| Human parainfluenza viruses | |
|---|---|
 | |
| Transmission electron micrograph of a parainfluenza virus. Two intact particles and free filamentousnucleocapsid | |
Scientific classification | |
| (unranked): | Virus |
| Realm: | Riboviria |
| Kingdom: | Orthornavirae |
| Phylum: | Negarnaviricota |
| Class: | Monjiviricetes |
| Order: | Mononegavirales |
| Family: | Paramyxoviridae |
| Groups included | |
| |
| Cladistically included but traditionally excluded taxa | |
Human parainfluenza viruses (HPIVs) are the viruses that causehuman parainfluenza. HPIVs are aparaphyletic group of four distinctsingle-strandedRNAviruses belonging to theParamyxoviridae family. These viruses are closely associated with both human and veterinary disease.[2] Virions are approximately 150–250 nm in size and contain negative senseRNA with agenome encompassing about 15,000nucleotides.[3]
The viruses can be detected viacell culture,immunofluorescentmicroscopy, andPCR.[4] HPIVs remain the second main cause of hospitalisation in children under 5 years of age for arespiratory illness (onlyrespiratory syncytial virus (RSV) causes more respiratory hospitalisations for this age group).[5]
The first HPIV was discovered in the late 1950s. The taxonomic division is broadly based onantigenic andgenetic characteristics, forming four majorserotypes orclades, which today are considered distinct viruses.[6] These include:
| Virus | GenBank acronym | NCBI taxonomy | Notes |
|---|---|---|---|
| Human parainfluenza virus type 1 | HPIV-1 | 12730 | Most common cause ofcroup |
| Human parainfluenza virus type 2 | HPIV-2 | 11212 | Causescroup and other upper and lower respiratory tract illnesses |
| Human parainfluenza virus type 3 | HPIV-3 | 11216 | Associated withbronchiolitis andpneumonia |
| Human parainfluenza virus type 4 | HPIV-4 | 11203 | Includes subtypes 4a and 4b |
HPIVs belong to two genera:Respirovirus (HPIV-1 & HPIV-3) andRubulavirus (HPIV-2 & HPIV-4).[3]
HPIVs are characterised by producing enveloped virions and containing single stranded negative senseRNA.[3] Non-infectious virions have also been reported to containRNA with positive polarity.[3] HPIV genomes are about 15,000nucleotides in length and encode six key structuralproteins.[3]
Thestructural gene sequence of HPIVs is as follows:3′-NP-P-M-F-HN-L-5′ (the protein prefixes and further details are outlined in the table below).[7]
| Structural protein | Location | Function |
|---|---|---|
| Hemagglutinin-neuraminidase (HN) | Envelope | Attachment and cell entry |
| Fusion Protein (F) | Envelope | Fusion and cell entry |
| Matrix Protein (M) | Within the envelope | Assembly |
| Nucleoprotein (NP) | Nucleocapsid | Forms a complex with theRNA genome |
| Phosphoprotein (P) | Nucleocapsid | Forms as part ofRNA polymerase complex |
| Large Protein (L) | Nucleocapsid | Forms as part ofRNA polymerase complex |
With the advent ofreverse genetics, it has been found that the most efficient human parainfluenza viruses (in terms of replication and transcription) have a genomenucleotide total that is divisible by the number 6. This has led to the "rule of six" being coined. Exceptions to the rule have been found, and its exact advantages are not fully understood.[8]
Electrophoresis has shown that themolecular weight of the proteins for the four HPIVs are similar (with the exception of thephosphoprotein, which shows significant variation).[3][9]
Viral replication is initiated only after successful entry into a cell by attachment and fusion between the virus and the host celllipid membrane. Viral RNA (vRNA) is initially associated with nucleoprotein (NP), phosphoprotein (P) and the large protein (L). Thehemagglutinin–neuraminidase (HN) is involved with viral attachment and thus hemadsorption andhemagglutination. Furthermore, the fusion (F) protein is important in aiding the fusion of the host and viral cellular membranes, eventually formingsyncytia.[10]
Initially the F protein is in an inactive form (F0) but can be cleaved byproteolysis to form its active form, F1 and F2, linked by di-sulphide bonds. Once complete, this is followed by the HPIV nucleocapsid entering thecytoplasm of the cell. Subsequently, genomic transcription occurs using the viruses own 'viral RNA-dependentRNA polymerase' (L protein). The cell's ownribosomes are then tasked withtranslation, forming the viral proteins from the viralmRNA.[10]
Towards the end of the process, (after the formation of the viral proteins) the replication of the viral genome occurs. Initially, this occurs with the formation of apositive-sense RNA (intermediate step, necessary for producing progeny), and finally,negative-sense RNA is formed which is then associated with thenucleoprotein. This may then be either packaged and released from the cell by budding or used for subsequent rounds oftranscription and replication.[11]
