Human Parainfluenza Virus Infection

Virological Characteristics and Classification

Parainfluenza viruses (PIV) belong to the Paramyxoviridae family and have single-stranded enveloped negative-sense RNA genomes. The classification of human PIV includes four main serotypes: The HPIV family consists of four serotypes which go from HPIV1 through HPIV4 and HPIV4 further separates into two distinct subtypes named HPIV4a and HPIV4b. These serotypes exhibit distinct taxonomic classifications: Human parainfluenza viruses HPIV1 and HPIV3 belong to the Respirovirus genus while HPIV2 and HPIV4 belong to the Rubulavirus genus.

Figure 1. HPIV virion and genome organization
(Source: Schmidt AC, et al. 2011)

Their genome consists of a single negative-sense RNA strand encoding six key proteins: The virus genome codes for six essential proteins: nucleoprotein, phosphoprotein, RNA polymerase, matrix protein, fusion protein, and hemagglutinin-neuraminidase protein. The parainfluenza virus utilizes HN and F as essential surface proteins. The HN protein binds the virus to host epithelial cell surface sialic acid residues to enable viral attachment. Through mediating membrane fusion between the viral envelope and host cell membrane the F protein enables the viral genome to enter the cell. HN protein helps detach new virus particles from the host cell by cleaving sialic acid residues. These two proteins are the main targets of neutralizing antibodies in the immune response. The viral envelope gains structural support through the lining of its interior by the M protein. The nucleocapsid complex formed by the NP binding to viral RNA functions as a template for the RNA-dependent RNA polymerase which consists of P and L proteins to facilitate viral RNA replication and transcription. The P protein contributes to the polymerase complex and produces accessory proteins that differ between serotypes and manage virus-host interactions. HPIV1 and HPIV3 produce short C proteins in their genetic code but HPIV2 produces a V protein which together they inhibit host immune functions by blocking type I interferon activity to help the virus avoid immune detection.

Table 1. Characterization of HPIV common structural proteins

(Source: Pawełczyk M, et al. 2017)

Pathogenic Mechanisms and Clinical Manifestations

The development of HPIV disease results from complex interactions between the virus and its host. HPIV targets and multiplies in ciliated epithelial cells located in both upper and lower parts of the respiratory system. The virus first infects the nasal cavity and oropharynx before moving to the lower respiratory tract where viral replication reaches its peak between 2 and 5 days after infection begins. The clinical presentation of HPIV infection depends on which body site is affected. The symptoms of upper respiratory tract infections generally resemble those of a common cold. Croup and bronchiolitis emerge from infections of the larynx and trachea and viral replication in distal airways advances to pneumonia.

An infection in the small airway epithelium triggers local inflammatory cell infiltration while the immune response from the host becomes a critical factor in disease development. The infection destroys ciliated epithelial cells which triggers excessive mucus production together with inflammatory cytokine release of IL-6 and TNF-α leading to blocked airways and decreased blood oxygen levels. Inflammation causes the subglottic region of the larynx to narrow which produces the primary symptoms of croup including hoarseness, cough and inspiratory stridor. The surrounding cricoid cartilage limits its elasticity which results in airway blockage creating a high-pitched inspiratory noise known as stridor. Airflow obstruction raises breathing effort and can trigger fatigue along with hypoxia and respiratory failure in severe situations. Adults who suffer from HPIV infection face mild symptoms while asthma patients develop worsened symptoms due to the viral infection causing airway hyperresponsiveness through pro-inflammatory cytokine and chemokine release.

Different serotypes show significant differences in tissue tropism: HPIV-1 and HPIV-2 target the larynx and trachea for infection while HPIV-3 shows preference for distal bronchi and alveoli infection HPIV-4 appears less frequently and causes milder symptoms like cough and runny nose but some research indicates it can also lead to severe lower respiratory tract infections.

Table 2. Kinetics of replication, cytokine release and clinical manifestations of infections with HPIV serotypes 1–3

(Source: Pawełczyk M, et al. 2017)

Treatment Strategies and Vaccine Development

No antiviral medication has been proven effective for HPIV infections thus treatment remains limited to supportive care for symptoms. Medical professionals administer oxygen therapy along with bronchodilators and corticosteroids to treat severe respiratory distress. Corticosteroids serve as the primary treatment for croup and show effectiveness in patients with varying severity levels. In critically ill children, corticosteroid administration reduces intubation rates by fivefold. For milder cases, corticosteroids shorten emergency department stays, reduce follow-up visits, and improve sleep quality. Heliox (a helium-oxygen mixture) has been proposed for croup management but is not routinely recommended due to challenges in administration and lack of proven superiority over conventional therapies.

Currently, there is no approved vaccine for the prevention of HPIV infection. Antibodies targeting the two viral surface glycoproteins-the F protein and HN-have virus-neutralizing effects. Both serum and nasal secretory antibodies against these proteins protect the host from HPIV infection and reduce disease severity. Therefore, vaccines that enhance serum and/or mucosal antibody responses may be beneficial, but successful vaccine development faces multiple challenges.

The HN protein from HPIV demonstrates greater stability than its counterpart in influenza A virus. Antigenic variations in the HPIV HN protein have developed over time which created differences in both serological and genetic aspects when compared to early isolates. The antigenic drift creates challenges for vaccine development because vaccines need to protect against changing viral strains. The limited and temporary cross-protection between HPIV serotypes requires the creation of multivalent vaccines.

Most vaccine research currently focuses on HPIV-3, the main serotype causing severe disease and pneumonia in infants and the elderly. Subunit vaccines are generally avoided in HPIV vaccine development. Current strategies include cold-adapted live-attenuated vaccines, bovine parainfluenza virus vaccines, and recombinant bovine/human parainfluenza virus vaccines. Because RSV and HPIV-3 affect similar age groups, recombinant vaccines expressing both RSV and HPIV proteins are being explored. Several candidate vaccines have already entered Phase I/II clinical trials in children.

PIV ELISA Kits

PIV Antibodies

PIV Antigens