Parainfluenza virus

Human Parainfluenza Virus
Virus classification
Group: ssRNA

Description and Significance

Upper and lower respiratory tract diseases in humans are mostly caused by Human Parainfluenza Viruses and as a group are called “Parainfluenza.” Human Parainfluenza Viruses are the second most common respiratory tract diseases while Respiratory Synctial Virus (RSV) is the first most common cause of upper and lower respiratory tract infections especially in infants and young children. It is less common among adults. HPIVs are Paramyxoviruses. Paramyxoviruses belong to Paramyxoviridae family of Mononegavirales order, which are negative sense single stranded RNA (-ssRNA) viruses meaning they are responsible for many diseases in humans and animals.

Genome Structure

The genome of the HPIVs is a non segmented negative sense single stranded RNA (-ssRNA) consisting of 15, 461 nucleotides. Negative sense RNA first make positive sense RNA through copying their genomes by RNA polymerase. The positive sense RNA molecule is translated into proteins acting as viral mRNA. Thus more –ssRNA are produced when the resultant proteins direct the synthesis of new virions such as capsid proteins and RNA repilcases.

Virus Structure and Metabolism

The Human Parainfluenza Virus consists of a nulceocapsid and an envelope with an average diameter of 120-300 nm. The nucleocapsid is a tubelike structure with helical symmetry and 12-18 nm in width. It contains the ssRNA molecule, the phoshphoprotein P, the major nucleoprotein NP and the RNA polymerase L protein. The L protein is necessary for viral transcription, P protein takes part in RNA synthesis and NP helps to maintain the genome structure. The envelope is a double layered membrane. The outer layer is covered with spikes which consist of lipoproteins and glycoproteins whereas the inner layer contains non glycosylated matrix protein M. The spikes's glycoproteins contain hemagglutinin neuraminidase HN and the cell fusion protein F. Viruses acquire the energy from host cells to grow and reproduce. Hemagglutinin in the HPIV’s outer layer spikes attaches the virus to the host cell’s neuraminic acid receptor and F protein facilitates the fusion of virus into the host cell membrane. Since –ssRNA cannot serve as a messenger, so the L protein, a transcriptase, transcribes the positive sense RNA from the viral genome (-ssRNA). The positive sense RNA serves as mRNA and P protein facilitates the protein synthesis by ribosomes and more –ssRNA strands are produced which are enveloped in double layered membrane. It is stated, “P protein directs the viral protein synthesis and are copied into negative-sense RNA strands which are integrated in the new virions. For envelopment, the virus-specific glycoproteins accumulate in the cell membrane. Assembly is completed by budding of the nucleocapsid through the cell membrane studded with glycoproteins.”

Ecology

HPIVs are pathogens and cause number of diseases since they belong to the paramyxoviridae family and all members of this family cause significant diseases. Kelly J. Henrickson states that “In fact this virus family is one of the most costly in terms of disease burden and economic impact to our planet.” (p : 243) HPIV is strongly affected by environmental conditions such as temperature, pH, humidity and the composition of the medium in which it is stored/grown. As temperature increases from 37°C, its survival decreases and it is inactivated within 15 minutes as the temperature approaches to 50°C. It is stable at lower temperatures such as 4°C and even when it is frozen at -70°C. Freezing might kill the virus or may harm its infectivity but even if a very small amount of infectivity survives, it is enough for the virus to recover. It can be recovered even after 26 years of being frozen. Reagents like bovine serum albumin, skim milk, dimethyl sulfoxide can help the virus in surviving for a long time if they are added into the virus’s culture before freezing. The optimal pH for the Virus’s stability is physiologic pH 7.0 to 8.0 while it loses its stability at pH 3.0 to 3.4, under low humidity and with virus desiccation.

