FHL1 promotes chikungunya and o&#39;nyong-nyong virus infection and pathogenesis with implications for alphavirus vaccine design

Ng, WH; Liu, X; Ling, ZL; Santos, CNO; Magalh&#227;es, LS; Kueh, AJ; Herold, MJ; Taylor, A; Freitas, JR; Koit, S; Wang, S; Lloyd, AR; Teixeira, MM; Merits, A; Almeida, RP; King, NJC; Mahalingam, S

FHL1 promotes chikungunya and o'nyong-nyong virus infection and pathogenesis with implications for alphavirus vaccine design

Author(s): Ng, WH; Liu, X; Ling, ZL; Santos, CNO; Magalhães, LS; Kueh, AJ; Herold, MJ; Taylor, A; Freitas, JR; Koit, S; Wang, S; Lloyd, AR; Teixeira, MM; Merits, A; Almeida, RP; King, NJC; Mahalingam, S;
Details: Publication Year 2023-10-26,Volume 14,Issue #1,Page 6605
Journal Title: Nature Communications
Abstract: Arthritogenic alphaviruses are positive-strand RNA viruses that cause debilitating musculoskeletal diseases affecting millions worldwide. A recent discovery identified the four-and-a-half-LIM domain protein 1 splice variant A (FHL1A) as a crucial host factor interacting with the hypervariable domain (HVD) of chikungunya virus (CHIKV) nonstructural protein 3 (nsP3). Here, we show that acute and chronic chikungunya disease in humans correlates with elevated levels of FHL1. We generated FHL1(-/-) mice, which when infected with CHIKV or o'nyong-nyong virus (ONNV) displayed reduced arthritis and myositis, fewer immune infiltrates, and reduced proinflammatory cytokine/chemokine outputs, compared to infected wild-type (WT) mice. Interestingly, disease signs were comparable in FHL1(-/-) and WT mice infected with arthritogenic alphaviruses Ross River virus (RRV) or Mayaro virus (MAYV). This aligns with pull-down assay data, which showed the ability of CHIKV and ONNV nsP3 to interact with FHL1, while RRV and MAYV nsP3s did not. We engineered a CHIKV mutant unable to bind FHL1 (CHIKV-ΔFHL1), which was avirulent in vivo. Following inoculation with CHIKV-ΔFHL1, mice were protected from disease upon challenge with CHIKV and ONNV, and viraemia was significantly reduced in RRV- and MAYV-challenged mice. Targeting FHL1-binding as an approach to vaccine design could lead to breakthroughs in mitigating alphaviral disease.
Publisher: NPG
Keywords: Humans; Animals; Mice; *Chikungunya Fever/prevention & control; *Chikungunya virus; O'nyong-nyong Virus; *Arthritis/genetics; *Vaccines; Muscle Proteins/genetics; Intracellular Signaling Peptides and Proteins; LIM Domain Proteins/genetics
Research Division(s): Blood Cells And Blood Cancer
PubMed ID: 37884534
Publisher's Version: https://doi.org/10.1038/s41467-023-42330-2
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-023-42330-2
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: s41467-023-42330-2.pdf - (1.81MB, application/pdf)

Creation Date: 2023-11-20 12:03:35

Last Modified: 2023-11-20 12:05:09