two-tailed Student’s t-test. e, HepG2 cells stably transduced with an empty vector or FHL1A were inoculated with increasing MOIs of CHIKV-M-Gluc. Infection was quantified 48 h later as indicated in c. Data shown are mean ± s.e.m. n = 2 independent experiments performed in duplicate. Two-way ANOVA with Tukey’s multiple comparison test. ****P < 0.0001.
Extended Data Fig. 6 CHIKV nsP3 interacts with FHL1A and FHL2.
a, Control or ∆FHL1 HAP1 cells were transfected with CHIKV-M-Gluc capped genomic RNA expressing Gaussia luciferase (Gluc). Gluc activity was monitored at the indicated time points. RLU, relative light units. Data are mean ± s.e.m. n = 3 independent experiments performed in quadruplicate. Two-tailed multiple t-tests with Holm-Sidak correction. b, Confocal microscopy of the colocalization of CHIKV nsP3 with FHL1 in fibroblasts inoculated with CHIKV nsP3–mCherry (MOI of 2), fixed 48 h after infection and stained with anti-FHL1 antibody. Images are representative of three experiments. c, Immunoassay of the interaction between CHIKV nsP3 and FHL1 isoforms in HEK293T cells transfected with Flag-tagged CHIKV nsP3 and either an empty vector or plasmids encoding the three HA-tagged FHL1 isoforms. Proteins from cell lysates were immunoprecipitated with anti-Flag antibody followed by immunoblot analysis with anti-Flag and anti-HA antibodies. d, Immunoassay of the interaction between CHIKV nsP3 and FHL2 in HEK293T cells transfected with Flag-tagged CHIKV nsP3 and either an empty vector or plasmids encoding HA-tagged FHL1 and FHL2. Proteins from cell lysates were immunoprecipitated with anti-Flag followed by immunoblot analysis with anti-Flag and anti-HA. e, Endogenous FHL1, G3BP1 or G3BP2 immunoprecipitation from control and ∆FHL1 HEK293T cells transfected with plasmids encoding Flag-tagged CHIKV, Sindbis (SINV) or Semliki forest virus (SFV) nsP3. Proteins from cell lysates were immunoprecipitated with anti-Flag antibody followed by immunoblot analysis with anti-Flag, anti-FHL1, anti-G3BP1 and anti-G3BP2 antibodies. f, Endogenous FHL1 immunoprecipitation from HEK293T cells transfected with plasmids encoding Flag-tagged full length CHIKV nsP3, CHIKV nsP3 carrying the SINV HVD (CHIKV/HVD-SINV) or Sindbis nsP3 carrying CHIKV HVD (SINV/HVD-CHIKV). Proteins from cell lysates were immunoprecipitated with anti-Flag antibody followed by immunoblot analysis with anti-Flag and anti-FHL1 antibodies. g, Purified GST-tagged nsP3 constructs and HA-tagged FHL1A detected by Coomassie blue staining. c–i, One representative experiment of three experiments is shown.
Extended Data Fig. 7 Mapping the FHL1–nsP3 interaction.
a, The sequence alignment of nsP3 protein HVD domains of representative members of New and Old World alphaviruses. Sequence alignment was performed with Clustal Omega and edited with Jalview. R1, R2 and R3 sequences of high homology between CHIKV strains and ONNV are defined by coloured lines. CHIKV(06–21) (GenBank accession number AM258992.1); CHIKV Ross (GenBank accession number MG280943.1); CHIKV H20235 (GenBank accession number MG208125.1); CHIKV 37997 (GenBank accession number AY726732.1); ONNV (GenBank accession number MF409176.1); SFV (GenBank accession number HQ848388.1); MAYV (GenBank accession number KY618137.1); SINV (GenBank accession number MF409178.1); EEEV (GenBank accession number Q4QXJ8.2); VEEV (GenBank accession number P27282.2). b, Left, schematic representation of CHIKV nsP3 constructs in which the R1, R2, R3 or R4 sequence was deleted. Right, HEK293T cells were transfected with FHL1A–HA and either an empty vector or plasmids encoding Flag-tagged nsP3 constructs. Cell lysates were immunoprecipitated with anti-Flag antibody followed by immunoblot analysis with anti-HA or anti-Flag antibodies. One experiment representative of three experiments is shown. c, Alignment of nsP3 regions containing the wild-type R4 sequence or the corresponding randomized sequence. Dashes represent identical amino acids. d, Control HEK293T cells were transfected with the indicated CHIKV capped in vitro transcribed RNA-expressing Renilla luciferase (Rluc). Rluc activity was monitored at indicated time points. RLU, relative light units. Data are mean ± s.e.m. n = 2 independent experiments performed in quadruplicate. Two-way ANOVA with Tukey’s multiple comparison test.
