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Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and

Madelaine Sugasti-Salazar1,2, Yessica Y Llamas-González1,3, Dalkiria Campos1

  • 1Grupo de Biología Celular y Molecular de Arbovirus, Instituto Conmemorativo Gorgas de Estudios de la Salud, Panamá 0816-02593, Panama.

Viruses
|July 2, 2021
PubMed

Insights

Mayaro virus (MAYV) replication is significantly impacted by p38, a key mitogen-activated protein kinase (MAPK). Inhibiting p38 reduces viral load and protein expression, suggesting p38 as a potential therapeutic target for MAYV infection.

Area of Science:

  • Virology
  • Cellular Biology
  • Molecular Medicine

Background:

  • Mayaro virus (MAYV) utilizes host cell machinery for replication.
  • Mitogen-activated protein kinases (MAPKs), including p38, JNK, and ERK1/2, are implicated in viral cycles.
  • The specific role of MAPKs in MAYV replication remains largely undetermined.

Purpose of the Study:

  • To investigate the impact of inhibiting specific MAPKs on MAYV replication.
  • To determine if MAYV utilizes p38, JNK, or ERK1/2 pathways for efficient replication.
  • To evaluate p38 as a potential therapeutic target against MAYV infection.

Main Methods:

  • MAYV replication was assessed in primary human dermal fibroblasts (HDFs) and HeLa cells.
  • Cells were treated with MAPK inhibitors (SB203580, SP600125, U0126, Losmapimod) or subjected to p38 isoform knockdown using PROTACs (NR-7h).
  • Viral yields were quantified by plaque assay, and viral protein expression was analyzed via immunoblot and immunofluorescence.

Main Results:

  • HDFs exhibited high susceptibility to MAYV infection.
  • The p38 inhibitor SB203580 dose-dependently reduced MAYV replication and E1 protein expression in both cell types.
  • Inhibition or knockdown of p38α/p38β isoforms (using Losmapimod or NR-7h) also dose-dependently impaired MAYV replication.

Conclusions:

  • The p38 pathway plays a significant role in Mayaro virus replication.
  • Targeting p38 MAPK activity presents a promising therapeutic strategy for controlling MAYV infections.
  • Further research into p38-MAYV interactions could lead to novel antiviral treatments.
Keywords:
LosmapimodMAPKsMayaroNR-7PROTACsSB203580inhibitionp38replication

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