Viral pathogenesis and genetics. Viral Pathogenesis Viral pathogenesis is the process by which a...

Viral pathogenesis and genetics

Transcript of Viral pathogenesis and genetics. Viral Pathogenesis Viral pathogenesis is the process by which a...

Viral pathogenesis and genetics

Viral PathogenesisViral pathogenesis is the process by which a viral infection leads to disease.

Viral pathogenesis is an abnormal situation of no value to the virus.

The majority of viral infections are subclinical. It is not in the interest of the virus to severely harm or kill the host.

The consequences of viral infections depend on the interplay between a number of viral and host factors.

Outcome of Viral Infection• Acute Infection

– Recovery with no residue effects

– Recovery with residue effects e.g. acute viral encephalitis leading to neurological sequelae.

– Death

– Proceed to chronic infection

• Chronic Infection– Silent subclinical infection for life e.g. CMV, EBV

– A long silent period before disease e.g. HIV, SSPE (Subacute sclerosing panencephalitis), PML (progressive multifocal leukoencephalopathy) Reactivation to cause acute disease e.g. herpes and shingles.

– Chronic disease with relapses and exacerbations e.g. HBV, HCV.

– Cancers e.g. EBV, HTLV-1, HPV, HBV, HCV, HHV-8

Factors in Viral Pathogenesis• Effects of viral infection on cells (Cellular Pathogenesis)

• Entry into the Host

• Course of Infection (Primary Replication, Systemic Spread,

Secondary Replication)

• Cell/Tissue Tropism

• Cell/Tissue Damage

• Host Immune Response

• Virus Clearance or Persistence

Cellular Pathogenesis• Cells can respond to viral infections in 3 ways: (1) No apparent

change, (2) Death, and (3) Transformation

• Direct cell damage and death from viral infection may result from – diversion of the cell's energy

– shutoff of cell macromolecular synthesis

– competition of viral mRNA for cellular ribosomes

– competition of viral promoters and transcriptional enhancers for cellular transcriptional factors such as RNA polymerases, and inhibition of the interferon defense mechanisms.

• Indirect cell damage can result from – integration of the viral genome– induction of mutations in the host genome– inflammation– host immune response.

Viral Entry• Skin - Most viruses which infect via the skin require a breach in the

physical integrity of this effective barrier, e.g. cuts or abrasions. Many viruses employ vectors, e.g. ticks, mosquitos or vampire bats to breach the barrier.

• Conjunctiva and other mucous membranes - rather exposed site and relatively unprotected

• Respiratory tract - In contrast to skin, the respiratory tract and all other mucosal surfaces possess sophisticated immune defense mechanisms, as well as non-specific inhibitory mechanisms (cilliated epithelium, mucus secretion, lower temperature) which viruses must overcome.

• Gastrointestinal tract - a hostile environment; gastric acid, bile salts, etc. Viruses that spread by the GI tract must be adapted to this hostile environment.

• Genitourinary tract - relatively less hostile than the above, but less frequently exposed to extraneous viruses (?)

Course of Viral Infection• Primary Replication

– The place of primary replication is where the virus replicates after gaining initial entry into the host.

– This frequently determines whether the infection will be localized at the site of entry or spread to become a systemic infection.

• Systemic Spread– Apart from direct cell-to-cell contact, the virus may spread via the blood

stream and the CNS.

• Secondary Replication– Secondary replication takes place at susceptible organs/tissues following

systemic spread.

Cell Tropism

Viral affinity for specific body tissues (tropism) is determined by

– Cell receptors for virus.

– Cell transcription factors that recognize viral promoters and enhancer sequences.

– Ability of the cell to support virus replication.

– Physical barriers.

– Local temperature, pH, and oxygen tension enzymes and non-specific factors in body secretions.

– Digestive enzymes and bile in the gastrointestinal tract that may inactivate some viruses.

Cell Damage• Viruses may replicate widely throughout the body without any

disease symptoms if they do not cause significant cell damage or death.

• Retroviruses do not generally cause cell death, being released from the cell by budding rather than by cell lysis, and cause persistent infections.

• Conversely, Picorna viruses cause lysis and death of the cells in which they replicate, leading to fever and increased mucus secretion in the case of Rhinoviruses, paralysis or death (usually due to respiratory failure) for Poliovirus.

Immune Response• The immune response to the virus probably has the greatest impact

on the outcome of infection.

• In the most cases, the virus is cleared completely from the body and

results in complete recovery.

• In other infections, the immune response is unable to clear the virus

completely and the virus persists.

• In a number of infections, the immune response plays a major

pathological role in the disease.

• In general, cellular immunity plays the major role in clearing virus

infection whereas humoral immunity protects against reinfection.