Pathology

When HPIV infects the body, the respiratory tract secretes inflammatory cytokines such as interferon-alpha (IFN), interleukin (IL-2 and IL-6,) and tumor necrosis factor alpha (TNF). Certain chemokines such as RANTES (regulated upon activation, normal T-cell expressed and secreted), macrophage inflammatory protein (MIP)–K have been detected in the nasal secretions. These are responsible for pathological changes in the respiratory tract and mark the onset of illness. The main pathological features of HPIV infection are airway inflammation, necrosis and sloughing of respiratory epithelium, edema, excessive mucus production, and interstitial infiltration of the lungs.

There are four serotypes of HPIV, HPIV-1, HPIV-2, HPIV-3 and HPIV-4. HPIV-4 has two sub types, HPIV-4a and 4b. Dr. Subhash Chundra Parija discusses the most common diseases caused by different serotypes of HPIVs in correlation with each other:

Croup:. In croup, vocal cords, trachea, bronchi and larynx swell due to the mucous secretions which cause laryngeal obstruction, fever, hoarse barking cough and aspiratory stridor. HPIV-1, 2, and 3 are the most frequent causes of croup. They account for almost 75% of all cases but only HPIV-1 is responsible for 18% of all croup cases and is considered the most common cause.

Bronchiolitis: Bronchiolitis is inflammation of the bronchioles. HPIV-1 and 3 are the most common cause of bronchiolitis, even though all four serotypes can be the cause. Bronchiolitis occurs mostly during the first year of life (which is 81% of the cases). The major symptoms are expiratory wheezing, rales, trachea retraction, air trapping and fever.

Pneumonias: Pneumonia is an inflammation of the lungs due to abnormal alveolar filling with fluid. Like bronchiolitis, HPIV-1 and 3 are the main causes of Pneumonia. Large percentage of hospitalized pneumonia patients are affected by HPIV-3 but each of the two viruses causes almost 10% of outpatient pneumonia cases. Pneumonia’s major symptoms are rales, fever and evidence of pulmonary consolidation.

Tracheobronchitis: Inflammation of the upper respiratory system in dogs refers to tracheobronchitis and is a highly contagious disease. It is also called “Kennel Cough” More than 25% of the causative agents of tracheobronchitis are HPIVs. All four HPIV types cause the tracheobronchitis but HPIV-3 and 4 are the major causes rather than HPIV-1 and 2.

Other infections: In routine, phyrngitis, conjunctivitis coryza and otitis media can occur with a lower respiratory tract infection or singly by HPIVs. Otitis media mostly causes by HPIV-3.

Infections in immune-compromised patients: The patients who receive intense immune-suppression after they undergo any organ or bone marrow transplantation have a higher risk to develop HPIV infection. Dr. Subhash states, “HPIV-2 causes giant cell pneumonia in persons with severe combined immunodeficiency diseases (SCIDs), and HPIV-3 has been found in persons with SCIDS and acute myeloid leukemia (AML) and in patients who have undergone bone marrow transplantation (BMT). The natural history of HPIV in patients infected with HIV is generally less severe than that in transplant recipients.”

Current Research

A daring treatment and a successful outcome: The need for targeted therapies for pediatric respiratory viruses

This article is about the fact that we need to develop targeted antiviral compounds for HPIVs rather than relying on untested, unproven and partially activated agents. Dr. Stankova treated a child with ribavirin for HPIV-3 infection. The patient had undergone two stem cell transplantations and was suffering with HPIV-3 infection. Dr. Stankova gave her ribavirin for 10 months. The patient recovered from the disease and never developed any severe respiratory disease again. Since there isn’t any vaccine or specific medicine for HPIVs treatment, Dr. Stankova wants to take the daring step of using ribavirin as a treatment for HPIV-3 infected patients but the authors of the article, Patricia DeLaMora and Anne Moscona are against this notion. They argue that ribavirin cannot be used as a treatment for HPIV-3 on regular basis because of its conflicting clinical data and uncertainty in most cases. They say that the child was treated with ribavirin for upper respiratory tract infection with HPIV-3 which also leads to the lower respiratory tract infection. The child, however did develop a lower respiratory tract infection and Dr. Stankova did not explain anything on the role of ribavirin in preventing progression of disease form upper respiratory tract infection to lower respiratory tract infection. They also say, “Published reports do not suggest a strong link between ribavirin use in cases of HPIVs infection and improved out come and there was no difference in mortality for treated and untreated patients suffering with HPIVs.” (p :121, 122)