The observable and morphological changes that can be seen in infected cells include the enlargement of thecytoplasm, decreasedmitotic activity and 'focal rounding', with the potential formation of multi-nucleate cells (syncytia).[12]
Thepathogenicity of HPIVs is mutually dependent on the viruses having the correct accessory proteins that are able to elicit anti-interferon properties. This is a major factor in theclinical significance of disease.[11]
The main host remains the human. However, infections have been induced in other animals (both under natural and experimental situations), although these were alwaysasymptomatic.[13]
It is estimated that there are 5 million children withlower respiratory infections (LRI) each year in the United States alone.[14] HPIV-1, HPIV-2 and HPIV-3 have been linked with up to a third of these infections.[15]Upper respiratory infections (URI) are also important in the context of HPIV, however, they are caused to a lesser extent by the virus.[16] The highest rates of serious HPIV illnesses occur among young children, and surveys have shown that about 75% of children aged 5 or older have antibodies to HPIV-1.[citation needed]
For infants and young children, it has been estimated that about 25% will develop "clinically significant disease".[17]
Repeated infection throughout the life of the host is not uncommon and symptoms of later breakouts includeupper respiratory tract illness, such ascold and a sore throat.[3] Theincubation period for all four serotypes is 1 to 7 days.[18] Inimmunosuppressed people, parainfluenza virus infections can cause severepneumonia, which can be fatal.[19]
HPIV-1 and HPIV-2 have been demonstrated to be the principal causative agent behindcroup (laryngotracheobronchitis), which is a viral disease of the upper airway and is mainly problematic in children aged 6–48 months of age.[20][21] Biennial epidemics starting in autumn are associated with both HPIV-1 and -2; however, HPIV-2 can also have yearly outbreaks.[14] Additionally, HPIV-1 tends to cause biennial outbreaks of croup in the fall. In the United States, large peaks have presently been occurring during odd-numbered years.[citation needed]
HPIV-3 has been closely associated withbronchiolitis andpneumonia, and principally targets those aged <1 year.[22]
HPIV-4 remains infrequently detected. It is now believed to be more common than previously thought but less likely to cause severe disease. By the age of 10, the majority of children are seropositive for HPIV-4 infection—this may be indicative of a large proportion ofasymptomatic or mild infections.[3]
Those with compromised immunity have a higher risk of infection and mortality and may fall ill with more extreme forms of LRI.[13] Associations between HPIVs andneurologic disease are known. For example, hospitalisation with certain HPIVs has a strong association withfebrile seizures.[23] HPIV-4b has the strongest association, up to 62% of HPIV-4b hospitalisations, followed by HPIV-3 (17%) and -1 (7%).[3]
HPIVs have also been linked with rare cases of viralmeningitis[24] andGuillain–Barré syndrome.[12]
HPIVs are spread from person to person (i.e.,horizontal transmission) by contact with infected secretions inrespiratory droplets or contaminatedsurfaces or objects. Infection can occur when infectious material contacts the mucous membranes of the eyes, mouth, or nose, and possibly through the inhalation of droplets generated by a sneeze or cough. HPIVs can remain infectious in airborne droplets for over an hour.[25]
The inflammation of the airway is a common attribute of HPIV infection. It is believed to occur due to the large scale upregulation ofinflammatory cytokines. Commoncytokines observed to be upregulated includeIFN–α, variousinterleukins (i.e.,IL–2,IL-6), andTNF–α. Variouschemokines and inflammatory proteins are also believed to be associated with the common symptoms of HPIV infection.[12]
Recent evidence suggests that the virus-specific antibodyimmunoglobulin E may be responsible for mediating the large-scale releases ofhistamine in thetrachea that are believed to causecroup.[12][26]
The body's primary defense against HPIV infection isadaptive immunity involving bothhumoral andcellular immunity. With humoral immunity, antibodies that bind to the surface viral proteins HN and F protect against later infection.[27] Patients with defective cell-mediated immunity also experience more severe infection, suggesting thatT cells are important in clearing infection.[12]
Diagnosis can be made in several ways, encompassing a range of multi-faceted techniques:[4]
Because of the similarity in terms of the antigenic profile between the viruses,hemagglutination assay (HA) or hemadsorption inhibition (HAdI) processes are often used. Bothcomplement fixation,neutralisation, andenzyme linked immunosorbent assays – ELISA, can also be used to aid in the process of distinguishing between viralserotypes.[3]
