BIOL 2421 Microbiology Lecture Notes: DNA Viruses

BIOL 2421 Microbiology Lecture Notes: DNA Viruses Dr. Weis

Nucleic Acid: DNA	Envelope	Capsid	Biosynthesis	Virus Family
ds	+	Icosahedron	nucleus	Herpesviridae
ds	+	Complex	cytoplasm	Poxviridae
ds	-	Icosahedron	nucleus	Adenoviridae
ds	-	Icosahedron	nucleus	Papoviridae
ds circular, RT	+	Icosahedron	nucleus	Hepadnaviridae

ss	-	Icosahedron	nucleus	Parvoviridae

HERPESVIRIDAE

Family name is taken from the Greek verb, herpein, meaning to “creep” which reflects the fact that this family of viruses often cause latent recurring infections which progress slowly. Reactivation may occur at any stage and can be frequent in occurrence.

Taxonomy

Subfamily Alphaherpesvirinae, Genera: Simplex virus, Varicellovirus

Subfamily Betaherpesvirinae, Genera: Cytomegalovirus, Muromegalovirus

Subfamily Gammaherpesvirinae, Genera: Lymphocryptovirus (herpes 4)

Genome: one molecule of ds DNA

Morphology: icosahedral capsule creating a spherical appearance

nucleocapsid surrounded by asymmetric tegument made up

of amorphous proteins and appears between the capsid and envelope.

Enveloped virus using inner nuclear membrane of host cell

Virus encoded glycoprotein spikes from surface of envelope

Types: 8 human serotypes

Human Herpesvirus 1 (Herpes simplex virus type 1, HSV1)

Human Herpesvirus 2 (Herpes simplex virus type 1, HSV2)

Syndrome: ulcers on gingiva, genitalia, lip, skin, KCS

Human Herpesvirus 3 (Varicella-zoster virus)

Syndrome: chickenpox [varicella]; shingles [zoster]

Human Herpesvirus 4 (Epstein-Barr virus)
Syndrome: Infectious mononucleosis, Burkitt’s lymphoma

Human Herpesvirus 5 (Cytomegalovirus)

Human Herpesvirus 6 (Human b lymphotropic virus) [Muramegalovirus]

Human Herpesvirus 7 (cryptic infection of T helper cell)

Human Herpesvirus 8 (Kaposi’s sarcoma in AIDS patients)

Herpes Simplex Virus:

HSV1 associated with oro-facial lesions

HSV2 associated with genital lesions

HSV

100% of adults have antibodies to HSV1

exposure usually in the first years of life

Virus shed from infected areas and spread occurs by direct contact

Primary infections are subclinical, vesicles develop 1-3 days post exposure

Gingivo-stomatitis most common form, inoculation via kissing

KCS – dendritic ulcers on cornea with conjunctivitis and edema

Genital Herpes- STD, eruptions last 10-14 days

Acute Necrotizing Encephalitis – temporal lobe infection, fatal

Summary of disease forms

Cutaneous – confined to skin, good prognosis

Generalized – disseminates to various organs, high fatality rate

Encephalitis – direct infection of brain tissue

Latent infections are established in the ganglia of sensory nerves that supply the site of the primary infection.

The virus exists as an episomal (plasmid) form as no viral genome is expressed. In oro-facial infections, the virus travels up the axon of the trigeminal nerve.

Latency may persist for years.

Reactivation: Virus travels down the axon to reinfect the skin or mucous

membrane in the area supplied by the nerve. Provoked by sunlight, stress,

Febrile illnesses, immunosuppression.

Clinical manifestations

* Cold sores @ muco-cutaneous junctions

* Genital herpes

* Keratitis

Laboratory Diagnosis: Culture and microscopy (EM)

Varicella Zoster Virus:

Varicella = Chickenpox

Zoster = Shingles

Varicella [chickenpox] is the primary infection. Common in childhood that presents as a mild febrile illness associated with generalized vesicular rash. Incubation 21 days. Lesions progress: macule -> papule->vesicle->pustule-> scab. Delayed infections in adults may be more severe with complications. Transmitted via direct contact or droplet. Latent infection in sensory ganglia. Complications:

* Post Infectious Encephalomyelitis

* Haemorrhagic Varicella – seen with immunocompromised patients

* Pneumonia – common in adults with chickenpox

Other Syndromes

* Congenital Varicella Syndrome: infants born to mothers who have varicella in early pregnancy causing mental retardation, atrophy

* Perinatal Varicella: infants born to mothers who acquire disease more than 5 days before delivery. If less than 5 days, neonate at risk.

Zoster (Shingles)

Reactivation of VZV often associated with immunosupression.

Virus travels down the axon and re-infects the dermatome supplied by the sensory ganglion, especially in the thoracic regions and those supplied by the trigeminal nerve.

Laboratory DX : EM, culture, Serology to detect specific IgM.

Therapy [Tx]:

Acyclovir a nucleoside anaologue of Guanosine. During viral DNA replication, the viral DNA polymerase incorporates Acyclovir into the growing DNA chain and interferes with DNA synthesis as it binds irreversibly to viral DNA polymerase and causing chain termination. Only HSV and VZV are sensitive to Acyclovir.

