Host Components Contributing to Respiratory Syncytial Virus Pathogenesis

Abstract

Respiratory syncytial virus (RSV) is the most prevalent viral etiological agent of acute respiratory tract infection. Although RSV affects people of all ages, the disease is more severe in infants and causes significant morbidity and hospitalization in young children and in the elderly. Host factors, including an immature immune system in infants, low lymphocyte levels in patients under 5 years old, and low levels of RSV-specific neutralizing antibodies in the blood of adults over 65 years of age, can explain the high susceptibility to RSV infection in these populations. Other host factors that correlate with severe RSV disease include high concentrations of proinflammatory cytokines such as interleukins (IL)-6, IL-8, tumor necrosis factor (TNF)-α, and thymic stromal lymphopoitein (TSLP), which are produced in the respiratory tract of RSV-infected individuals, accompanied by a strong neutrophil response. In addition, data from studies of RSV infections in humans and in animal models revealed that this virus suppresses adaptive immune responses that could eliminate it from the respiratory tract. Here, we examine host factors that contribute to RSV pathogenesis based on an exhaustive review of in vitro infection in humans and in animal models to provide insights into the design of vaccines and therapeutic tools that could prevent diseases caused by RSV.

Keywords: RSV; disease; host factors; innate and adaptive immune response; pathogenesis.

Figure 1

Model of RSV pathogenesis in the human respiratory tract. Once RSV enters the upper respiratory tract, the virus primarily infects ciliated cells in the large airways. The viral NS2 protein induces cell rounding, extrusion, and detachment from the apical zone of the airway epithelium through, generating an accumulation of these cells in the lumen of the airway ducts. RSV also induces proliferation of goblet cells, via infection of basal cells, which differentiate, causing high mucus production and recruitment of eosinophils and massive numbers of neutrophils in the airway ducts. The latter immune cells release NETs in response to RSV infection. All of these components accumulate and move to the distal airways, leading to bronchial obstruction of the narrow ducts, and collapse of alveoli, causing acute inflammation and pathology in the lungs.

Figure 2

Model of the innate immune response and Th2 response against RSV infection in the human respiratory tract. RSV infection of ciliated cells induces the release of TSLP and IL-33, which are recognized by TSLP and ST2 receptors on ILC2 cells, respectively. This recognition causes the release of IL-5 and IL-13, which induce increased mucus secretion by the goblet cells and recruit neutrophils and eosinophils in the lung, respectively. Neutrophils can generate a network of DNA called NETs, which can trap and eliminate different pathogens. On the other hand, TSLP induces OX40L expression on the surface of dendritic cells, which causes these cells to migrate to the lymph nodes where they interact with naïve CD4+ T cells by binding of OX40 on these cells. The resulting Th2 immune response causes inflammation in the lung.