Induction and Subversion of Human Protective Immunity: Contrasting Influenza and Respiratory Syncytial Virus

Abstract

Respiratory syncytial virus (RSV) and influenza are among the most important causes of severe respiratory disease worldwide. Despite the clinical need, barriers to developing reliably effective vaccines against these viruses have remained firmly in place for decades. Overcoming these hurdles requires better understanding of human immunity and the strategies by which these pathogens evade it. Although superficially similar, the virology and host response to RSV and influenza are strikingly distinct. Influenza induces robust strain-specific immunity following natural infection, although protection by current vaccines is short-lived. In contrast, even strain-specific protection is incomplete after RSV and there are currently no licensed RSV vaccines. Although animal models have been critical for developing a fundamental understanding of antiviral immunity, extrapolating to human disease has been problematic. It is only with recent translational advances (such as controlled human infection models and high-dimensional technologies) that the mechanisms responsible for differences in protection against RSV compared to influenza have begun to be elucidated in the human context. Influenza infection elicits high-affinity IgA in the respiratory tract and virus-specific IgG, which correlates with protection. Long-lived influenza-specific T cells have also been shown to ameliorate disease. This robust immunity promotes rapid emergence of antigenic variants leading to immune escape. RSV differs markedly, as reinfection with similar strains occurs despite natural infection inducing high levels of antibody against conserved antigens. The immunomodulatory mechanisms of RSV are thus highly effective in inhibiting long-term protection, with disturbance of type I interferon signaling, antigen presentation and chemokine-induced inflammation possibly all contributing. These lead to widespread effects on adaptive immunity with impaired B cell memory and reduced T cell generation and functionality. Here, we discuss the differences in clinical outcome and immune response following influenza and RSV. Specifically, we focus on differences in their recognition by innate immunity; the strategies used by each virus to evade these early immune responses; and effects across the innate-adaptive interface that may prevent long-lived memory generation. Thus, by comparing these globally important pathogens, we highlight mechanisms by which optimal antiviral immunity may be better induced and discuss the potential for these insights to inform novel vaccines.

Keywords: B cell; CD4+ T cell; RIG-I like receptor; influenza; innate immunity; respiratory disease; respiratory syncytial virus; toll-like receptor.

Figure 1

Schematic representation of comparative age distribution of respiratory syncytial virus (RSV), 2009 pandemic influenza and seasonal influenza mortality. RSV is a leading viral cause of infant death (8), with maternal antibodies offering temporally constrained protection to neonates against seasonal flu and RSV. This is limited in the case of novel pandemic influenza strains not previously encountered by the maternal immune system. Young adults are disproportionately affected by pandemic influenza strains, relative to seasonal influenza and RSV. Pandemic and seasonal influenza, as well as RSV all cause dramatic mortality in elderly individuals, reflecting the age-related decline of immune function in this population (8, 19).

