Overview

What are human parainfluenza viruses?

Human parainfluenza viruses (HPIVs) are viruses that infect the lungs and airways, causing upper and lower respiratory infections. These infections typically affect infants and children under the age of 5. These respiratory infections usually result in symptoms that are similar to those of the common cold, including:¹

• Having a runny nose
• Having a sore throat
• Coughing
• Sneezing

However, HPIVs may be responsible for more serious illnesses that affect the respiratory system, including the following:

• Pneumonia
• Bronchitis
• Croup
• Bronchiolitis

Why study the genetic makeup of human parainfluenza viruses?

Studying the genetic makeup of HPIVs has allowed these viruses to be grouped into four different serotypes, depending on their genetic and antigenic differences (antigens are proteins found on the surface of viruses and are how your immune system distinguishes viruses as a foreign invader from your body cells). The four serotypes are HPIV-1, HPIV-2, HPIV-3 and HPIV-4. These genetic differences mean that the different serotypes are more associated with different respiratory illnesses. For example, HPIV-1 and HPIV-2 are more likely to cause croup, whereas HPIV-3 and HPIV-4 are more associated with causing pneumonia or bronchiolitis. This highlights how understanding the genetic differences between the different serotypes of parainfluenza can allow us to gain an understanding of what type of infection these viruses may cause. This allows healthcare professionals to formulate treatment plans.²

Structure of parainfluenza viruses

Basic viral morphology

Enveloped virus

HPIVs are enveloped viruses, meaning that they have an outer coat made of part of a host cell’s plasma membrane (a membrane layer that separates and protects the inside of a cell from the outside environment). A new HPIV obtains its envelope when it is being formed inside a host cell (which is one of your human cells) and the new virus buds off the host cell, using some of the host cell’s plasma membrane to form an envelope.^2,3

Negative-sense RNA genome

The genetic information within HPIVs is not like our own deoxyribonucleic acid (DNA), which is double-stranded and in the shape of a double helix. In contrast, HPIVs have ribonucleic acid (RNA) as their genetic material. RNA differs from DNA in that it is single-stranded, not double-stranded. One of the building blocks of RNA is different to DNA too, with uracil being used instead of thymine. However, despite their differences, both RNA and DNA serve the purpose of coding for proteins.⁴

The RNA found within HPIVs is in the ‘negative sense’, meaning that in order to synthesise their messenger RNA strands they use the genome sense strand.⁵ Messenger RNA strands direct the virus to make proteins.  The sense strand, used to make messenger RNA, is called the sense strand as when you read it in the right direction, this provides the genetic code to build a protein.

Genomic organisation

Non-segmented genome

HPIVs have a non-segmented genome, meaning that their genome consists of one segment of genetic material (RNA). This one segment of genetic material has a length of 14.9-17.3 kilobases, and this genetic material codes for six common structural proteins, which are key to the virus's function.²

Key genes and proteins

The key structural proteins that are encoded in the HPIV genome are the following:

• Fusion protein
• Hemagglutinin-neuraminidase
• RNA polymerase
• Nucleoprotein
• Phosphoprotein
• Matrix protein

Of these six structural proteins, the fusion protein and hemagglutinin-neuraminidase are known as membrane-associated proteins, meaning that they are found on the surface of the virus. The matrix protein is found on the inner surface of the lipid bilayer, a layer underneath the surface of the virus, as seen in the below image. Whereas, RNA polymerase, nucleoprotein, and phosphoprotein are nucleocapsid-associated proteins. The nucleocapsid is a part of the virus that contains the genetic material (RNA), surrounded by a protein known as a capsid, which acts as a shell, protecting the genetic material.^2,5

Image of HPIV from https://doi.org/10.1172/JCI25669.

Here the phosphoprotein (P), nucleocapsid protein (NP), RNA polymerase (L), matrix protein (M), fusion (F) protein, and haemagglutinin-neuraminidase (HN) protein are visualised.

