ORTHOMYXOVIRUSES

Influenza Virus

Disease—

Influenza A virus causes worldwide epidemics (pandemics) of influenza, influenza B virus causes major outbreaks of influenza, and influenza C virus causes mild respiratory tract infections but does not cause outbreaks of influenza. Pandemics occur when a variant of influenza A virus that contains a new hemagglutinin against which people do not have preexisting antibodies

Characteristics—The two major antigens are the hemagglutinin (HA) and the neuraminidase (NA) on separate surface spikes. The function of the hemagglutinin is to bind to the cell surface receptor (neuraminic acid, sialic acid) to initiate infection of the cell. The neuraminidase cleaves neuraminic acid (sialic acid) to release progeny virus from the infected cell as well as degrades the protective layer of mucus in the respiratory tract

There are two types of antigenic changes:

1) Antigenic shift in these proteins as a result of reassortment of RNA segments accounts for the epidemics of influenza caused by influenza A virus. Influenza A viruses of animals are the source of the new RNA segments.

2) Antigenic drift due to mutations also contributes. The virus has many serotypes because of these antigenic shifts and drifts. The antigenicity of the internal nucleocapsid protein determines whether the virus is an A, B, or C influenza virus.

NB: Because influenza B virus is only a human virus, there is no animal source of new RNA segments. Influenza B virus therefore does not undergo antigenic shifts. It does, however, undergo enough antigenic drift . Influenza B virus has no antigens in common with influenza A virus.

 

 Influenza viruses have both group-specific and typespecific antigens.

(1) The internal ribonucleoprotein is the group-specific antigen that distinguishes influenza A, B, and C viruses.

(2) The hemagglutinin and the neuraminidase are the type-specific antigens located on the surface. Antibody against the hemagglutinin neutralizes the infectivity of the virus (and prevents disease), whereas antibody against the group-specific antigen (which is located internally) does not. Antibody against the neuraminidase does not neutralize infectivity but does reduce disease by decreasing the amount of virus released from the infected cell

Summary of Replicative Cycle

The virus adsorbs to the cell when the viral hemagglutinin interacts with sialic acid receptors on the cell surface.

The virus then enters the cell in vesicles and uncoats within an endosome. Uncoating is facilitated by the low pH within the endosome.

Protons pass through the ion channel formed by the M2 protein into the interior of the virion. This disrupts the virion envelope and frees the nucleocapsid to enter the cytoplasm and then migrate to the nucleus where the genome RNA is transcribed.

The virion RNA polymerase transcribes the eight genome segments into eight mRNAs in the nucleus. Synthesis of the eight mRNAs occurs in the nucleus because a methylated guanosine “cap” is required. The cap is obtained from cellular nuclear RNAs in a process called “cap snatching.”

Most of the mRNAs move to the cytoplasm, where they are translated into viral proteins. Some of the viral mRNAs remain in the nucleus, where they serve as the template for the synthesis of the negative-strand RNA genomes for the progeny virions.

Two newly synthesized proteins, NP protein and matrix protein, bind to the progeny RNA genome in the nucleus, and that complex is transported to the cytoplasm.

The helical ribonucleoprotein assembles in the cytoplasm, matrix protein mediates the interaction of the nucleocapsid with the envelope, and the virion is released from the cell by budding from the outer cell membrane at the site where the hemagglutinin and neuraminidase are located.

The neuraminidase releases the virus by cleaving neuraminic acid on the cell surface at the site of the budding progeny virions.

Pathogenesis— After the virus has been inhaled, the neuraminidase degrades the protective mucus layer, allowing the virus to gain access to the cells of the upper and lower respiratory tract epithelium. The infection is limited primarily to this area because the proteases that cleave the hemagglutinin are located in the respiratory tract.

 

PARAMYXOVIRUSES

Paramyxoviruses contains an RNA-dependent RNA polymerase, which transcribes the negative-polarity genome into mRNA. The genome is therefore not infectious. The envelope is covered with spikes, which contain hemagglutinin, neuraminidase, or a fusion protein that causes cell fusion and, in some cases, hemolysis

 

Measles Virus

Summary of Replicative Cycle

• After adsorption to the cell surface via its hemagglutinin, the virus penetrates and uncoats
• Virion RNA polymerase transcribes the negative-strand genome into mrna.
• Multiple mrnas are synthesized, each of which is translated into the specific viral proteins
• The helical nucleocapsid is assembled
• The matrix protein mediates the interaction with the envelope, and the virus is released by budding from the cell membrane.

Characteristics – Vitamin A supplementation greatly reduces the severity of measles. Patients with deficient cell-mediated immunity (e.g., AIDS patients) have a severe, life-threatening disease when they contract measles.

Pathogenesis—Initial site of infection is the upper respiratory tract. Virus spreads to local lymph nodes and then via the blood to other organs, including the skin. Giant cell pneumonia and encephalitis can occur. The maculopapular rash is due to cellmediated immune attack by cytotoxic T cells on virus-infected vascular endothelial cells in the skin.

Immunity — Lifelong immunity occurs in individuals who have had the disease. Maternal antibody passes the placenta, and infants are protected during the first 6 months of life.

Mumps Virus

Summary of Replicative Cycle – Replication is similar to that of measles virus

Pathogenesis— The virus infects the upper respiratory tract and then spreads through the blood to infect the parotid glands, testes, ovaries, pancreas, and, in some cases, meninges. Alternatively, the virus may ascend from the buccal mucosa up Stensen’s duct to the parotid gland. Lifelong immunity occurs in persons who have had the disease. Maternal antibody passes the placenta and provides protection during the first 6 months of life.

 

Respiratory Syncytial Virus

Characteristics—Unlike other paramyxoviruses, it has only a fusion protein in its surface spikes. The fusion protein causes cells to fuse, forming multinucleated giant cells (syncytia). It has no hemagglutinin.