Immune Pathological Response• Enhanced viral injury could be due to one or a mixture of the following


– Increased secondary response to Tc cells (Cytotoxic T cells) e.g. HBV

– Specific Antibody-dependentcell-mediated-cytotoxicity  ADCC or complement mediated cell lysis

– Binding of un-neutralized virus-Ab complexes to cell surface Fc receptors, and thus increasing the number of cells infected e.g. Dengue haemorrhagic fever, HIV. An Fc receptor is a protein found on the surface of certain cells - including natural killer cells, macrophages, neutrophils, and mast cells - that contribute to the protective functions of the immune system. 

– Immune complex deposition in organs such as the skin, brain or kidney e.g. rash of rubella and measles.

Viral Clearance or Persistence• The majority of viral infections are cleared but certain viruses

may cause persistent infections. There are 2 types of chronic persistent infections.

• True Latency - the virus remains completely latent following primary infection e.g. HSV, VZV (Varicella zoster virus). Its genome may be integrated into the cellular genome or exists as episomes. Episomes are the eukaryotic equivalent of bacterial plasmids. In general, in eukaryotes, episomes are closed circular DNA molecules that are replicated in the nucleus. Viruses are the most common examples of this, such as herpesviruses, adenoviruses, and polyomaviruses.

• Persistence - the virus replicates continuously in the body at a very low level e.g. HIV, HBV, CMV, EBV.

Mechanisms of Viral Persistence– antigenic variation– immune tolerance, causing a reduced response to an antigen, may be due to

genetic factors, pre-natal infection, molecular mimicry– restricted gene expression – down-regulation of MHC class I expression, resulting in lack of recognition

of infected cells e.g. Adenoviruses – down-regulation of accessory molecules involved in immune recognition

e.g. LFA-3 and ICAM-1 by EBV. – infection of immuno privileged sites within the body e.g. HSV in sensory

ganglia in the CNS– direct infection of the cells of the immune system itself e.g. Herpes viruses,

Retroviruses (HIV) - often resulting in immunosuppression.

Pathogenesis: Cycle of infection

– Infection– Primary site replication– Spread (not all viruses)– Secondary site replication (not all viruses)– Shedding, transmission

From Medical Microbiology, 5th ed., Murray, Rosenthal & Pfaller, Mosby Inc., 2005, Fig. 49-1

Viral pathogenesis

Routes of entry and shedding

Portals of entry of viruses into the host, and sites of shedding from the host. (From Fields Virology, 4th ed, Knipe & Howley, eds, Lippincott Williams & Wilkins, 2001, Figure 9-2)

Mousepox pathogenesis

The pathogenesis of mouse-pox (ectromelia). (From Fields Virology, 4th ed, Knipe & Howley, eds, Lippincott Williams & Wilkins, 2001, Figure 9-6)

From Medical Microbiology, 5th ed., Murray, Rosenthal & Pfaller, Mosby Inc., 2005, Fig. 49-3

Modes of infection

Plaque assay (the real thing) vaccinia

Fields Virology, 4th ed, Knipe & Howley, eds, Lippincott Williams & Wilkins, 2001, Fig. 2-5

Fields Virology, 4th ed, Knipe & Howley, eds, Lippincott Williams & Wilkins, 2001, Fig. 2-5

Vaccinia temperature sensitive, drug resistant mutant

Examples of Viral Pathogenesis

Rubella Transmitted by the respiratory route and replicates

upper/lower respiratory tract and then local lymphoid


Following an incubation period of 2 weeks, a viremia occurs

and the virus spreads throughout the body.

Clinical Features:- maculopapular rash due to immune complex deposition



arthropathy (up to 60% of cases)

Rubella infection during pregnancy• Rubella virus enters the fetus during the maternal viremic phase

through the placenta.

• The damage to the fetus seems to involve all germ layers and results from rapid death of some cells and persistent viral infection in others.

Preconception Risks

0-12 weeks 100% risk of fetus being congenitally infected

  resulting in major congenital  abnormalities.

Spontaneous abortion occurs in 20% of cases.

13-16 weeks deafness and retinopathy 15%

after 16 weeks normal  development, slight risk of  deafness and retinopathy

Herpes Simplex Virus• HSV is spread by contact, as the virus is shed in saliva, tears, genital

and other secretions.

• Primary infection is usually trivial or subclinical in most individuals. It is a disease mainly of very young children i.e. those below 5 years.

• About 10% of the population acquires HSV infection through the genital route and the risk is concentrated in young adulthood.

• Following primary infection, 45% of orally infected individuals and 60% of patients with genital herpes will experience recurrences.

