Rhinovirus

Rhinoviruses are non-enveloped (do not have a lipid layer as an envelope) viruses with a positive-stranded RNA genome, with a diameter between 24 nm and 30 nm. They belong to the genus Enterovirus of the family Picornaviridae (= small RNA viruses) and form the three species: Rhinovirus A-C (formerly: human rhinovirus A-C ) RHVA-C. More than 150 serotypes have now been described (HRVA - n=83, HRVB - n=33, HRVC - n=55). According to NCBI, HRV-87 is a subtype of Enterovirus D, and several other unclassified rhinoviruses are also listed.

Structure: Rhinoviruses, like all picornaviruses, possess four capsid proteins (VP1 to VP4) which, in addition to packaging the genome, also serve in part as receptors for attachment to a cell. The capsid of rhinoviruses has a layer thickness of about 5 nm. The single-stranded RNA genome encodes four structural proteins consisting of viral proteins (VP1-4) and seven non-structural proteins (consisting of two proteases (2A and 3C), one polymerase, one a polymerase, one putative ring helicase/ATPase , VPg and two other proteins that are either cleaved or involved as precursors in viral replication. The icosahedral virion consists of 60 monomers, and one monomer consists of the four structural proteins VP1 VP2, VP3 and VP4 (inside the viron). VP1-3 are recognized more by antibodies as surface proteins(see vaccination strategies).

Binding strategy: After binding of the cellular receptor, the N-terminus of VP1 is turned outward from the virion and VP4 is released, which together form a pore for cell membrane penetration through which viral RNA is delivered into the cytosol. Approximately 90% of strains of species A and B use ICAM-1 as the cellular receptor, and the remaining 10% use the LDL receptor. Species C strains use the CDHR3 receptor.

Rhinoviruses are relatively acid-sensitive compared to most other enteroviruses. They are not gastric juice resistant. In contrast, they are thermostable and are thus able to replicate in the cool nasal mucosa (Moriyama M et al. 2020).

Rhinoviruses have cytolytic properties for epithelial cells of the nasopharynx. After entry of the virus, focal destruction of the epithelium occurs within 48 hours. Large-scale necrosis does not occur. The infection usually remains localized. In a fraction of infected persons, the infection may spread to the deeper airways with the development of bronchitis or bronchopneumonia.

Rhinoviruses are the most common causative agent of common cold and major cause of respiratory infections in children and adults (Monto AS 2002; Regamey N et al 2008). On average, adults suffer between 2 and 5 rhinovirus infections per year, while children may have up to 10 infections per year (Stepanova E et al. 2019).

The incubation period is 1-4 days. During this period, viruses are already detectable in the nose.

In addition, rhinoviruses cause middle ear and sinusitis, obstructive bronchitis and pneumonia in different age groups, although much less frequently. These can lead to serious complications in immunocompromised and elderly patients (Kaiser L et al 2006).

Rhinoviruses as causative agents of acute bronchitis and pneumonia: due to their predilection to replicate at low temperatures (maximum virulence and replication rate at 33-35 °C), it was assumed that infections with rhinoviruses were limited to the upper respiratory tract. This can be refuted in this way. Various studies showed that rhinoviruses can also infect the lower respiratory tract and lead to obstructive bronchitis, bronchiolitis and pneumonia (Papadopoulos NG et al. 2000; Regamey N et al. 2008). In a clinical study of over 250 hospitalized children, rhinoviruses were isolated as the most common causative agent of viral pneumonia in childhood, with an incidence of 24% (Juven T et al. 2000).

Rhinoviruses and the exacerbation of chronic respiratory diseases: While the incidence of rhinovirus infections in healthy populations is well known, their exact role in pulmonary exacerbations of chronic lung diseases such as asthma, COPD and cystic fibrosis (CF) is largely unknown. Rhinoviruses are thought to cause the majority (80%) of all exacerbations in asthmatics and nearly half of all exacerbations in COPD patients (Corne JM et al 2002).

Bronchial asthma: In asthma patients, data exist linking rhinovirus infections to the development of the disease. Thus, it has been shown that symptomatic infections with rhinoviruses in early childhood are among the main risk factors for the development of bronchial asthma. Furthermore, infection with rhinoviruses can lead to an exacerbation of acute asthmatic symptoms and/or to an intensification of the inflammatory process in the respiratory tract. This is caused by the upregulation of the cell adhesion molecule ICAM-1 by the inflammatory process. ICAM-1 is the receptor in 90% of rhinoviruses. This explains the increased susceptibility of asthmatics to this infection (Hof H et al. 2019).

Cystic fibrosis (CF) respiratory infections play a significant role in pulmonary morbidity in CF patients. While the significance of bacterial infections in CF is widely known, the pathogenetic role of viruses in CF patients is still unclear. It is known that more than 40% of all pulmonary exacerbations and about half of all hospitalizations of CF patients are caused by respiratory viruses (20, 21). The clinical impact of viral infections in CF patients is greater (increased and prolonged symptoms), and the prognosis is worse than in healthy individuals (van Ewijk BE et al. (2005).Furthermore, the onset of bacterial infection, especially by Pseudomonas aeruginosa, may be favored by viral infections.

Unfortunately, there is currently a lack of suitable means to adequately combat rhinoviruses. Treatment is still symptomatic. Any immunity that develops is only short-lived and type-specific and does not provide any safety against re-infection in the case of >150 serotypes. Active (such as for influenza) and passive vaccination (such as for RSV) could be used preventively (Stepanova E et al. 2019).

In the 1960s and 1970s, several studies with formalin-inactivated RV vaccines administered to humans found that strong, long-lasting, strain-specific protective immunity was established. After experimental infection with different rhinovirus strains, a correlation was found between serum antibody titer and disease severity, indicating homotypic protection. However, there was little or no cross-reactivity between different rhinovirus strains, which meant that the vaccine had low efficacy in the field.

Prospect: An alternative approach is to use conserved RV proteins or peptides as vaccine antigens, administered as recombinant proteins together with an adjuvant or using a vector delivery system (see Vector vaccines below). The rhinovirus capsid consisting of the VP1, VP2, VP3 and VP4 proteins are the main targets for anti-RV immune responses. Due to their sequence variation, there is a high antigenic diversity between strains. However, recent advances in the understanding of RV-induced immune responses and viral capsid structures have led to an improved understanding of the parts of the viral proteins that are promising vaccine targets (Stepanova E et al. 2019).

Another approach for designing cross-reactive RV vaccines is to use immunogens that induce T-cell-mediated immune responses. The simplest strategy is to combine a conserved region of the RV with an adjuvant that enhances the T-cell response. Promising CD4 T-cell epitopes are found in the VP1 and VP2 capsid proteins of several RV group A serotypes. The identified T-cell epitopes are promising for the design of a broadly protective vaccine against human rhinoviruses.

Antibiotics: Studies show that substances commonly used in clinical practice, such as the macrolide antibiotic azithromycin, have immunomodulatory properties that could have an effect against rhinoviruses (Gielen V et al. 2010).