RESPIRATORY SYNCYTIAL VIRUS

Nabili S, Giuliani L. Respiratory syncytial virus. International Journal of Infection. 2024;8(2):53-57

S. Nabili¹ and L. Giuliani^2*

¹ Department of Ophthalmology, University Hospitals Of Morecambe Bay NHS Foundation Trust, United Kingdom;
² European Cancer and Environmental Institute (ECERI), Bruxelles, Belgium.

*Correspondence to:
Livio Giuliani, PhD,
European Cancer and Environmental Institute (ECERI),
Bruxelles, Belgium.
e-mail: giuliani.livio@gmail.com

Received: 03 April, 2024 Accepted: 10 August, 2024

ISSN 1972-6945 [online] Copyright 2024 © by Biolife-publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

Respiratory syncytial virus (RSV) is a common and highly contagious virus that primarily affects the respiratory system, particularly in young children, older adults, and individuals with weakened immune systems. RSV causes lung and airway damage, resulting in the common respiratory disease. The virus enters the airways and creates epithelial inflammation with edema of the submucosa and adventitia. The infection involves the pulmonary alveoli and can cause epithelial necrosis and inflammation due to the accumulation of immune cells. RSV is known to induce alterations in the innate and adaptive immune system response. It activates the NF-κB pathway which leads to the transcription of pro-inflammatory cytokines. Infection triggers the innate immune response to the virus, involving pattern recognition receptors (PRRs) and Toll-like receptors (TLRs), particularly TLR3 and 4 that recognize RSV RNA. These receptors trigger signaling pathways that lead to the production of inflammatory cytokines, such as type I interferons (IFNs), IL-6, TNF, and IL-1β. Prophylaxis for RSV is performed either with monoclonal antibodies or with the recently developed vaccine.

KEYWORDS: Respiratory syncytial virus, respiratory disease, inflammation, immune response, virus, infection

INTRODUCTION

Respiratory syncytial virus (RSV) is a virus that primarily causes respiratory tract infections, especially in infants, young children, the elderly, and immunocompromised individuals (1). It is a major cause of hospitalization in infants. It usually causes mild cold-like symptoms but can also cause serious respiratory illnesses such as bronchiolitis and/or pneumonia (2). RSV is an RNA virus belonging to the Paramyxoviridae family that is divided into types A and B based on the antigenic differences of the membrane glycoproteins F and G, which are responsible for the adhesion and penetration of the microorganism into the membrane of the host cell (3).

Once it has penetrated the subject’s airways, the virus localizes at the level of the smaller branches. Edema of the submucosa and adventitia appears simultaneously with epithelial inflammation (4). This results in obstruction of the small airways, with the appearance of areas of atelectasis, hyperinflation, and often, small areas of consolidation. RSV is a contagious virus and a common cause of respiratory disease worldwide (5). The virus can affect the lungs and airways of an infected individual, potentially causing severe disease or death (6).

The infection can cause necrosis of the epithelium followed by a process of regeneration of cells that accumulate inside the small lumen with inflammatory cells (7). This situation causes a substantial alteration of the normal gas exchange at the pulmonary level with consequent hypoxemia, associated with hypercapnia in the most severe forms (8). Alveoli are generally normal, except those immediately adjacent to the bronchioles. Extensive involvement of the alveoli may occur, with increased cellularity and formation of alveolar sweat.

Specific anti-RSV antibodies play an important role in the pathogenesis of the disease (9). In this regard, it has been shown that the presence of specific IgE for RSV in nasopharyngeal secretions of individuals affected by bronchiolitis correlates with the severity of the disease and with possible development of respiratory sequelae.

Numerous studies demonstrate that there is an association between RSV bronchiolitis, recurrent wheezing, and asthma (10). Several analyses show that the highest frequency of asthma occurs when both a family history of atopy and RSV bronchiolitis are present as risk factors, although some cases have been described without a history of atopy (11). One of the most accredited hypotheses to describe this relationship considers the possibility that RSV can induce alterations in the response modalities of the innate immune system (12).

DISCUSSION

RSV infection activates both innate and adaptive immune responses (13). In the innate immune response to the virus, pattern recognition receptors (PRRs) are activated. Infection by RSV involves PRRs and Toll-like receptors (TLRs), particularly TLR3 and 4 that recognize RSV RNA (14). This recognition triggers signaling pathways that lead to the production of type I interferons (IFNs) and pro-inflammatory cytokines such as IL-6, TNF, and IL-1β (15).

Once RSV has penetrated the lung, the virus can directly or indirectly damage the bronchial epithelium by downregulating the p53 gene responsible for cellular apoptosis (16). The resulting viral replication stimulates the expression of genes that regulate the cascade of pro-inflammatory chemokines such as CCL5, CCL2, CCL3, CXCL8, CXCL6, and CXCL10, and cytokines IL-1, 6, 11, GM-CSF, and TNF (17). In this way, the virus predisposes both children and adults to the onset of chronic respiratory disease.

Macrophages, dendritic cells (DCs), natural killer (NK) cells, and neutrophils also play a key role (18). Macrophages are activated when the RSV F protein binds to their wall through TLR-3 and -4 (18). Once recruited into the lungs, they activate the transcription factor NF-kB with the consequent production of pro-inflammatory cytokines, such as TNF, and the chemokines CXCL6 and CXCL12 (19).

Plasmacytoid DCs, a subset of DCs found in the blood and peripheral lymphatic tissue, produce IFN-a and b which are pro-inflammatory cytokines that inhibit viral replication (20). By way of its NS1 and NS2 proteins, RSV is able to inhibit the production of IFN-a and b persisting within the bronchial tree in its active form (21).