• The actual frequency of recurrences varies widely between individuals. The mean number of episodes per year is about 1.6.

Pathogenesis• During the primary infection, HSV spreads locally and a short-lived

viraemia occurs, whereby the virus is disseminated in the body. Spread to the to craniospinal ganglia occurs.

• The virus then establishes latency in the craniospinal ganglia.

• The exact mechanism of latency is not known, it may be true latency where there is no viral replication or viral persistence where there is a low level of viral replication.

• Reactivation - It is well known that many triggers can provoke a recurrence. These include physical or psychological stress, infection; especially pneumococcal and meningococcal, fever, irradiation; including sunlight, and menstruation.

Clinical ManifestationsHSV is involved in a variety of clinical manifestations which includes ;-

1. Acute gingivostomatitis

2. Herpes Labialis (cold sore)

3. Ocular Herpes

4. Herpes Genitalis

5. Other forms of cutaneous herpes

7. Meningitis

8. Encephalitis

9. Neonatal herpes

Dengue (1)• Dengue  is the biggest arbovirus problem in the world today  with

over 2 million cases per year. Dengue is found in SE Asia, Africa and the Caribbean and S America.

• Flavivirus, 4 serotypes, transmitted by Aedes mosquitoes which reside in water-filled containers.

• Human infections arise from a human-mosquitoe-human cycle

• Classically, dengue presents with a high fever, lymphadenopathy, myalgia, bone and joint pains, headache, and a maculopapular rash.

Distribution of Dengue

Man-Arthropod-Man Cycle

Dengue (2)• Severe cases may present with haemorrhagic fever and shock

with a mortality of 5-10%. (Dengue haemorrhagic fever or Dengue shock syndrome.)

• Dengue haemorrhagic fever and shock syndrome appear most often (90%) in patients previously infected by a different serotype of dengue, thus suggesting an immuno-pathological mechanism.

• Antibody-dependent enhancement - Binding of heterotypic antibodies to the virus, and subsequent infection of macrophages with Fc receptors.

Hepatitis B Virus

Incubation period: Average 60-90 daysRange 45-180 days

Clinical illness (jaundice): <5 yrs, <10% 5 yrs, 30%-50%

Acute case-fatality rate: 0.5%-1%

Chronic infection: <5 yrs, 30%-90% 5 yrs, 2%-10%

Premature mortality fromchronic liver disease: 15%-25%

Hepatitis B - Clinical Features

Symptomatic Infection

Chronic Infection

Age at Infection

Chronic Infection (%)



matic In



Birth 1-6 months 7-12 months 1-4 years Older Childrenand Adults












Outcome of Hepatitis B Virus Infection

by Age at Infection



ic In





Spectrum of Chronic Hepatitis B Diseases

1. Chronic Persistent Hepatitis - asymptomatic

2. Chronic Active Hepatitis -symptomatic exacerbations of hepatitis

3. Cirrhosis of Liver

4. Hepatocellular Carcinoma

HIV Pathogenesis• The profound immunosuppression seen in AIDS is due to the depletion

of T4 helper lymphocytes.

• In the immediate period following exposure, HIV is present at a high level in the blood (as detected by HIV Antigen and HIV-RNA assays).

• It then settles down to a certain low level (set-point) during the incubation period. During the incubation period, there is a massive turnover of CD4 cells, whereby CD4 cells killed by HIV are replaced efficiently.

• Eventually, the immune system succumbs and AIDS develop when killed CD4 cells can no longer be replaced (witnessed by high HIV-RNA, HIV-antigen, and low CD4 counts).

HIV half-lives• Activated cells that become infected with HIV produce virus immediately

and die within one to two days.

• Production of virus by short-lived, activated cells accounts for the vast majority of virus present in the plasma.

• The time required to complete a single HIV life-cycle is approximately 1.5 days.

• Resting cells that become infected produce virus only after immune stimulation; these cells have a half-life of at least 5-6 months.

• Some cells are infected with defective virus that cannot complete the virus life-cycle. Such cells are very long lived, and have an estimated half-life of approximately three to six months.

• Such long-lived cell populations present a major challenge for anti-retroviral therapy.

Summary• Viral Pathogenesis depends on the complex interplay of a large number of viral

and host factors.

• Viral factors include cell tropism and cellular pathogenesis.

• The immune response is the most important host factor, as it determines whether

the virus is cleared or not.

• Sometimes, the immune response itself is responsible for the damage (Auto

immune responses).• Cycle of infection• Effects on cells (Abortive, lytic, persistent, latent, transforming infections• Effects on the organism• Genetics (Mutation, genotype, phenotype, reversion, recombination, selection