Mortality caused by HPIVs in developed regions of the world remains rare. Where mortality has occurred, it is principally in the three core risk groups (very young, elderly andimmuno-compromised). Long-term changes can however be associated with airway remodeling and are believed to be a significant cause of morbidity.[28] The exact associations between HPIVs and diseases such aschronic obstructive pulmonary disease (COPD) are still being investigated.[29]
In developing regions of the world, preschool children remain the highest mortality risk group. Mortality may be a consequence of primary viral infection or secondary problems, such as bacterial infection. Predispositions, such asmalnutrition and other deficiencies, may further elevate the chances of mortality associated with infection.[12]
Overall, LRIs cause approximately 25–30% of total deaths in preschool children in the developing world. HPIVs are believed to be associated with 10% of all LRI cases, thus remaining a significant cause of mortality.[12]
Numerous factors have been suggested and linked to a higher risk of acquiring the infection, inclusive ofmalnutrition,vitamin A deficiency, absence of breastfeeding during the early stages of life,environmental pollution and overcrowding.[30]
Despite decades of research, novaccines currently exist.[31]
Recombinant technology has however been used to target the formation of vaccines for HPIV-1, -2 and -3 and has taken the form of several live-attenuated intranasal vaccines. Two vaccines in particular were found to beimmunogenic and well tolerated against HPIV-3 inphase I trials. HPIV-1 and -2 vaccine candidates remain less advanced.[17]
Vaccine techniques which have been used against HPIVs are not limited to intranasal forms, but also virusesattenuated by cold passage, host range attenuation, chimeric construct vaccines and also introducing mutations with the help ofreverse genetics to achieve attenuation.[32]
Maternalantibodies may offer some degree of protection against HPIVs during the early stages of life via thecolostrum in breast milk.[33]
Ribavirin is one medication which has shown good potential for the treatment of HPIV-3 given recentin-vitro tests (in-vivo tests show mixed results).[12] Ribavirin is a broad-spectrumantiviral, and as of 2012, was being administered to those who are severelyimmuno-compromised, despite the lack of conclusive evidence for its benefit.[12] Protein inhibitors and novel forms of medication have also been proposed to relieve the symptoms of infection.[13]
Furthermore,antibiotics may be used if a secondary bacterial infection develops.Corticosteroid treatment andnebulizers are also a first line choice againstcroup if breathing difficulties ensue.[12]
Parainfluenza viruses last only a few hours in the environment and are inactivated by soap and water. Furthermore, the virus can also be easily destroyed using common hygiene techniques and detergents, disinfectants and antiseptics.[4]
Environmental factors which are important for HPIV survival arepH,humidity,temperature and themedium within which the virus is found. The optimal pH is around the physiologic pH values (7.4 to 8.0), whilst at high temperatures (above 37 °C) and low humidity, infectivity reduces.[34]
The majority of transmission has been linked to close contact, especially innosocomial infections. Chronic care facilities and doctors' surgeries are also known to be transmission 'hotspots' with transmission occurring viaaerosols, large droplets and alsofomites (contaminated surfaces).[35]
The exact infectious dose remains unknown.[13]
In economically disadvantaged regions of the world, HPIV infection can be measured in terms of mortality. In the developed world where mortality remains rare, the economic costs of the infection can be estimated. Estimates from the US are suggestive of a cost (based onextrapolation) in the region of $200 million per annum.[3]
Influenza viruses belong to theOrthomyxoviridae family; Parainfluenza viruses (HPIVs) belong to theParamyxoviridae family. Influenza typically causes more severe illness than parainfluenza. While both can cause upper respiratory symptoms, influenza is more likely to result in high fever, body aches, and fatigue. Parainfluenza often produces milder, cold-like symptoms such as runny nose, cough, and low-grade fever.[36] Influenza has a distinct seasonal pattern, with outbreaks occurring mainly in winter months. Parainfluenza viruses circulate year-round, with each type having its own seasonal patterns. The viruses have a tendency towards different complications: influenza is more likely to cause severe pneumonia in high-risk groups; parainfluenza is more likely to cause croup in children. Influenza has effective vaccines available and can be treated with antiviral medications like neuraminidase inhibitors. There are currently no vaccines or specific antiviral treatments for parainfluenza viruses. Parainfluenza tends to infect young children, with most children being infected by age 5. Influenza can affect all ages.[37][38]