Human parainfluenza viruses (HPIVs) are the viruses that cause human parainfluenza. HPIVs are a
paraphyletic
In taxonomy (general), taxonomy, a group is paraphyletic if it consists of the group's most recent common ancestor, last common ancestor and most of its descendants, excluding a few Monophyly, monophyletic subgroups. The group is said to be pa ...
group of four distinct single-stranded
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
virus
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsky's 1 ...
es belonging to the ''
Paramyxoviridae
''Paramyxoviridae'' (from Ancient Greek, Greek ''para-'' “by the side of” and ''myxa'' “mucus”) is a family of negative-strand RNA viruses in the order ''Mononegavirales''. Vertebrates serve as natural hosts. Diseases associated with this ...
'' family. These viruses are closely associated with both human and veterinary disease. Virions are approximately 150–250 nm in size and contain negative sense
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
with a
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
encompassing about 15,000
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
s.
![1ztm](https://upload.wikimedia.org/wikipedia/commons/3/3a/1ztm.jpg)
The viruses can be detected via
cell culture
Cell culture or tissue culture is the process by which cells are grown under controlled conditions, generally outside of their natural environment. The term "tissue culture" was coined by American pathologist Montrose Thomas Burrows. This te ...
,
immunofluorescent
Immunofluorescence is a technique used for light microscopy with a fluorescence microscope and is used primarily on microbiological samples. This technique uses the specificity of antibodies to their antigen to target fluorescent dyes to specifi ...
microscopy
Microscopy is the technical field of using microscopes to view objects and areas of objects that cannot be seen with the naked eye (objects that are not within the resolution range of the normal eye). There are three well-known branches of micr ...
, and
PCR PCR or pcr may refer to:
Science
* Phosphocreatine, a phosphorylated creatine molecule
* Principal component regression, a statistical technique
Medicine
* Polymerase chain reaction
** COVID-19 testing, often performed using the polymerase chain r ...
.
HPIVs remain the second main cause of hospitalisation in children under 5 years of age for a
respiratory illness (only
Respiratory syncytial virus (RSV) causes more respiratory hospitalisations for this age group).
Classification
The first HPIV was discovered in the late 1950s. The taxonomic division is broadly based on
antigenic
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
and
genetic characteristics, forming four major
serotypes or clades, which today are considered distinct viruses.
These include:
HPIVs belong to two genera: ''
Respirovirus
''Respirovirus'' is a genus of viruses in the order ''Mononegavirales'', in the family ''Paramyxoviridae''. Rodents and human serve as natural hosts. There are seven species in this genus. Diseases associated with this genus include: croup and ot ...
'' (HPIV-1 & HPIV-3) and ''
Rubulavirus
''Rubulavirinae'' is a subfamily of viruses in the family ''Paramyxoviridae''. Humans, apes, pigs, and dogs serve as natural hosts. There are currently 18 species in the two genera ''Orthorubulavirus'' and ''Pararubulavirus''. Diseases associated ...
'' (HPIV-2 & HPIV-4).
Viral structure and organisation
HPIVs are characterised by producing enveloped virions and containing single stranded negative sense
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
.
Non-infectious virions have also been reported to contain
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
with positive polarity.
HPIV genomes are about 15,000
nucleotides in length and encode six key structural
proteins
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
.
The
structural gene
A structural gene is a gene that codes for any RNA or protein product other than a regulatory factor (i.e. regulatory protein). A term derived from the Lac operon, ''lac'' operon, structural genes are typically viewed as those containing sequences ...
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).
With the advent of
reverse genetics, it has been found that the most efficient human parainfluenza viruses (in terms of replication and transcription) have a genome
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
total that is divisible by the number 6. This has led to the "rule of six" being coined. Exceptions to this rule have been found and its exact advantages are not fully understood.
Electrophoresis
Electrophoresis, from Ancient Greek ἤλεκτρον (ḗlektron, "amber") and φόρησις (phórēsis, "the act of bearing"), is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric fie ...
has shown that the
molecular weight (MW) of the proteins for the four HPIVs are similar (with the exception of the
phosphoprotein, which shows significant variation).