Cytomegalovirus (Herpesvirus 5)

Most individuals are infected early in life and by adulthood 70-90% of people have IgG antibodies. Virus is secreted in saliva and spread by direct contact or can be spread during blood transfusions. Following primary infection, virus becomes latent and may reactivate.

Syndromes:

* Congenital Infection

* Immunosuppressed Individuals

Congenital Infection: Mother becomes exposed to HCMV during pregnancy and infant at risk causing mental retardation and deafness. Can at time cause a generalized infection affecting the liver, spleen, bone marrow, and brain. Affected organs show enlarged cells [cytomegalo].

Immunosuppressed: Organ transplant patients and AIDS can develop life threatening diseases due to dissemination: interstitial pneumonia, retinitis, enteritis

DX: Immunofluoresence of antigen, Culture, Serology: IgM and IgG

Tx : Gancyclovir or Foscarnet [highly toxic drugs, use only in life threatening cases]

Epstein-Barr Virus (Herpesvirus 4)

Widespread infection, most individuals have antibodies by adulthood.

Virus latent form in B lymphocytes. Reactivation of virus – direct spread via saliva.

Syndromes:

Primary

* Infectious Mononucleosis: see below

* Chronic EBV infection: B cell latency, transforms B cell

* X-linked lymphproliferative syndrome : recessive, fatal

Reactivation

* Lympho-perliferative disorders in immunosuppressed individuals

* Burkitts Lymphoma

* Nasopharyngeal carcinoma

Infectious Mononucleosis

Incubation period 4-7 weeks

Route of infection: saliva

Signs: Lymphadenopathy, fever, sore throat, hepatomegaly, splenomegaly
DX: Paul-Bunnell Test – heterophile antbodies that agglutinate sheep RBCs

Serology: IgG or IgM to capsid antigen or IgG to nuclear antigens

Burkitt’s Lymphoma

High grade B cell lymphoma as EBV is a co-factor causing this malignancy

EBV transforms B cells

Co-factor action may be responsible for other cancers.

Nasopharyngeal carcinoma

Malignant tumor of squamous epithelium of nasopharynx.

Herpesvirus 6

* Lymphoproliferative disorders

* Roseola Infantum: febrile rash occurs in first few months of life

* Mononucleosis: cervical lymphadenopathy in adults

* Fourth Disease

Herpesvirus 7

* Cryptic infection of Helper T cells: fatal encephalitis

Herpesvirus 8

* Karposi’s sarcoma in AIDS patients

POXVIRIDAE

Family name taken from the major disease syndrome caused by this family of viruses, the pox, which is an elevated skin lesion.

Largest of all the viruses and considered to be an evolutionary intermediate between viruses and bacteria.

Structure:

Viral particles rounded to ovoid with an envelope. Complex structure consisting of a nucleoid, one molecule of linear ds DNA, enclosed within a biconcave core that is flanked by 2 lateral bodies. External coat is made up of lipids and tubular proteins that create a filamentous appearance.

Human Disease Syndromes:

Variola Virus: agent of smallpox, infect epithelial, endothelial: reticular, vascular

Monkey Pox: similar to small pox with added lymphadenopathy

Vaccinia Virus: used to vaccinate against small pox, creates localized pustule

Cowpox Virus: agent of cowpox, self-limiting disease, ulcerative vesicles on hands

Orf Virus: contagious pustular dermatitis of individuals who handle sheep/goats

Pseudocowpox: paravaccinai, epithelial cell infection, nonulcerative

Molluscum contagiosum virus: self limiting venereal epithelial cell infection

Yaba Monkey tumor virus: histocytoma of the head or lilmbs

Tanapox virus: tanapox, self limiting epithelial cell infection

Smallpox

Variola, Genus Orthopox

Only disease that has been globally eradicated, international vaccination program.

Source: direct or droplet from infected persons. No animal or vector. No latency

Incubation: 10-12 days

Syndrome: fever, macular rash on day three à vesicles which become pustular, ulcerated, scabbed, and healed with scarring.

Dx: EM of negatively stined vesicle fluid. Some culture in chick embryos.

ADENOVIRIDAE

The original virus in this group was isolated from adenoid tissue, thus the name adenovirus. The 89 members of this group have a linear ds DNA in a non enveloped icosahedral capsomer with12 penton fibers. These 12 surface protein projections of the nucleocapsid are distinct and extend like a long fiber shaft with a globular knob at the end. This fiber contains a hemagglutinin that is antigenically distinct for each serotype and the globular knob functions in attachment of the virus particle to the host cell. The fibers are easily detached during preparation. Adenoviruses that affect humans are usually mild pathogens that typically cause respiratory illness or conjunctivitis (“pink-eye”). Spread by direct contact or respiratory droplet. Animal pathogens are more severe.