Role of fusion protein and hemagglutinin-neuraminidase protein

Both fusion protein and hemagglutinin-neuraminidase protein have a role in initiating infection in the host, as both proteins allow entry into the host cells. This is where the virus will begin to replicate and cause infection.⁶

Role of RNA polymerase protein, nucleoprotein and phosphoprotein

RNA polymerase is used to replicate the RNA genome. This process is essential for the production of new HPIVs to infect a host.^7,8 Additionally, both nucleoprotein and phosphoprotein play a role in the replication of HPIVs.⁹

Role of matrix protein

Matrix protein has a role in ensuring that new viruses bud off the host cell, using part of the host cell’s plasma membrane as an envelope.¹⁰

Implications of genetic makeup

Pathogenesis and virulence

Host-virus interactions

HPIVs initiate infection by binding to cell surface receptors on the host cell, then using the two glycoproteins: fusion protein and hemagglutinin-neuraminidase protein, the HPIV can fuse with the cell membrane of the host cell. This allows the HPIV to release viral replication machinery into the host cell, allowing the host cell to be used for the replication of HPIVs, resulting in infection.

Factors influencing disease severity

HPIVs can accumulate a variety of mutations, however, not all will affect how the virus initiates infection and disease severity. A set of mutations in the globular domain of the hemagglutinin-neuraminidase protein have made viruses more fusogenic, potentially facilitating more virus-to-host cell fusion and further infection.¹²

Diagnosis of parainfluenza viruses

If you have been infected with HPIV and require a specific viral diagnosis that will confirm the serotype of the virus, you will need a sample of the virus infecting you to be obtained and genetically analysed. This can be conducted via the following, after obtaining a swab from either the throat or a nasopharyngeal swab:¹

• Molecular Assays: Polymerase Chain Reaction (PCR) is a type of molecular assay that is rapid, sensitive, and is used to detect the viral RNA genome that is present, allowing for accurate diagnosis of the type of HPIV causing the infection
• Viral cell culture: allows the HPIV to be isolated and the serotype identified in a cell culture

Impact on public health

Epidemiology of parainfluenza viruses

Seasonal patterns

The seasonal patterns of all four serotypes of HPIVs vary as follows:¹

• HPIV-1: this virus follows a biennial pattern, where there is a peak in cases typically at the end of the year, in the months of September to December of odd-numbered years
• HPIV-2: this virus again follows a biennial pattern in alternating years to HPIV-1, and the number of cases is much smaller
• HPIV-3: this virus has annual outbreaks, typically from April to June
  •  During even-numbered years, when HPIV-1 is not circulating, HPIV-3 circulates for longer, sometimes extending into the early Autumn seasons
  • There may also be a second period of activity where cases peak from November to December

Global distribution

HPIV has a global distribution and is estimated to be responsible for 13% of all lower respiratory infections in children.

Genetic variability and vaccines

Currently, there is no vaccine against HPIV. Vaccine efforts are targeted towards HPIV-3, due to this serotype of the virus being responsible for a high number of hospitalisations. Knowing the symptoms and illnesses that different serotypes can cause can help to aid in the development of a vaccine.¹³

Summary

• Human parainfluenza viruses (HPIVs) cause respiratory infections, many of which infect children under the age of 5, and result in symptoms similar to that of the common cold
• There are 4 different serotypes of HPIVs, which have genetic and antigenic variances, these serotypes are HPIV-1, HPIV-2, HPIV-3 and HPIV-4
• HPIVs are enveloped viruses
• HPIVs have single-stranded genetic material called RNA, which is non-segmented (meaning it is one single piece of genetic material), and is described as being in the negative sense, due to the sense of the strand of DNA the RNA encodes itself off of
• The RNA in HPIV encodes for 6 structural proteins, known as fusion protein, matrix protein, haemagglutinin-neuraminidase protein, RNA polymerase, nucleoprotein, and phosphoprotein
• HPIVs initiate infection by using fusion protein and haemagglutinin-neuraminidase protein to make contact with the host cell and gain entry into the host cell to begin replicating and initiating infection
• The different serotypes of HPIVs have different seasonal patterns on when they are causing the most infections
• Currently, there is no vaccination for the different serotypes of HPIVs, however, more knowledge of the different serotypes and the type of infection they cause should aid the development of vaccinations