Human Herpes virus , Chapter 11: Pox Viruses , Virology - Mumps, Measles, Rubella + Other Childhood Exanthems

HHV Tropism Range

Widest range of cell tropism

Alpha Herpes Virus Characteristics

Rapid replication, neuronal latency

HHV alpha subgroup members

HSV1, HSV2, VZV (HHV3)

Beta Herpes Virus Characteristics

Slow replication, limited host range

Beta herpes virus subgroup members

HHV5 (CMV), HHV6, HHV7

Gamma Herpes Virus Characteristics

Rapid replication, lymphotrophic

Gamma HHV subgroup members

HHV (EBV), HHV8 (KSHV)

Herpes family

herpesviridae

Herpes virion structure

Large, icosahedral capsid surrounds core, Tegument, envelope

Herpes virus genome

dsDNA, linear

Herpes virus envelope proteins

Glycoprotein gB-gE and gH-gM

Herpes virus infections

After primary infection all herpesviruses establish lifelong latent infections with periodic reactivations

HSV transmission

horizontal and vertical

HSV 1 disease

orofacial infections involving skin, mouth, conjunctive, nervous system

HSV 2 disease

Primarily genital infections

HSV 1 prevalence

Highly prevalent in population

What determines site of latency?

Location of primary infection

Orofacial infection site of latency

Trigeminal ganglion

Genital infection site of latency

dorsal ganglion in the sacral region

HSV attachment and entry

Initial binding (adhesion) to heparan sulfate --> binding higher affinity receptors --> fusion with cell membrane

HSV pathogenesis overview

infection in muco-epithelial cells --> viral-mediated multinucleated giant cells --> lytic and associated inflammatory response --> latency in neuronal cells

Viral DNA in nucleus...

circularizes and viral gene expression can be initiated

3 distinct classes of mRNAs

Immediate early (IE)

Early (E)

Late (L)

Herpes virus envelope origin

inner lamella of the nuclear membrane of host cell

Viral DNA replication.....

Completed by viral DNA polymerase

Rolling circle method

DNA concatemers

cleaved and packaged into preassembled capsids in the nucleus

Herpes Latency

viral DNA maintained as episome in nucleus

1-10 latent genes regularly expressed

MircoRNAs expressed

HSV reactivation causes

sunlight, UV light, fever, excitement, emotional stress, trauma

HSV primary infection symptoms

Commonly asymptomatic

If symptomatic

- Gingivostomatitis

-Fever, malaise, myalgia, sore throat, headache, fatigue, cervical lymphadenopathy

Clinical disease

vesicular grouped/single lesions --> pustular --> ulcerate --> dry vs mucosal --> scabs vs re-epithelization

HSV infection complications

Conjunctival/corneal infection --> blindness

HSV encephalitis

HSV1 and HSV2 distinguished by

type-specific monoclonal antibodies

HSV diagnosis

PCR, Tzanck smear

HSV treatment

Acyclovir

C-section may be performed to reduce neonatal infection

Acyclovir

Antiviral: treats HSV

Nucleoside analog: converted by thymidine kinase (viral enzyme) to monophosphate form, then converted to triphosphate form (active form) by cellular enzymes

What is the most infectious HHV

Varicella --> vaccination has decreased incidence

Seasonality of Varicella

Occurs most frequently during the winter and spring months

Varicella incubation period

11-21 days

Varicella transmission

Respiratory, direct contact with vesicular or pustular lesions

Varicella communicability

24-48 hrs before rash onset and 3-4 days into rash phase

Varicella primary infection disease

Chickenpox

Varicella reactivation disease

Shingles

VZV latency-associated transcript (VLT)

Expressed in ganglion where VZV DNA resides = suggests role for VLT in VZV latency

VZV latency site

Sensory ganglia

- Dorsal root ganglia

-trigeminal ganglia

VZV reactivation factors

Shingles: advancing age, decreasing VZV-specific T cells, immunosuppression, etc.

VZV reinfection control vs reactivation

Antibodies prevent reinfection

Cell-mediated immunity controls reactivation

Chickenpox rash

Vesicular. Pruritic (itchy)

Back of head and ears --> centrifugal spread to face, neck, trunk, limbs

Involvement of mucous membranes common

Lesions appear in stages of spread during the course of the disease

Skin lesions form rapidly as fluid-filled vesicles that become turbid after 1-2 days --> crust over

VZV complications

Mortality = rare, increases with age of primary infection

severe dieaase in immunocompromised patients with visceral affection

Diagnosis

Clinical symptoms, Tzanck smear, antigen test, PCR

Tzanck smear

May reveal giant multinucleated cells

Doesn't distinguish between all HHV types

VZV Treatment

Acyclovir considered based on age, immune system status

VZV vaccine?

