Poxviridae

Introduction Poxviruses are the largest and most complex of viruses. The family encompasses a large group of agents that are similar morphologically and share a common nucleoprotein antigen. Infections with most poxviruses are characterized by a rash, although lesions induced by some members of the family Even though smallpox was declared eradicated from the world (in 1980) after an intensive campaign coordinated by the World Health Organization, there is concern that the virus could be reintroduced as a biologic weapon.

Properties of Poxviruses
Important properties of the poxviruses are listed in Table 1.
Virion: Complex structure, oval or brick-shaped, 400 nm in length x 230 nm in diameter; external surface shows ridges; contains core and lateral bodies

Composition: DNA (3%), protein (90%), lipid (5%) Genome: Double-stranded DNA, linear; size 130375 kbp; has terminal loops; has low G + C content (3040%) except for Parapoxvirus (63%)

Proteins: Virions contain more than 100 polypeptides; many enzymes are present in core, including transcriptional system Envelope: Virion assembly involves formation of multiple membranes Replication: Cytoplasmic factories Outstanding characteristics: Largest and most complex viruses; very resistant to inactivation Virus-encoded proteins help evade host immune defense system Smallpox was the first viral disease eradicated from the world

Structure & Composition

Poxviruses are large enough to be seen as featureless particles by light microscopy. By electron microscopy, they appear to be brick-shaped measuring about 400 x 230 nm. Their structure is complex and conforms to neither icosahedral nor helical symmetry. The external surface of particles contains ridges. There is an outer lipoprotein membrane, or envelope, that encloses a core and two structures of unknown function called lateral bodies

 Classification  Poxviruses are divided into two subfamilies based on whether they infect vertebrate or insect hosts.  The vertebrate poxviruses fall into eight genera, with the members of a given genus displaying similar morphology and host range as well as some antigenic relatedness.  Most of the poxviruses that can cause disease in humans are contained in the genera Orthopoxvirus and Parapoxvirus; there are also several that are classified in the genera Yatapoxvirus and Molluscipoxvirus (Table 2)

Table 2. Poxviruses Causing Disease in Humans.

Genus Orthopoxvirus Virus Variola Vaccinia Buffalopox Monkeypox Cowpox Parapoxvirus Primary Host Humans Humans Water buffalo Disease Smallpox (now eliminated) Localized lesion; used for smallpox vaccination

Human infections rare; localized lesion Rodents, monkeys Human infections rare; generalized disease Cows Human infections rare; localized ulcerating lesion Human infections rare; localized lesion Many benign skin nodules Human infections rare; localized lesion Human infections very rare and accidental; localized skin tumors

Orf Sheep Pseudocowpox Cows Bovine papular stomatitis Cows Tanapox Yabapox Monkeys Monkeys

Molluscipoxvirus Molluscum contagiosum Humans Yatapoxvirus

Poxvirus Replication
The replication cycle of vaccinia virus is summarized in Figure. Poxviruses are unique among DNA viruses in that the entire multiplication cycle takes place in the cytoplasm of infected cells. It is possible, however, that nuclear factors may be involved in transcription and virion assembly. Poxviruses are further distinguished from all other animal viruses by the fact that the uncoating step requires a newly synthesized, virusencoded protein. The "uncoating" protein that acts on the cores is among the more than 50 polypeptides made early after infection. The second-stage uncoating step liberates viral DNA from the cores; it requires both RNA and protein synthesis. The synthesis of host cell macromolecules is inhibited at this stage.

Pathogenesis & Pathology of Smallpox

The portal of entry of variola virus was the mucous membranes of the upper respiratory tract. After viral entry, the following are believed to have taken place: (1) primary multiplication in the lymphoid tissue draining the site of entry; (2) transient viremia and infection of reticuloendothelial cells throughout the body; (3) a secondary phase of multiplication in those cells, leading to (4) a secondary, more intense viremia; and (5) the clinical disease. By the sixth to ninth days, lesions in the mouth tended to ulcerate and discharge virus. Thus, early in the disease, infectious virus originated in lesions in the mouth and upper respiratory tract. Later, pustules broke down and discharged virus into the environment of the smallpox patient. Histopathologic examination of the skin showed proliferation of the prickle-cell layer. Those proliferated cells contained many cytoplasmic inclusions with mononuclear cells,

Pathogenesis & Pathology of Smallpox Clinical Findings

The incubation period of variola (smallpox) was 1014 days. The onset was usually sudden. One to 5 days of fever and malaise preceded the appearance of the exanthems, which began as macules, then papules, then vesicles, and finally pustules. These formed crusts that fell off after about 2 weeks, leaving pink scars that faded slowly. In each affected area, the lesions were generally found in the same stage of development (in contrast to chickenpox). A "Smallpox Recognition Card" prepared by the World Health Organization shows the typical rash. Lesions were most abundant on the face and less so on the trunk. In severe cases, the rash was hemorrhagic. The case-fatality rate varied from 5% to 40%. In mild variola, called variola minor, or in vaccinated persons, the mortality rate was under 1%.

Immunity
All viruses within the Orthopoxvirus genus are so closely related antigenically that they cannot be easily differentiated serologically. Infection with one induces an immune response that reacts with all other members of the group. An attack of smallpox gave complete protection against reinfection. Vaccination with vaccinia induced immunity against variola virus for at least 5 years and sometimes longer. Antibodies alone are not sufficient for recovery from primary poxvirus infection. In the human host, neutralizing antibodies develop within a few days after onset of smallpox but do not prevent progression of lesions, and patients may die in the pustular stage with high antibody levels. Cell-mediated immunity is probably more important than circulating antibody..