Viral entry and replication
Viral replication is initiated only after successful entry into a cell by attachment and fusion between the virus and the host cell
lipid membrane. Viral RNA (
vRNA
Many eukaryotic cells contain large ribonucleoprotein particles in the cytoplasm known as Vault (organelle), vaults. The vault complex comprises the major vault protein (Major vault protein, MVP), two minor vault proteins (PARP4, VPARP and TEP1), ...
) is initially associated with nucleoprotein (NP), phosphoprotein (P) and the large protein (L). The
hemagglutinin–
neuraminidase (HN) is involved with viral attachment and thus hemadsorption and
hemagglutination. Furthermore, the fusion (F) protein is important in aiding the fusion of the host and viral cellular membranes, eventually forming
syncytia.
Initially the F protein is in an inactive form (F
0) but can be cleaved by
proteolysis
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...
to form its active form, F
1 and F
2, linked by di-sulphide bonds. Once complete, this is followed by the HPIV nucleocapsid entering the
cytoplasm of the cell. Subsequently, genomic transcription occurs using the viruses own 'viral RNA-dependent
RNA polymerase
In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that synthesizes RNA from a DNA template.
Using the enzyme helicase, RNAP locally opens the ...
' (L protein). The cell's own
ribosomes
Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to f ...
are then tasked with
translation, forming the viral proteins from the viral
mRNA.
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 a
positive-sense RNA
In molecular biology and genetics, the sense of a nucleic acid molecule, particularly of a strand of DNA or RNA, refers to the nature of the roles of the strand and its complement in specifying a sequence of amino acids. Depending on the context, ...
(intermediate step, necessary for producing progeny), and finally,
negative-sense RNA is formed which is then associated with the
nucleoprotein. This may then be either packaged and released from the cell by budding or used for subsequent rounds of
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
and replication.
The observable and morphological changes that can be seen in infected cells include the enlargement of the
cytoplasm, decreased
mitotic activity and 'focal rounding', with the potential formation of multi-nucleate cells (syncytia).
The
pathogenicity of HPIVs is mutually dependent on the viruses having the correct accessory proteins that are able to elicit anti-
interferon
Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...
properties. This is a major factor in the
clinical significance In medicine and psychology, clinical significance is the practical importance of a treatment effect—whether it has a real genuine, palpable, noticeable effect on daily life.
Types of significance Statistical significance
Statistical significance ...
of disease.
Host range
The main host remains the human. However, infections have been induced in other animals (both under natural and experimental situations), although these were always
asymptomatic
In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered asy ...
.
Clinical significance
It is estimated that there are 5 million children with
lower respiratory infections (LRI) each year in the United States alone.
HPIV-1, HPIV-2 and HPIV-3 have been linked with up to a third of these infections.
Upper respiratory infections
An upper respiratory tract infection (URTI) is an illness caused by an acute infection, which involves the upper respiratory tract, including the nose, sinuses, pharynx, larynx or trachea. This commonly includes nasal obstruction, sore throat, to ...
(URI) are also important in the context of HPIV, however, they are caused to a lesser extent by the virus. 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.
For infants and young children, it has been estimated that about 25% will develop "clinically significant disease".
Repeated infection throughout the life of the host is not uncommon and symptoms of later breakouts include
upper respiratory tract illness, such as
cold and a sore throat.
The
incubation period for all four serotypes is 1 to 7 days. In
immunosuppressed
Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...
people, parainfluenza virus infections can cause severe
pneumonia, which can be fatal.
HPIV-1 and HPIV-2 have been demonstrated to be the principal causative agent behind
croup
Croup, also known as laryngotracheobronchitis, is a type of respiratory infection that is usually caused by a virus. The infection leads to swelling inside the trachea, which interferes with normal breathing and produces the classic symptoms o ...
(
laryngotracheobronchitis
Croup, also known as laryngotracheobronchitis, is a type of respiratory infection that is usually caused by a virus. The infection leads to swelling inside the trachea, which interferes with normal breathing and produces the classic symptoms o ...
), which is a viral disease of the upper airway and is mainly problematic in children aged 6–48 months of age.
Biennial epidemics starting in Autumn are associated with both HPIV-1 and 2; however, HPIV-2 can also have yearly outbreaks.
