Induction of protective effector immunity to prevent pathogenesis caused by the respiratory syncytial virus. Implications on therapy and vaccine design

Abstract

Human respiratory syncytial virus (hRSV) is the leading cause of respiratory illness in infants and young children around the globe. This pathogen, which was discovered in 1956, continues to cause a huge number of hospitalizations due to respiratory disease and it is considered a health and economic burden worldwide, especially in developing countries. The immune response elicited by hRSV infection leads to lung and systemic inflammation, which results in lung damage but is not efficient at preventing viral replication. Indeed, natural hRSV infection induces a poor immune memory that allows recurrent infections. Here, we review the most recent knowledge about the lifecycle of hRSV, the immune response elicited by this virus and the subsequent pathology induced in response to infection in the airways. Novel findings about the alterations that this virus causes in the central nervous system and potential therapies and vaccines designed to treat or prevent hRSV infection are discussed.

Keywords: T helper type 1/type 2 cells; hRSV; lung; vaccination; viral.

Figure 1

Human respriatory syncytial virus (hRSV) recognition by airways epithelial cells: upon infection, different hRSV components activate pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are crucial in the hRSV recognition and the triggering of innate immune response against this pathogen; TLR2 and TLR4, expressed in the cell surface, and TLR3 and TLR7, present in cytoplasmatic endosomes, are activated in response to hRSV and promote the secretion of pro-inflammatory cytokines, such as interleukin-8 (IL-8), IL-1β and IL-6 through the nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3) pathway. Also retinoic acid-inducible gene (RIG-1) and nucleotide-binding oligomerization domain (NOD2), which belong to RIG-I-like receptors (RLRs) and NOD-1-like receptors (NLRs), respectively, participate in the recognition of viral RNA associated with mitochondrial anti-viral signalling (MAVS) in the mitochondrial membrane in the cytoplasm leading to activation of NF-κB and IRF3.

Figure 2

Inflammatory environment after human respiratory syncytial virus (hRSV) infection. Human RSV infection has been associated with an inefficient immunity characterized by a T helper type 2 (Th2) and Th17 polarized response and a weak Th1 response. Human RSV enters lung epithelial cells and induces the secretion of cytokines and chemokines such as interleukin-6 (IL-6), IL-8, RANTES, CCL3, MIP-2, CXCL10 to promote the recruitment of neutrophils infiltrating the infection site. Also, resident dendritic cells (DCs) migrate to draining lymph nodes to activate T-cell responses against hRSV characterized by an exacerbated Th2 and Th17 response. Indeed, epithelial cells expressed MHC-II, the co-stimulatory molecules CD80 and CD86 that can activate naive T cells to Th2 and Th17 polarization after hRSV infection. The pro-inflammatory cytokines and effector cells in the environment cause damage in the epithelium, which causes the characteristic pathology of hRSV.