Laboratory Diagnosis
Several tests are available to confirm the diagnosis of smallpox. Now that the disease is presumably eradicated, it is important to diagnose any cases that resemble smallpox. The tests depend upon direct microscopic examination of material from skin lesions, recovery of virus from the patient, identification of viral DNA or antigen from the lesion, and, least importantly, demonstration of antibody in the blood.

 Picornaviruses represent a very large virus family with respect to the number of members but one of the smallest in terms of virion size and genetic complexity. They include two major groups of human pathogens: enteroviruses and rhinoviruses. Enteroviruses are transient inhabitants of the human alimentary tract and may be isolated from the throat or lower intestine. Rhinovirus Group Rhinoviruses are the common cold viruses. They are the most commonly recovered agents from people with mild upper respiratory illnesses. They are usually isolated from nasal secretions but may also be found in throat and oral secretions. These virusesas well as coronaviruses, adenoviruses, enteroviruses, parainfluenza viruses, and influenza viruses cause upper respiratory tract infections, including the common cold syndrome

Picornaviruses

Table 3. Important Properties of Picornaviruses.

Virion: Icosahedral, 2830 nm in diameter, contains 60 subunits Composition: RNA (30%), protein (70%) Genome: Single-stranded RNA, linear, positive-sense, 7.28.4 kb in size, MW 2.5 million, infectious, contains genome-linked protein (VPg) Proteins: Four major polypeptides cleaved from a large precursor polyprotein. Surface capsid proteins VP1 and VP3 are major antibody-binding sites. VP4 is an internal protein. Envelope: None Replication: Cytoplasm Outstanding characteristics: Family is made up of many enterovirus and rhinovirus types that infect humans and lower animals, causing various illnesses ranging from poliomyelitis to aseptic meningitis to the common cold.

Rhinovirus
Classification Human rhinovirus isolates are numbered sequentially. More than 100 species are known. Isolates within a species share more than 70% sequence identity within certain protein-coding regions. Human rhinoviruses can be divided into major and minor receptor groups. Viruses of the major group use intercellular adhesion molecule-1 (ICAM-1) as receptor and those of the minor group bind members of the lowdensity lipoprotein receptor (LDLR) family.

Pathogenesis
The virus enters via the upper respiratory tract. High titers of virus in nasal secretionswhich can be found as early as 24 days after . Thereafter, viral titers fall, although illness persists. In some instances, virus may remain detectable for 3 weeks. There is a direct correlation between the amount of virus in secretions and the severity of illness. Replication is limited to the surface epithelium of the nasal mucosa. Biopsies have shown that histopathologic changes are limited to the submucosa and surface epithelium. These include edema and mild cellular infiltration. Nasal secretion increases in quantity and in protein concentration. Rhinoviruses rarely cause lower respiratory tract disease.

 Immunity
Neutralizing antibody to the infecting virus develops in serum and secretions of most persons(ranged from 37% to over 90%). Antibody develops 721 days after infection; the time of appearance of neutralizing antibody in nasal secretions parallels that of serum antibodies. Because recovery from illness usually precedes appearance of antibodies, it seems that recovery is not dependent on antibody. However, antibody may accomplish final clearance of infection. Serum antibody persists for years but decreases in titer.

Treatment & Control

No specific prevention method or treatment is available. Antiviral drugs are thought to be a more likely control measure for rhinoviruses because of the problems with vaccine development. A 5-day course of high doses of intranasal interferon-alfa has been shown to be effective in preventing the spread of rhinoviruses .

Orthomyxoviruses
Introduction Respiratory illnesses are responsible for more than half of all acute illnesses each year in the United States. The Orthomyxoviridae (influenza viruses) are a major determinant of morbidity and mortality caused by respiratory disease, and outbreaks of infection sometimes occur in worldwide epidemics. Influenza has been responsible for millions of deaths worldwide. Influenza type A is antigenically highly variable and is responsible for most cases of epidemic influenza. Influenza type B may exhibit antigenic changes and sometimes causes epidemics. Influenza type C is antigenically stable and causes only mild illness in immunocompetent individuals

Table3. Important Properties of Orthomyxoviruses.1 Virion: Spherical, pleomorphic, 80120 nm in diameter (helical nucleocapsid, 9 nm) Composition: RNA (1%), protein (73%), lipid (20%), carbohydrate (6%) Genome: Single-stranded RNA, segmented (eight molecules), negative-sense, 13.6 kb overall size Proteins: Nine structural proteins, one nonstructural Envelope: Contains viral hemagglutinin (HA) and neuraminidase (NA) proteins Replication: Nuclear transcription; capped 5' termini of cellular RNA scavenged as primers; particles mature by budding from plasma membrane Outstanding characteristics: Genetic reassortment common among members of the same genus Influenza viruses cause worldwide epidemics

A comparison of influenza A virus with other viruses that infect the human respiratory tract is shown in Table 393. Influenza virus is considered here.

Table -4. Comparison of Viruses that Infect the Human Respiratory Tract.
Virus Disease Number of Serotypes Lifelong Vaccine Viral Latency Immunity Available to Disease Many Many One One One One Many Many Many No No No Yes Yes Yes No No No + + + + -

RNA viruses Influenza A virus Parainfluenza virus Respiratory syncytial virus Rubella virus Measles virus Mumps virus Rhinovirus Coronavirus Coxsackievirus

Influenza Croup Bronchiolitis Rubella Measles Parotitis, meningitis Common cold Common cold Herpangina, pleurodynia

DNA viruses Herpes simplex virus type 1 Epstein-Barr virus

Gingivostomatitis Infectious mononucleosis

One One One Many

No Yes Yes1

+ -

+ + + +

Varicella-zoster virus Adenovirus

Chickenpox, shingles Pharyngitis, pneumonia

No