Variola Virus

Smallpox Clinical Syndromes

5-17 day incubation period, there is high fever, fatigue, headache, backache, and malaise followed by rash in mouth and then body. Vomiting, diarrhea, and excessive bleeding soon follow. The simultaneous outbreak of the vesicular rash distinguishes it from varicella-zoster which erupts in successive crops. 

What diseases are caused by Variola?

Variola Virus

Diseases contracted by farm animal handlers.

Orf (peudocowpox) - (poxvirus of sheep and goats) resulting from direct contact w/ animal lesions. A single granulomatous lesion forms.

Vaccinia (Cowpox) - A single nodule appears at point of contact and is hemorrhagic

 Lesions can be mistaken for anthrax and usually regress in 25-35 days. 

Largest of the DNA viruses (230nmx300nm). Ovoid or brick shaped with a membrane-enveloped core, lateral bodies and an outer membrane envelope. 

Carry enzymes such as DNA dep RNA pol.

Circular ds DNA Chromosome.

It is unique to other DNA viruses in that it replicates entirely in the cytoplasm. Replicates in inclusion bodies called "Gaurnieri."

After the virus enters the cell, the packaged-enzyme uncoatase removes the membrane around the core.

Viral core has RNA pol, polyadenylate and capping enzymes, and transcription initiators.

It is contracted through inhalation-> Replicates in the upper respiratory tract (asymptomatic)-> moves into the lymphatics through infected macrophages-> disseminates to the lymph nodes, spleen, liver, bone marrow and skin through Secondary Viremia-> Causes hemorrhaging of small blood vessels in the dermis giving rash and pox.

This virus also produces proteins which reduce the production of IFN and Ab's, and it will spread from cell to cell to avoid detection by the immune system. 

Develops due to direct contact with lesions. A lytic infection develops, and it created small wart-like lesions that do not spread extensively.

These lesions are typically found on the trunk, genitals and extremities.

Incubation time is 8-20 weeks.

"Fifth disease"

erythema infectiosum

Caused by B19.

• Smallest of the DNA viruses (18-23nm).
• It is nonencapsulated-icosahedron, with a single ssDNA genome. 
• These genomes can packaged as either + or -sense
• The genome encodes 3 structural and 2 nonstructural proteins

1. Parvovirus has receptors of the blood group P antigen on erythroid precursors, mediating its entry and uncoating.
2. The ssDNA is then taken to the nucleus.
3. The complimentary strand will only be synthesized if the cell is in S phase (some necessary factors are present)
4. The ssDNA has an IRS sequence (inverted repeat sequence) that will fold over to serve as the primer for DNA pol→dsDNA
5. The 2 nonstructural and the 3 structural proteins (VP1, VP2 and VP3) are made in the cytoplasm.
6. Packaging is completed upon cell lysis.

• Phase 1: the febrile stage, and the patient is infectious. The viruses replicates in the upper respiratory tract and erythroid cells in the bone marrow. This is the first week of infection, and the production of erythrocytes in halted. After 8 days, a large viremia occurs, releasing virions into the oral and respiratory secretions.
• Phase 2: this "symptomatic phase" is mediated by antibodies, and B19 is eliminated. The symptoms are rash and arthralgia (painful joints).  

• 65% of the adult population had contracted B19 by age 40.
• The disease presents as erythema infectiosum in children and as arthralgia and arthritis in adults.
• Spread by respiratory droplets and oral secretions

1. Clinical Syndromes: Erythema infectiosum
2. In Adults?
3. Aplastic Crisis. Who should be concerned?
4. Hydrops fetalis

1. For first 7-10 days, it is prodromal with no symptoms(contagious). Culminates in "slapped appearance" on the cheeks and subsides in 1-2wks.
2. Polyarthritis (rarely get the rash).
3. Hemolytic anemia cases, such as Sickle-cell patients, can be at risk of complete decimation of their erythrocytes=reticulocytopenia. This syndrome is caused by a combination of the killed erythroid precursors by B19, and the fact that their cells already have the tendency to hemolyse (anemia)
4. Is anemia and heart failure of a fetus. This occurs when B19 crosses the placenta of a seronegative mother. No effect on seropositive mothers.