Adenovirus serotypes 3,7,14,21: cause Acute respiratory Distress (ARD), common cold

Adenovirus serotypes 11, 21 causes acute hemorrhagic cystitis

Adenovirus serotypes 8,11,19,37 causes epidemic keratoconjunctivitis

Adenovirus serotypes 40, 41 causes gastroenteritis

Adenovirus serotypes 1,2,3,5 causes hepatitis

PAPOVIRIDAE

The family name is taken from the disease caused by the members of this group: Papilloma, Polyoma, and Vacuolating viruses. These are small viruses with circular ds DNA in a noneveloped icosahedron capsid. The 72 capsomers are mixed: there are pentavalent capsomeres at the 12 vertices and hexavalent capsomeres that make ups the remaining 60 capsomeres. Members of this family include:

Papilloma virus: causes papilloms (warts) by infecting and causing hyperplasia of the squamous epithelial cells.

BK virus: causes a nephritis and / or urethritis

JC virus: causes progressive multifolcal leukoencephalopathy

Human Papilloma Virus [HPV]

Spread by direct contact through damaged epithelial cells

Narrow host [humans] and tissue specificity: germinal epithelium

80 different types based on DNA sequencing. 3 major groups of HPV’s

1) Cutaneous warts

2) Epidermodysplasia verruciformis

3) Mucosal HPV infections

Cutaneous Warts

HPV types 1-4, 7, 10, 26-38

This virus causes benign tumor (warts) of keratinized squamous epithelia.

In most people, skin warts regress spontaneously

This cutaneous group has been classified traditionally according to clinical

Appearance and location. The four clinical types are:

a) Verruca vulgaris or common wart

b) Deep Hyperkeratotic palmoplantar wart or myrmecia

c) Superficial mosaic type palmoplantar wart

d) Verruca plana or flat wart

Epidermodysplasia verruciformis

HPV types 5,8,9,12, 14, 15, 7, 19-25

Rare, life long genetic disease, with autosomal recessive inheritance.

Seen in marriages of related persons and infected people develop widespread

Warts. 30% chance of malignancy, usually in sunexposed or traumatized areas.

Mucosal HPV lesions

HPV 6, 11, 16, 13, 18, 26, 31, 32, 35, 39, 42-45, 51-56, 58, 59, 62, 68

These infect the genital tract, oral cavity, conjunctiva, and respiratory tract.

A majority of these infections are latent, with no visible lesions.

Most common sexually transmitted viruses causing cytological abnormalities and

Dysplasias, some of which can be linked to cervical cancers. (16, 18, 31, 35)

Condylomata acuminate (genital warts) are the most common benign genital tumor.

DX : cytology, histology, DNA – PCR

Prevention: research to develop a HPV vaccine. Phase 1 trial.

HEPADNAVIRIDAE

Family name comes from the major disease caused by members of this group [hepatitis] and the type of nucleic acid found in the virion [DNA].

Circular partially ds DNA genome with reverse transcriptase

Enveloped virus with an icoshadral nucleocapsid “core” which is surrounded by an outer coat.

The virion coat contains a surface antigen HBsAg and this outer coat is sometimes extended as a sphere or even tubular tail on one side of the virus particle.

The hepatitis B virus (Dane particle) causes

Human hepatitis [acute]

Serum Hepatitis (type B or long incubation hepatitis) [chronic, active]

Hepatocellular carcinoma [chronic, slow]

Transmitted: Parentally via blood (transfusions, needles, organ donation, dialysis)

Horizontally [close personal contact] or vertically (carrier mother to baby)

Direct or indirect

Incubation: 2-4 months

Disease: Virus replicated in the liver, sheds excess surface proteins into the blood. Virus pesists in the liver causing on going liver damage. More severe illness than Hepatitis A. If infected individuals fail to eliminate virus, becomes chronic infection. If virus persists and is more aggressive in destruction, can lead to liver failure or cirrhosis. If virus persists and is less aggressive, can result in patient developing hepatocellular carcinoma.

DX : serology via surface antigen [HBsAg] or antibody response to surface Ag or core

TX: passive immunity à HepB immune globulin

Inteferon A and B

Prevention: active immunity à vaccination using HgsAg, 3 doses, 1 month apart

a) Infants (starting at 6 weeks)

b) People at risk: health care workers, close assoc. with carriers

PARVOVIRIDAE

The smallest of the DNA containing viruses and named for the Latin, parvus, which means small. Linear ss DNA with a nonenveloped, icoshahedron capsid. 50% have + ss DNA, 50% have –ssDNA.. Respiratory droplet spread with 17 day incubation. Can also be spread from mother to child during pregnancy.

Members of this family causing human infections are:

B19 virus- causes 5^th disease (erythema infectiosum or slapped cheek disease), bone marrow aplasia and polyarthralgia. Target tissue is the erythroid cell line with P antigen and replicates in red cell precursors in the bone marrow and causes a temporary shutdown in erythropoeisis. Not normally a problem, unless have red cell disorder (Sickle cell, spherocytosis, hemolysis).

Adeno-associated virus – cryptic in mucosal epithelial cells.

DDx: Rubella DX: IgM antibodies, PCR of viral DNA

TX: passive immunity à immunoglobulin

For humans, most symptoms resolve spontaneously