They suggest that targeted antiviral compounds for HPIVs can be developed. They say that their research shows that the binding of viral hemagglutinin-neuraminidase (HN) protein to the host cell is a critical step which activates the fusion (F) protein to fuse the virus into the host cell. If this step is interrupted, host’s cell can be saved from the virus attack. They have identified the specific receptor interacting sites on HPIV-3 and believe that the binding inhibitors can be designed specifically to fit into the globular head of HN which will prevent the virus from attaching to the host cell and thus from the attack of HPIV disease. They suggest further that specific peptides can be designed to prevent F protein from activation. They say that, “These several potential therapeutic targets are being actively pursued. It is to be hoped that future dedicated physicians like Stankova et al. will not have to rely on a long shot or a guess, but will have at the ready several strategies to protect and treat children with parainfluenza virus infection.” (p :122)

Human Parainfluenza Type 4 Infections, Canada

In this study Dionne, Moisan and other researchers have discussed some virologic characteristics and clinical manifestations associated with HPIV-4 infections at their hospital in Canada during 2004-2005. They say that this is a rare pathogen and it is associated with mild illness but they also found evidences where HPIV-4 caused severe infections. From October 20, 2004 - March 8, 2005, they found 9 respiratory specimens positive for HPIV-4 and it was detected as a severe disease causing virus. Out of these 9 patients, 6 were children with acute bronchiolitis, less than 5/6 months old and one of them, 1.5 month old, had to stay in an intensive care unit. Among 3 of the adults, one was 25 years old and other two were above 80. The 25 year old man was suffering with pharyngitis and buccal ulcerative lesions, the 90 year old woman had a flulike illness and the 84 year old woman was suffering with severe bronchospasm and pulmonary edema. They had to stay in the hospital, were given antimicrobial drugs and eventually recovered.

The reasons for this virus considered to be rare is that it is isolated only occasionally from respiratory tract infections. The previous methods used to detect the virus are not useful due to the virus’s slow growth in LLC-MK2 cell culture and hemadsorption reaction is also occasionally weak. It was lately found that the RT-PCR method is useful for HPIV-4 detection because of the RT-PCR methods. It was also found that HPIV-4 was responsible for 43% of all HPIVs isolated in the laboratory during 2004-2005.

Parainfluenza virus 4 detection in infants.

This study states the importance of the use of the real time PCR method for detection of HPIV-4 infections. It says that the real time PCR detected the HPIV-4 infections in infants which were undetected by viral cultures.

The first child was a 5 week old infant with rhinitis and developed tachypnoea, dyspnoea and cyanosis. Her heart beat was 170 per minute, her chest X-ray showed hyperinflation with atelectasis of right middle lobe, and she had a productive cough and rhinorrhea with a clear nasal discharge. The other child was 14-months old and was suffering with persistent rhinitis, productive cough, fever, and weight loss due to vomiting. Both children’s nasal wash were tested in cell cultures and real time PCR. The cell culture did not show any viral detection but the PCR results were positive for the HPIV-4 infection. The one reason for infrequent detection of HPIV-4 is that the cell culture is less sensitive than for the other HPIVs while the other reason is that HPIV-4 might be the cause of severe illness like pneumonia and bronchiolitis when its diagnosis is done.

This study tells that now real time PCR is using preferentially for the detection of respiratory tract disease is because of its rapid and sensitive results. If PCR is not used, almost more than 50% of the respiratory infections may be undiagnosed. It is stated, “PCR is able to expand the number of infections detected and reduce the patients with no viral infection detected. An example of this is human metapneumovirus (hMPV), which is poorly detected by other methods.” (p. 529). Since immune-compromised patients have higher risk to develop life threatening pneumonia due to HPIV-4 infection, it is indispensable to use PCR for quick infection detection so that treatment can be provided on time.