Diagnosis is made by clinical presentation.

There is no treatment.

• There is a (-) sense ssRNA associated with: nucleoprotein (NP), polymerase phosphoprotein (P) and large protein (L).
• F promotes fusion to membranes, hemolysis and viral entry. Requires proteolytic cleavage for fusion of membranes.
• Hemagglutinin-neuraminidase (HN), hemagglutinin (H) and G promote viral attachment. 
• Note: it will always be F with one of the other 3.

1. HN, H or G will bind to a sialic-acid residue on a glycoprotein= either CD46 (a protein which inhibits complement fixation on self) or CD150 SLAM (signaling lymphocyte activating molecule- which regulate TH1 and TH2 responses). Measles disrupts the function of both.
2. RNA pol is part of the nucleocapsid, and replication takes place in the cytosol. Copies several mRNA and full-length (+)ssRNA (that serve as templates for the synthesis of (-) ssRNA that is packaged).
3.  Genomes then associate with L, N, and NP to form nucleocapsids which associate with M (matrix) protein on viral glycoprotein-modified PMs. Mature virions then bud.

In unvaccinated areas, it is a common disease-> can be deadly

Before 1960, 90% of US population got it.

It is passed through respiratory droplets.

1. 7-13 day incubation period where the patient has typical CCC and P (cough, coryza, conjunctivitis and photophobia) of a bad cold
2. 2 days after this, Koplik spots appear on the buccal mucosa (near molars on inside of cheeks). Described as grains of salt surrounded by a red halo. Lesions subside in 1-2 days.
3. 12-24 hours after Koplik spots, exanthema erupts (Maculopapular rash) beneath ears and will cover the entire body in 1-2 days. Fever is highest now.

1. Giant cell pneumonia without a rash in T Cell-deficient children.
2. Encephalitis - rare (0.5%), but 15% mortality - is caused by: 1.) direct infection of the neurons, 2.) Post-infectious encephalitis= immune-mediated 3.) Subacute Sclerosing Panencephalitis (sspe)= caused by a defective measels virus produced during the acute phase (neurologic problems worsen over the years after the infection).
3. Atypical measles is caused by prior sensitization with insufficient protection (people who received older inactivated vaccination). This can enhance the immunophathogenic response to wild measles virus. The illness begins abruptly and is more intense. 

Usually done easily upon inspection.

You can also see syncytia with Giemsa staining.

There is also a 4x increase in measles Ab in titer.

Most children are given an attenuated live virus before age 2 along with mumps and rubella (MMR).

Since there is only one serotype for this disease (it only infects humans), it is a good candidate for eradication. 

There are no antiviral treatments.

What disease does Rubella virus cause?

What Class is rubella in?

What is the model virus for this class?

German Measles

Togavirus

Alphavirus

+ssRNA within an icosahedral capsid.

Has an envelope that is very tight due to the membrane glycoprotein C terminus interacting with the capsid, taking on the icosahedral shape.

45-75nm

They are zoonoses typically spread by arthropods

Live in many animals.

1. The virus enters the cell by R' mediated endocytosis.
2. The viral membrane fuses with the endosomal membrane once the endosome becomes acidic
3. the (+)ssRNA acts as mRNA and binds to ribosomes
4. The first 2/3 of the genome (42S early RNA) are synthesized as 4 individual proteins: NSPs 1-4 (nonstructural proteins) Which are components of the RNA pol.
5. The RNA pol synthesizes the last 1/3 of the genome (26S late RNA) which encodes the E1-E3 membrane glycoproteins, the capsid (C) proteins.
6. The RNA pol also synthesizes new copies of the (+)ssRNA genome
7. The C proteins (1st) and E proteins are assembled and glycosylated in the ER. 
8. The capsid is released from the ER, where the C proteins interact with the ssRNA genome, encapsulating it.
9. The E proteins are moved to the golgi, and expressed on the PM.
10. New virions bud.