NK cells contain a serine protease called granzyme B that triggers the classic pathway of programmed cell death. In subjects affected by RSV bronchiolitis, NK cells cause a reduced expression of this enzyme, which triggers constant viral replication (22).

During RSV infection, 75% of recruited cells are neutrophils (23). Their role in the pathogenesis of the disease is clear; these cells produce large amounts of cytokines and have a long survival rate due to delayed apoptosis and are also the main cells involved in long-term exacerbations. The surfactant proteins SP-A, -B, and -D produced by the alveoli and airway epithelial cells also play a pathogenetic role (24). They bind the F and G proteins of the virus and help prevent RSV infection by promoting its clearance. Affected subjects show low levels of SP-A, -B, and -D, which results in prolonged persistence of the virus in the airways and poor viral clearance.

DCs and macrophages are also important in engulfing and processing the virus. These innate immune reactions induce the production of cytokines and present viral antigens to activate adaptive immune cells. NK cells recognize virus-infected cells, causing cell lysis and secreting antiviral cytokines such as IFN-γ to limit viral replication (25). Humoral or adaptive immunity involves B cells and plasma cells which produce neutralizing antibodies to the RSV fusion protein (F) and glycoprotein (G). Antibody neutralization prevents the virus from entering host cells, although this immune effect tends to wear off and lead to reinfection of the host. CD8+ cytotoxic T lymphocytes (CTLs) kill infected cells; while CD4+ helper T cells support both CTLs and B cell functions (26). However, T cell dysfunction can lead to increased inflammation.

RSV causes infection and activates inflammatory mechanisms that help control the infection, but excessive inflammation can lead to tissue damage and exacerbation of respiratory symptoms (10.1007/s12016-013-8368-9). The excess production of inflammatory cytokines, including IL-1, IL-6, IL-8, and TNF, can cause a ‘cytokine storm’ characterized by the excessive release of immune mediators (27). TNF and IL-1β contribute to vascular permeability, which leads to fluid accumulation in the lungs and worsens inflammation. The IL-1 and TLR families share similar functions and are associated with innate immunity.

It has been reported that over 95% of organisms use the innate immune system for survival (28). IL-1 triggers inflammation through IL-1 receptors, while TLRs induce inflammation through microorganisms. IL-6 is involved in fever induction and acute phase responses, while IL-8 is an attractive chemokine that primarily recruits neutrophils to the site of inflammation. Reactive oxygen species (ROS) are produced by infected immune cells and are a defense mechanism due to their capability to kill RSV, but they also cause oxidative stress and tissue damage (29). ROS can damage the lung epithelium causing leaks and altered permeability, which are serious symptoms.

The RSV F protein is involved in the entry of the virus into the host cell. The role of the F protein is to fuse the virus to the target cell, and it is the main target for neutralizing antibodies. In addition to mediating the attachment of the virus to the cell, the G protein modulates immune responses (30). This protein acts similarly to chemokines and can bind to host immune receptors, such as CX3CR1, inhibiting immune responses and promoting immune evasion (31). This allows the virus to carry out its pathogenic action and cause persistent inflammation.

RSV encodes the NS1 and NS2 proteins, which antagonize the response to IFN. They block the signaling pathways that induce the production of antiviral IFN, weakening the host’s ability to control viral replication. RSV infection recruits large numbers of granulocytes to the lungs. These immune cells release proteolytic enzymes, ROS, and inflammatory mediators, which can cause tissue injury and worsen airway inflammation, a hallmark of severe RSV disease (32).

RSV activates the NF-κB pathway, which leads to the transcription of pro-inflammatory cytokines. NF-κB activation is a major contributor to lung inflammation and exacerbation of respiratory symptoms in RSV infections (33). The JAK-STAT pathway is involved in mediating IFN signaling. RSV uses its NS proteins to interfere with JAK-STAT signaling, reducing host antiviral defenses and contributing to immune dysregulation (34).

When RSV infection is severe, a pathological immune response occurs that is harmful to the body. If the severe immune reaction involves adaptive immunity with Th2 lymphocytes, there may be excess production of some cytokines such as IL-4, IL-5, and IL-13, with airway inflammation and mucus production. In addition, excessive infiltration of immune cells, such as granulocytes, can cause bronchial blockage and alter respiratory function (10.1128/JVI.73.10.8485-8495.1999).

Prophylaxis

Prophylaxis is necessary to avoid or prevent the spread of RSV. It is the passive protection of the lower respiratory tract (36). Currently, the main form of prophylaxis, which aims to prevent or reduce RSV infection, is with the use of monoclonal antibodies such as palivizumab (synagis) and nirsevimab (beyfortus) (37). The monoclonal antibody palivizumab is given to high-risk infants, such as premature infants, and those with chronic lung disease or congenital heart disease (38). Nirsevimab is a newer generation monoclonal antibody approved by the FDA in July 2023, that provides broader and longer-lasting protection than palivizumab and is aimed at preventing severe RSV disease in infants and children (37). Active immunization with a recombinant bivalent vaccine is now available in Europe and the United States to protect infants and the elderly, but also adults at risk.

CONCLUSIONS

RSV infection triggers an immune response that can lead to a pathological state mediated by inflammation. RSV infection causes a complex immune response involving both protective and pathological mechanisms. While innate and adaptive immune responses are critical for viral clearance, they can also drive inflammation, causing lung damage and worsening respiratory conditions. Understanding the biochemical mechanisms of immunity and inflammation at play in RSV infection can guide vaccine development and targeted therapies that won’t trigger excessive inflammation.

Conflict of interest

The authors declare that they have no conflict of interest.

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