Figure 2

Comparative immunity in respiratory syncytial virus (RSV) and influenza. Within the mucosal surfaces of the lung the host immune response to each virus feature intersecting and non-overlapping traits. (A) Influenza and RSV establish infection in the lung epithelial cells, initiating the release of type 1 interferons (IFNs) which act in a feedback loop along with release of proinflammatory cytokines such as interleukin (IL)-1β and IL-18, and upregulation of IFN-stimulated genes (ISGs) to promote an inflammatory environment. This inflammatory milieu, which in influenza recruits conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs) as the primary type 1 IFN producing antigen-presenting cells (APCs), promotes optimal signaling and memory generation. This includes polyfunctional CD8⁺ and Th1 T cells, and immunocompetent IgG⁺ and IgA⁺ ASCs and memory B cells (MBCs). Following viral clearance T cells remain in the lung as T resident memory (Trm) and MBCs and T cells traffic into the systemic compartment. RSV infection of the lung follows a broadly similar pattern, although the primary type 1 IFN producing APCs are alveolar macrophage (AM) and cDCs. The lower levels of type 1 IFN produced during infection impact the generation of memory responses with poorly functional T cells, skewing toward Th2/Th17 generation in early life and a profound defect in the induction of an IgA⁺ MBC subset. As the influenza virus establishes infection within a lung epithelial cell (B) it enters the endosome and following viral uncoating it triggers TLR3 signaling with double-stranded RNA (dsRNA) and TLR 7/8/9 with single-stranded RNA (ssRNA), in addition retinoic acid inducible gene-I (RIG-I) and the inflammasome are stimulated by contact with dsRNA and ssRNA, respectively. These signaling pathways individually stimulate nuclear factor-κB (NF-κB), IRFs and upregulate ISGs and the production of type 1 IFNs. These mediators are released by the cell and recognized by IFNα receptor (IFNAR), leading to positive feedback, which also stimulates the sequestration of virus by IFN-induced transmembrane protein (IFITM), preventing viral spread. Influenza acts to mitigate the actions of the pattern recognition receptors (PRRs), especially RIG-I and the inflammasome through NS1-mediated inhibition, while hemagglutinin (HA) has recently been found to trigger ubiquitination of IFNα receptor (IFNAR), downregulating IFNAR1 expression. In the case of RSV infection within a lung epithelial cell (C) the action of the intracellular PRRs is augmented by the engagement of the extracellular TLRs 4/2/6. RSV strategically targets signaling pathways at multiple points, most notably the action of G protein upon TLR7/8/9 and TLRs 4/2/6, and NS1 upon a number of pathways, particularly STAT signaling.

Figure 2

Comparative immunity in respiratory syncytial virus (RSV) and influenza. Within the mucosal surfaces of the lung the host immune response to each virus feature intersecting and non-overlapping traits. (A) Influenza and RSV establish infection in the lung epithelial cells, initiating the release of type 1 interferons (IFNs) which act in a feedback loop along with release of proinflammatory cytokines such as interleukin (IL)-1β and IL-18, and upregulation of IFN-stimulated genes (ISGs) to promote an inflammatory environment. This inflammatory milieu, which in influenza recruits conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs) as the primary type 1 IFN producing antigen-presenting cells (APCs), promotes optimal signaling and memory generation. This includes polyfunctional CD8⁺ and Th1 T cells, and immunocompetent IgG⁺ and IgA⁺ ASCs and memory B cells (MBCs). Following viral clearance T cells remain in the lung as T resident memory (Trm) and MBCs and T cells traffic into the systemic compartment. RSV infection of the lung follows a broadly similar pattern, although the primary type 1 IFN producing APCs are alveolar macrophage (AM) and cDCs. The lower levels of type 1 IFN produced during infection impact the generation of memory responses with poorly functional T cells, skewing toward Th2/Th17 generation in early life and a profound defect in the induction of an IgA⁺ MBC subset. As the influenza virus establishes infection within a lung epithelial cell (B) it enters the endosome and following viral uncoating it triggers TLR3 signaling with double-stranded RNA (dsRNA) and TLR 7/8/9 with single-stranded RNA (ssRNA), in addition retinoic acid inducible gene-I (RIG-I) and the inflammasome are stimulated by contact with dsRNA and ssRNA, respectively. These signaling pathways individually stimulate nuclear factor-κB (NF-κB), IRFs and upregulate ISGs and the production of type 1 IFNs. These mediators are released by the cell and recognized by IFNα receptor (IFNAR), leading to positive feedback, which also stimulates the sequestration of virus by IFN-induced transmembrane protein (IFITM), preventing viral spread. Influenza acts to mitigate the actions of the pattern recognition receptors (PRRs), especially RIG-I and the inflammasome through NS1-mediated inhibition, while hemagglutinin (HA) has recently been found to trigger ubiquitination of IFNα receptor (IFNAR), downregulating IFNAR1 expression. In the case of RSV infection within a lung epithelial cell (C) the action of the intracellular PRRs is augmented by the engagement of the extracellular TLRs 4/2/6. RSV strategically targets signaling pathways at multiple points, most notably the action of G protein upon TLR7/8/9 and TLRs 4/2/6, and NS1 upon a number of pathways, particularly STAT signaling.