Summary of Replicative Cycle – Replication is similar to that of measles virus

Pathogenesis—Infection involves primarily the lower respiratory tract in infants and is localized to the respiratory tract. Multinucleated giant cells caused by the viral fusion protein are a hallmark. Maternal antibody passed to the infant may react with the virus, form immune complexes, and damage the respiratory tract cells

 

Parainfluenza Virus

Characteristics—surface spikes consist of hemagglutinin (H), neuraminidase (N), and fusion (F) proteins. Unlike influenza viruses, the antigenicity of its hemagglutinin and neuraminidase is stable.

Summary of Replicative Cycle – Replication is similar to that of measles virus

Pathogenesis— These viruses cause upper and lower respiratory tract disease without viremia (virus in blood). Parainfluenza viruses 1 and 2 are major causes of croup.

 

CORONAVIRUSES

Characteristics—The receptor for the SARS coronavirus on the surface of cells is angiotensin converting enzyme-2.

Summary of Replicative Cycle

• The virus adsorbs to cells via its surface spikes (hemagglutinin), after which it enters the cytoplasm, where it is uncoated.
• The positive-strand genome is translated into two large polypeptides, which are self-cleaved by the virus-encoded protease.
• Two of these peptides aggregate to form the RNA polymerase that replicates the genome.
• In addition, mRNAs are synthesized, and then translated into the structural proteins.
• The virus is assembled and obtains its envelope from the endoplasmic reticulum. Replication occurs in the cytoplasm.

Pathogenesis—Infection is typically limited to the mucosal cells of the respiratory tract. At least 50% of infections are asymptomatic. Immunity is brief and reinfection occurs. Pneumonia caused by SARS coronavirus is characterized by diffuse edema in alveolar space resulting in hypoxia.

Update on: COVID – 19

 

TOGAVIRUSES

Rubella Virus

Characteristics—Its surface spikes contain hemagglutinin

Summary of Replicative Cycle

• After penetration of the cell and uncoating, the plus-strand RNA genome is translated into several nonstructural and structural proteins.
• One of the nonstructural rubella proteins is an RNA-dependent RNA polymerase, which replicates the genome first by making a minus-strand template and then, from that, plus strand progeny.
• Both replication and assembly occur in the cytoplasm, and the envelope is acquired from the outer membrane as the virion exits the cell.

Pathogenesis—The initial site of infection is the nasopharynx, from which it spreads to local lymph nodes. It then disseminates to the skin via the bloodstream. The rash is attributed to both viral replication and immune injury. During maternal infection, the virus replicates in the placenta and then spreads to fetal tissue. If infection occurs during the first trimester, a high frequency of congenital malformations occurs. Maternal antibody protects against fetal infection. Natural infection leads to lifelong immunity.

RHABDOVIRUSES

Rabies Virus

Summary of Replicative Cycle

• Rabies virus attaches to the acetylcholine receptor on the cell surface.
• After entry into the cell, the virion RNA polymerase synthesizes five mRNAs that code for viral proteins.
• After replication of the genome viral RNA by a virus encoded RNA polymerase, progeny RNA is assembled
• with virion proteins to form the nucleocapsid, and the envelope is acquired as the virion buds through the cell membrane.

Pathogenesis—Viral receptor is the acetylcholine receptor. Replication of virus at the site of the bite, followed by axonal transport up the nerve to the central nervous system. After replicating in the brain, the virus migrates peripherally to the salivary glands, where it enters the saliva. When the animal is in the agitated state as a result of encephalitis, virus in the saliva can be transmitted via a bite.

Within the central nervous system, encephalitis develops, with the death of neurons and demyelination. Infected neurons contain an eosinophilic cytoplasmic inclusion called a Negri body, which is important in laboratory diagnosis of rabies

Negri body:

Prevention—Preexposure prevention of rabies consists of the vaccine only.

Postexposure prevention consists of:

(1) Washing the wound

(2) Giving rabies immune globulins (passive immunization), mostly into the wound

(3) Giving the inactivated vaccine (active immunization) made in human cell culture. The decision to give the immune serum and the vaccine depends on the circumstances.

As much as possible of the RIG is given into the bite site, and the remainder is given intramuscularly.

Prevention of rabies in dogs and cats by using a killed vaccine has reduced human rabies significantly.

 

RETROVIRUSES

HUMAN T CELL LYMPHOTROPIC VIRUS

There are two important human retroviruses: human T-cell lymphotropic virus, which is described here, and human immunodeficiency virus (HIV)

Important Properties

• The virions of both HTLV and HIV contain a reverse transcriptase, integrase, and protease.
• The envelope proteins of HTLV are gp46 and gp21, whereas those of HIV are gp120 and gp41.
• However, HTLV does not kill T cells, whereas HIV does. HTLV causes malignant transformation that “immortalizes” the infected T cells and allows them to proliferate in an uncontrolled manner.

Summary of Replicative Cycle

• HTLV primarily infects CD4-positive T lymphocytes.
• Within the cytoplasm, reverse transcriptase synthesizes a DNA copy of the genome, which migrates to the nucleus and integrates into cell DNA.
• Viral mRNA is made by host cell RNA polymerase and transcription is upregulated by Tax protein.
• The Rex protein controls the synthesis of the gag/pol mRNA, the env mRNA, and their subsequent transport to the cytoplasm, where they are translated into structural viral proteins.
• Full-length RNA destined to become progeny genome RNA is also synthesized and transported to the cytoplasm.
• The virion nucleocapsid is assembled in the cytoplasm, and budding occurs at the outer cell membrane.
• Cleavage of precursor polypeptides into functional structural proteins is mediated by the virus-encoded protease.