Respiratory Syncytial Virus Fusion Protein Mediates Inhibition of Mitogen-Induced T-Cell Proliferation by Contact

Abstract

Human respiratory syncytial virus (HRSV) and bovine respiratory syncytial virus (BRSV) are major pathogens in infants and calves, respectively. Experimental BRSV infection of calves and lambs is associated with lymphopenia and a reduction in responsiveness of peripheral blood lymphocytes (PBLs) to mitogens ex vivo. In this report, we show that in vitro mitogen-induced proliferation of PBLs is inhibited after contact with RSV-infected and UV-inactivated cells or with cells expressing RSV envelope proteins on the cell surface. The protein responsible was identified as the RSV fusion protein (F), as cells infected with a recombinant RSV expressing F as the single envelope protein or cells transfected with a plasmid encoding F were able to induce this effect. Thus, direct contact with RSV F is necessary and sufficient to inhibit proliferation of PBLs. Interestingly, F derived from HRSV was more efficient in inhibiting human PBL proliferation, while F from BRSV was more efficient in inhibiting bovine PBLs. Since various T-cell activation markers were upregulated after presenter cell contact, T lymphocytes are viable and may still be activated by mitogen. However, a significant fraction of PBLs were delayed or defective in G 0 /G 1 to S-phase transit.

Bovine respiratory syncytial virus infection

“…BRSV-infected cells are able to inhibit mitogen-induced lymphocyte proliferation, in vitro, and this effect was found to be mediated by direct contact of the lymphocytes with the F protein [116]. The precise mechanisms responsible for this inhibition are not known, however, contact with the F protein resulted in a defect or delay in the transit of lymphocytes from G 0 /G 1 to S-phase.…”

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

“…116 HRSV Fusion (F) protein: this viral protein is required for the fusion of viral particle with the host cells 4 and also play a direct role in the ability of hRSV to decrease the proliferation of these cells by contact. 117 In fact, when Vero cells express the F protein or are infected with a version of hRSV that only have F protein on its surface, they reduce the proliferation and response to mitogen stimulus. 117 HRSV small hydrophobic (SH) protein: it is thought that this protein works as an important viroporin during hRSV pathogenesis.…”

“…117 In fact, when Vero cells express the F protein or are infected with a version of hRSV that only have F protein on its surface, they reduce the proliferation and response to mitogen stimulus. 117 HRSV small hydrophobic (SH) protein: it is thought that this protein works as an important viroporin during hRSV pathogenesis. 118 This protein also inhibits apoptosis in order to promote viral replication, as recombinant hRSV lacking the SH protein induced a significant cytopathic effect in different cell lines, compare with WT hRSV.…”

Serum Antibodies Critically Affect Virus-Specific CD4+/CD8+ T Cell Balance during Respiratory Syncytial Virus Infections

“…A total of 1 3 10 6 CFSE-labeled PBMCs were stimulated with live RSV (moi 2) or with 1 mg/ml nonstructural protein (NS) [41][42][43][44][45][46][47][48][49] in AIM V (Invitrogen) with 2% IgG-depleted heat-inactivated AS in the presence of 20 U/ml human (h)IL-2 (11147528001, Roche, Basel, Switzerland). After 24 h, cells stimulated with NS [41][42][43][44][45][46][47][48][49] were restimulated with 1 mg/ml peptide/hIL-2. After 7 d, the expanded CD8 + T cells were restimulated with 1 mg/ml peptide or not restimulated in the presence of 1 mg/ml anti-CD28 (340975, BD Biosciences,), 1 mg/ml antiCD49d (BD Biosciences, 340976), 20 U/ml hIL-2 (11147528001, Roche), and 10 mg/ml brefeldin A (B7651, Sigma-Aldrich).…”