Varicella virus vaccine

Live, attenuated

2 doses

12-15 months, 4-6 years

Shingrix

Vaccine recommended as two doses 2-6 months apart for immunocompetent adults 50+ (despite previous vaccination status)

90% effective in preventing shingles

Other VZV prevention methods

high-toter immune globulin administered ASAP and as late as 10 days post exposure = useful in preventing infection in people with no VZV immunity

Family of pox viruses

Poxviridae

Pox viruses: general virology/structure

Nucleosome, lateral bodies, core, core membrane (dumbbell shape), outer membrane

Large virion size

Capsid: brick-shaped or ellipsoid particles

Pox virus genome type

double-stranded DNA, linear with single-stranded ends

Pox virus envelope

Outer lipoprotein membrane surrounds core + 2 lateral bodies (function unknown)

Pox virus site of replication

Cytoplasm (only DNA viruses that can completely replicate in the cytoplasm)

Why can pox viruses replicate in the cytoplasm?

They encode all essential enzymes, proteins, and factors needed for viral replication in the cytoplasm of an infected host cell

What do pox viruses resemble?

A bacterium

How many uncoating steps do pox viruses have?

2

What happens in first stage of pox virus uncoating?

Viral core is exposed but not DNA. Early proteins act on the core to make the full uncoating possible

Second stage of pox virus uncoating

Removes the viral DNA from the cores

Pox virus immune evasion stragies

Viral complement control proteins (VCPs): bind to C3b and C4b to prevent C3/C5 formation which blocks MAC, opsonization and chemotaxis

How many types of smallpox are there?

Two antigenically identical types, major and minor

Which type of smallpox is more deadly?

Major

Smallpox hosts?

Humans are the only host

Are there asymptomatic carriers of smallpox?

No

Smallpox current threat

Eliminated from the world in 1980

Threat of bioterrorism

Describe smallpox's level of contagiousness

Highly contagious

ID50: ~100-1000 virions by respiratory route = LOW

Smallpox transmission

respiratory droplets and fomites

Smallpox contagious time

First week of rash after fever (7-10 days) but not during the incubation period

Smallpox case fatality ratio

30-40%

Smallpox incubation period

~12-14 days

Smallpox clinical manifestations

Abrupt onset (fever, chills, myalgia)

3-4 days later centrifugal maculopapular rash --> 10-12 vesiculopustular --> crust and heal

All lesions are in the same stage of development

Smallpox diagnosis

Skin lesion samples: PCR tests, rapid ID of virus particles use direct exam (electron microscope) to differentiate between smallpox and chickenpox

Serologic tests: Can be used but can't distinguish between orthopoxvirus infection after ~2-3 weeks of infection

Smallpox treatment

Supportive care, vaccinia vaccination, post-exposure prophylaxis, methisazone (inhibit mRNA synthesis), approved antivirals

Molluscum contagiosum

Mumps family and genus name

Family: paramyxoviridae Genus: Orthorubulavirus

Mumps genome and structure

(-)ssRNA, helical nucleocapsid, enveloped

Mumps: transmission

person to person; respiratory droplets

Mumps transmissible period

7 days before to 9 days after onset of illness

What percent of people infected with mumps develop disease?

30-40%

What age group has the highest incidence of mumps?

5-15 years old

Mumps: cellular receptors

SLAM/CD150 and Nectin-4

Mumps incubation period?

Average 16-18 days. Total range 12-29 days.

Mumps entry

respiratory tract epithelium + local lymph nodes

In primary viremia of a mumps infection what target tissues is infection disseminated to?

parotid glands and CNS (possible secondary viremia and tropism for epithelial cells)

Common mumps symptom

painful swelling of one or both parotid gland/s

Mumps: what samples are used for diagnosis

Saliva, pharynx + other affected sites (ex. CSF and urine)

Mumps diagnostic tests

RT-PCR detecting viral nucleic acid

Virus culture

ELISA, EIA, IF detect IgM, IgG

IgM early provides diagnosis

Mumps treatment

no specific treatment

mumps vaccine

live attenuated, ideally given 12-15 months and repeated at 4-6 years

single dose = seroconversion in ~80% of recipients, increases to ~90% after two doses

Measles family and genus

Family: paramyxoviridae Genus: Morbillivirus

Measles Genome

Linear, (-)ssRNA

Measles virion structure

Enveloped, matrix protein, helical nucleocapsid, Hemagglutinin (H), fusion (F) protein

What population/s have the highest incidence of measles?

Children and unvaccinated people

Measles Infectious rate

85% (95% infected become ill) ?

Measles mode of transmission

person to person; respiratory droplets/aerosol