Extended Data Fig. 8 CHIKV infection of myoblasts and fibroblasts derived from patients with EDMD.
a, Schematic of FHL1A proteins from three patients with EDMD (P1, P2 and P3). b, Schematic of FHL1 genomic organization in the patient with a LINE1 insertion within exon 4 (P4). c, Myoblasts and fibroblasts from patients with EDMD or healthy donors were infected with increasing MOIs of CHIKV21, and infection was quantified 24 h later by flow cytometry using the anti-E2 3E4 monoclonal antibody. Data are mean ± s.e.m. n = 2 experiments performed in duplicate for myoblasts; n = 3 independent experiments performed in duplicate for fibroblasts. Two-way ANOVA with Dunnett’s multiple comparison test. d, Fibroblasts from patients with EDMD or healthy donors were inoculated with increasing MOIs of CHIKV Ross, CHIKV Brazza, CHIKV H20235, and infection was quantified 24 h later by flow cytometry using the anti-E2 3E4 monoclonal antibody. Data are mean ± s.e.m. n = 3 independent experiments performed in duplicate. Two-way ANOVA with Dunnett’s multiple comparison test. e, Immunoblot of ectopic FHL1 expression in primary fibroblasts (PF2 and PF4) obtained from patients that were stably transduced with an empty vector or a plasmid encoding HA–FHL1A. One representative of two experiments performed in duplicate is shown. Data are mean ± s.d. ****P < 0.0001.
Extended Data Fig. 9 Mouse FHL1 interacts with CHIKV nsP3 and restores infection in ∆FHL1 cells.
a, Sequence alignment of mouse and human FHL1A proteins. b, HEK293T cells were co-transfected with Flag-tagged CHIKV nsP3 and plasmids encoding HA-tagged mouse FHL1 (mFHL1) or human FHL1A (hFHL1A). Proteins from cell lysates were immunoprecipitated with anti-HA antibody followed by immunoblot analysis with anti-Flag (nsP3) and anti-HA (FHL1) antibodies. c, Immunoblot of FHL1 ectopic expression in ∆FHL1 HEK293T cells stably transduced with a plasmid encoding mouse FHL1 or human FHL1A. b, c, Data are representative of three experiments. d, Cells showed in c were inoculated with increasing MOIs of CHIKV21. Infection was quantified by flow cytometry at 24 h after infection using anti-E2 3E4 monoclonal antibody. Data are mean ± s.d. n = 3 independent experiments performed in duplicate. Two-way ANOVA with Dunnett’s multiple comparison test. e, Left, immunoblot of endogenous FHL1 in control and ∆FHL1 C2C12 mouse cells. Right, control and ∆FHL1 cells were inoculated with CHIKV21 or MAYV (MOI of 2) and infection was quantified at 24 h after infection by flow cytometry using anti-E2 3E4 or anti-E2 265 monoclonal antibodies. One representative experiment of three experiments is shown. ****P < 0.0001.
Supplementary information
Supplementary Figure
Supplementary Figure 1: Uncropped gels with size marker indications.
Supplementary Figure
Supplementary Figure 2: Figure exemplifying the gating strategy.
Supplementary Table
Supplementary Table 1: List of genes and scores after MAGeCK analysis. FDR was determined using the Benjamini-Hochberg procedure.
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Meertens, L., Hafirassou, M.L., Couderc, T. et al. FHL1 is a major host factor for chikungunya virus infection. Nature 574, 259–263 (2019). https://doi.org/10.1038/s41586-019-1578-4
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DOI: https://doi.org/10.1038/s41586-019-1578-4
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