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.
HPIV-3 has been closely associated with
bronchiolitis and
pneumonia and principally targets those aged <1 year.
HPIV-4 remains infrequently detected. However, it is now believed to be more common than previously thought, but is less likely to cause severe disease. By the age of 10, the majority of children are sero-positive for HPIV-4 infection which may be indicative of a large proportion of
asymptomatic
In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered asy ...
or mild infections.
Important epidemiological factors that are associated with a higher risk of infection and mortality are those who are
immuno-compromised
Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
and may be taken ill with more extreme forms of LRI.
Associations between HPIVs and
neurologic disease are known; for example, hospitalisation with certain HPIVs has a strong association with
febrile seizures. HPIV-4B has the strongest association (up to 62%) followed by HPIV-3 and -1.
HPIVs have also been linked with rare cases of virally caused
meningitis
Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, headache, and neck stiffness. Other symptoms include confusion or ...
and
Guillain–Barré syndrome.
HPIVs are spread from person to person ('horizontal transmission') by contact with infected secretions through
respiratory droplets or contaminated surfaces or objects. Infection can occur when infectious material contacts 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.
Overall, HPIVs remain best known for its effects on the
respiratory system and this appears to be where the majority of the focus has been upon.
Airway inflammation
The inflammation of the airway is a common attribute of HPIV infection. It is believed to occur due to the large scale up-regulation of inflammatory
cytokines
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
. Common cytokines, expected to be up-regulated, include IFN–α, various other
interleukins (IL–2, IL-6) and TNF–α. Various
chemokines and inflammatory proteins are also believed to be associated with the common symptoms of HPIV infection.
Recent evidence seems to suggest that virus-specific antibodies (IgE) may be responsible for mediating large-scale releases of
histamine in the
trachea, which are believed to cause
croup
Croup, also known as laryngotracheobronchitis, is a type of respiratory infection that is usually caused by a virus. The infection leads to swelling inside the trachea, which interferes with normal breathing and produces the classic symptoms o ...
.
More detail on the pathways and interactions can be foun
here
Immunology
The body's primary defense against HPIV infection remains
humoral immunity
Humoral immunity is the aspect of immunity that is mediated by macromolecules - including secreted antibodies, complement proteins, and certain antimicrobial peptides - located in extracellular fluids. Humoral immunity is named so because it in ...
. This is mainly directed against surface proteins which can be found on the virus. In particular the proteins HN and F prove to be most immunogenic in terms of stimulating the immune system.
Recently the importance of the 'cell mediated immune system' has been scrutinized. Reports have shown that those with defective
adaptive immune response
The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
s are at a higher risk of severe infection.
Diagnosis
Diagnosis can be made in several ways, encompassing a range of multi-faceted techniques:
* Isolation and detection of the virus in
cell culture
Cell culture or tissue culture is the process by which cells are grown under controlled conditions, generally outside of their natural environment. The term "tissue culture" was coined by American pathologist Montrose Thomas Burrows. This te ...
.
* Detection of viral antigens directly within bodily
respiratory tract
The respiratory tract is the subdivision of the respiratory system involved with the process of respiration in mammals. The respiratory tract is lined with respiratory epithelium as respiratory mucosa.
Air is breathed in through the nose to th ...
secretions using
immunofluorescence
Immunofluorescence is a technique used for light microscopy with a fluorescence microscope and is used primarily on microbiological samples. This technique uses the specificity of antibodies to their antigen to target fluorescent dyes to specif ...
,
enzyme immunoassays or fluoroimmunoassays.
*
Polymerase chain reaction (PCR).
* Analysis of specific
IgG antibodies
Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...
showing a subsequent rise in
titre following infection (using paired serum specimens).
Because of the similarity in terms of the antigenic profile between the viruses,
hemagglutination assay
The hemagglutination assay or haemagglutination assay (HA) and the hemagglutination inhibition assay (HI or HAI) were developed in 1941–42 by American virologist George Hirst as methods for quantifying the relative concentration of viruses, bact ...
(HA) or hemadsorption inhibition (HAdI) processes are often used. Both
complement fixation
The complement fixation test is an immunological medical test that can be used to detect the presence of either specific antibody or specific antigen in a patient's serum, based on whether complement fixation occurs. It was widely used to diagnos ...
