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THE CHEMOKINE CCL5 INHIBITS THE REPLICATION OF INFLUENZA A VIRUS THROUGH SAMHD1 MODULATION
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Abstract
Influenza A virus (IAV) is the main etiological agent of acute respiratory tract infections.
During IAV infection, interferon triggers the overexpression of restriction factors (RFs), the
intracellular antiviral branch of the innate immune system. Conversely, severe influenza is
associated with an unbalanced pro-inflammatory cytokine release. It is unclear whether
other cytokines and chemokines released during IAV infection modulate RFs to control
virus replication. Among the molecules enhanced in the infected respiratory tract, ligands
of the CCR5 receptor play a key role, as they stimulate the migration of inflammatory cells
to the alveoli. We investigated here whether ligands of the CCR5 receptor could enhance
RFs to levels able to inhibit IAV replication. For this purpose, the human alveolar basal
epithelial cell line (A549) was treated with endogenous (CCL3, CCL4 and CCL5) or
exogenous (HIV-1 gp120) ligands prior to IAV infection. The three CC-chemokines tested
reduced infectious titers between 30% to 45% upon 24 hours of infection. Eploying RT PCR, a panel of RF mRNA levels from cells treated with CCR5 agonists was evaluated,
which showed that the SAMHD1 expression was up-regulated four times over control
upon exposure to CCL3, CCL4 and CCL5. We also found that IAV inhibition by CCL5 was
dependent on PKC and that SAMHD1 protein levels were also increased after treatment
with CCL5. In functional assays, we observed that the knockdown of SAMHD1 resulted in
enhanced IAV replication in A549 cells and abolished both CCL5-mediated inhibition of
IAV replication and CCL5-mediated cell death inhibition. Our data show that stimuli
unrelated to interferon may trigger the upregulation of SAMHD1 and that this RF may
directly interfere with IAV replication in alveolar epithelial cells.
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