The Chemokine CCL5 Inhibits the Replication of Influenza A Virus Through SAMHD1 Modulation

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.

Genetic Associations and Differential mRNA Expression Levels of Host Genes Suggest a Viral Trigger for Endemic Pemphigus Foliaceus

“…The overexpression of CCL5 was also reported in several autoimmune thyroid disorders [ 111 ]. CCL5 is one of the major HIV-suppressive factors produced by CD8+ T cells [ 112 , 113 ], and high levels of CC-chemokines, including CCL5, suppress the replication of IAV-infected cells [ 114 ]. Moreover, during acute HCV infection, the increased expression of CCL5 is crucial for the induction of Th1 responses and the control of HCV infection and liver disease [ 115 ].…”

Bioinformatics analysis in identifying significantly expressed immune related genes in influenza A virus infection

“…This chemokine functions as a natural ligand for the chemokine receptor CCR5 [14]. Ligands of CCR5 receptor play a key role among the molecules enhanced in the infected respiratory tract as they triggers the migration of inflammatory cells to the alveoli [15]. This process is triggered by IAV-induced-cytokine storm; the protective antiviral effects promoted by the interferon (IFN) are overwhelmed by other cytokines, like TNF-α and IL-6.…”

The Dual Role of CCR5 in the Course of Influenza Infection: Exploring Treatment Opportunities

“…More recently, the direct role of CCL5:CCR5 in epithelial antiviral responses was uncovered. CCL5:CCR5 was shown to reduce influenza A replication in human epithelial cells by inducting the antiviral restriction factor SAM domain and HD domain-containing protein 1 (SAMHD1) ( 30 ). Keeping with that, the CCR5 agonist gp120 was shown to reduce A(H1N1)pdm09 replication in vitro in an IFITM3-dependent manner in human macrophages and human epithelial cervical cancer (HeLa) cells ( 45 ).…”

“…In this regard, CCR5 activation during different phases of influenza infection might also lead to different outcomes. Indeed, CCR5 activation during the initial stages of influenza infection ensure the proper recruitment of leukocytes and activation of antiviral pathways in the epithelial cells (Figure 1 left panel) (14,23,29,30). However, sustained or exaggerated CCR5 activation during severe/exacerbated influenza infection might fuel the inflammatory responses leading to increase pulmonary damage and dysfunction (Figure 1 CCR5 and its cognate chemokines are rapidly induced postinfluenza infection in both humand and mice and ensure the prompt recruitment of leukocytes to the airways for an effective response (31).…”