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.
Highlights
Severe acute respiratory tract infections (SARI) represent the fourth most common cause of death in the world (World Health Organization, 2020)
We reported that the Influenza A virus (IAV) replication cycle is impaired in macrophages exposed to HIV-1 or its glycoprotein gp120 via the IFN-induced transmembrane protein 3 (IFITM3), which acts as a cellular antiviral restriction factor (RF) (Mesquita et al, 2014)
We found that HIV-1 gp120 and b-chemokines, especially CCL5, enhanced SAM domain and HD domain-containing protein 1 (SAMHD1) levels, which were consistently associated with inhibition of IAV replication
Summary
Severe acute respiratory tract infections (SARI) represent the fourth most common cause of death in the world (World Health Organization, 2020). This public health problem leads to 4.5 million deaths per year and morbidity, leading to a substantial public health burden. The b-chemokines CCL3, CCL4 and CCL5 bind to the CCR5 receptor and participate in leukocyte activation, chemotaxis, cytokine secretion and cell proliferation (Velasco-Velázquez and Pestell, 2013; Flanagan, 2014). Once exacerbated, these signs may cause massive tissue damage, reducing the O2 exchange and causing respiratory distress
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