, neutralisation and
enzyme linked immunosorbent assay
The enzyme-linked immunosorbent assay (ELISA) (, ) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay uses a solid-phase type of enzyme immunoassay (EIA) to detect the presence ...
s – ELISA, can also be used to aid in the process of distinguishing between viral
serotypes.
Morbidity and mortality
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 and
immuno-compromised
Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
). Long term changes can however be associated with airway remodelling and are believed to be a significant cause of morbidity. The exact associations between HPIVs and diseases such as
chronic obstructive pulmonary disease (COPD) are still being investigated.
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 as
malnutrition and other deficiencies may further elevate the chances of mortality associated with infection.
Overall, LRI's cause approximately 25–30% of total deaths in preschool children in the developing world. HPIVs is believed to be associated with 10% of all LRI cases, thus remaining a significant cause of mortality.
Risk factors
Numerous factors have been suggested and linked to a higher risk of acquiring the infection, inclusive of
malnutrition,
vitamin A deficiency
Vitamin A deficiency (VAD) or hypovitaminosis A is a lack of vitamin A in blood and tissues. It is common in poorer countries, especially among children and women of reproductive age, but is rarely seen in more developed countries. Nyctalopia (ni ...
, absence of breastfeeding during the early stages of life,
environmental pollution and overcrowding.
Prevention
Despite decades of research, no
vaccines currently exist.
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 be
immunogenic and well tolerated against HPIV-3 in
phase I trials
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
. HPIV-1 and -2 vaccine candidates remain less advanced.
Vaccine techniques which have been used against HPIVs are not limited to intranasal forms, but also viruses
attenuated by cold passage, host range attenuation, chimeric construct vaccines and also introducing mutations with the help of reverse genetics to achieve attenuation.
Maternal
antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
may offer some degree of protection against HPIVs during the early stages of life via the
colostrum in breast milk.
Medication
Ribavirin is one medication which has shown good potential for the treatment of HPIV-3 given recent
in-vitro tests (
in-vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and pl ...
tests show mixed results).
Ribavirin is a broad-spectrum
antiviral, and as of 2012, was being administered to those who are severely
immuno-compromised
Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
, despite the lack of conclusive evidence for its benefit.
Protein inhibitors and novel forms of medication have also been proposed to relieve the symptoms of infection.
Furthermore,
antibiotics may be used if a secondary bacterial infection develops.
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...
treatment and
nebulizers are also a first line choice against
croup
Croup, also known as laryngotracheobronchitis, is a type of respiratory infection that is usually caused by a virus. The infection leads to swelling inside the trachea, which interferes with normal breathing and produces the classic symptoms o ...
if breathing difficulties ensue.
Interactions with the environment
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.
Environmental factors which are important for HPIV survival are
pH,
humidity,
temperature and the
medium 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.
The majority of transmission has been linked to close contact, especially in
nosocomial infections
A hospital-acquired infection, also known as a nosocomial infection (from the Greek , meaning "hospital"), is an infection that is acquired in a hospital or other health care facility. To emphasize both hospital and nonhospital settings, it is ...
. Chronic care facilities and doctors' surgeries are also known to be transmission 'hotspots' with transmission occurring via
aerosols
An aerosol is a suspension of fine solid particles or liquid droplets in air or another gas. Aerosols can be natural or anthropogenic. Examples of natural aerosols are fog or mist, dust, forest exudates, and geyser steam. Examples of anthrop ...
, large droplets and also
fomites (contaminated surfaces).
The exact infectious dose remains unknown.
Economic burden
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 on
extrapolation) in the region of $200 million per annum.
References
Further reading
*
Human Parainfluenza Viruses (HPIVs)
External links
– information provided by the
CDC
The Centers for Disease Control and Prevention (CDC) is the National public health institutes, national public health agency of the United States. It is a Federal agencies of the United States, United States federal agency, under the United S ...
{{DEFAULTSORT:Human Parainfluenza Viruses (hPIV)
Respiratory diseases
Rubulaviruses
Paramyxoviridae
Viral respiratory tract infections
Atypical pneumonias