It is contracted through respiratory droplets, and causes no readily detectable cytopathological effects.

The main worry the cause of congenital cataracts in infected pregnant mothers.

1. Describe the pathogenesis of Rubella virus.
2. In the fetus?

1. It infects upper respiratory tract and spreads to lymph nodes (lymphadenopathy) followed by viremia. Infections of other tissue and mild rash result. 
2. Virus not cytolytic. However normal growth, mitosis and chromosomal structure are altered in fetus producing teratogenic effects. 

Abs are generated after viremia, and its appearance correlates with the appearance of rash. Only one serotype, and lifelong immunity results. Immune complexes cause rash and arthralgia. 

1. Virus is normally benign in children. After a 14-21 day incubation period symptoms are a 3-day maculopapular or macular rash and swollen glands. 
2. Infection in adults is more severe and includes arthralgia and arthritis and sometimes thrombocytopenia or postinfectious encephalopathy.
3. Congenital disease in newborns is the chief concern = cataracts, retardation and deafness.

RT-PCR can be used to detect it.

IgM and a 4x increase in IgG titer are also indicative.

No treatment available.

Best option is to vaccinate w/ live cold-adapted RA27/3 vaccine strain (MMR) at 2yrs.

Only one serotype so eradication is possible.

Chickenpox

Upon recurrence: shingles and herpes zoster.

VZ and HSV are both members

Latent infection of neurons

Importance of cell-mediated immunity

Blister-like lesions

Like HSV, VZ produces thymidylate synthase, and is therefore susceptible to antiviral therapy.

Where does the Varicella Zoster virus replicate?

How does it spread throughout the body>

VZ spreads and replicates in the respiratory tract.

Viremia after replication in the respiratory tract will lead to skin lesions (chickenpox etc).

Replicates slower and in fewer cells than HSV.

Unlike HSV, latently-infected cells produce a detectable protein.

1. Primary infection begins in tonsils and mucosa
2. Spreads through blood and lymph to the reticuloendothelial system.
3. 11-13 days later, a secondary viremia spreads the virus throughout entire body and skin.
4. Virus overcomes IFN-a, and transmits from cell to cell, except for terminally-differentiated epithelial cells,
5. Blister forms here, and is the infectious point
6. In the event of recurrence, the virus will travel back down this neural pathway and present as herpes zoster or shingles

IFN-α is important to minimize the tissue spread of VZ, but Ab's are important in preventing viremic spread.

Passive immunization with VZ immune globulin (VZIG) is protective if done within 4 days of infection.

Adults have higher cell-mediated responses, therefore they have much worse reaction than children (especially in the lung).

Waning immune system is the reason for the recurrence of VZ late in life as shingles.

VZ can be passed through respiratory route or through direct contact.

Parents are contagious with or without symptoms.

This is a life-long disease.

Has similar CPEs to HSV (takes longer for them to show up with VZ)

Show Cowdry type A Bodies and syncytia.

Isolation of the virus is not done because it is labile in transport, and crusted-over skin tests negative.

Can use ELISA for serological analysis.

Human Herpes Virus 6 (HHV6)

Childhood disease is called exanthema subitum "Roseola" - caused by HHV6B or HHV7

Infection occurs early in life.

Virus replicates in the salivary gland, and is shed and transmitted in saliva.

HHV6 like CMV, infects lymphocytes, monocytes, epithelial cells, and neurons. It establishes a latent infection in T cells and monocytes. Infected cells appear large and have inclusions.

Likely to become activated in AIDS patients. 

1. Characterized by high fever of a few days followed by generalized rash that lasts 1-2 days. DTH (delayed-type hypersensitivity) cells in skin may be cause of rash. The disease is controlled by cell mediated immunity but there is a lifelong latent infection of T cells. 
2. May cause a mononucleosis syndrome and lympadenopathy.
3. Associated with multiple sclerosis and Chronic fatigue syndrome

Divide the exanthematous viruses into:

DNA viruses

RNA viruses