Pathogenesis of Viral InfectionsPathogenesis of Viral Infections

Viral pathogenesisViral pathogenesis

““No virus is known to do good. It has been No virus is known to do good. It has been well said that a virus is a piece of bad news well said that a virus is a piece of bad news

wrapped up in protein.”wrapped up in protein.”

Medawar and Medawar

Viral PathogenesisViral Pathogenesis Viral pathogenesis is the process by which a viral Viral pathogenesis is the process by which a viral

infection leads to disease.infection leads to disease.

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

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

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

Infection Vs DiseaseInfection Vs Disease

INFECTION:–Entry of virus into the body, INFECTION:–Entry of virus into the body, produces no symptoms or transient produces no symptoms or transient symptoms due to local irritationsymptoms due to local irritation

DISEASE:–Virus at Target organ, produces DISEASE:–Virus at Target organ, produces signs and symptoms associated with signs and symptoms associated with diseasedisease

Basic Concepts

Pathogenesis is a result of: • injury to discrete populations of cells • in particular target organs • producing signs & symptoms of disease in a given host.

Extent of disease depends on: • Virus dose • Route of entry • Replication efficiency

Both the host & the virus are seeking a reproductive advantage

• new viruses are evolving continuously • natural selection favors viruses with low pathogenicity /virulence (so they don't eradicate

their hosts)

Most viral infections are asymptomatic

Disease is an “unusual” consequence of infection.

IntroductionIntroduction Viral pathogenesis concerns itself with the Viral pathogenesis concerns itself with the

mechanisms by which viruses cause injury to mechanisms by which viruses cause injury to cells in different tissues and organs to produce cells in different tissues and organs to produce the signs and symptoms of disease.the signs and symptoms of disease.

Considering viral diseases, there are two Considering viral diseases, there are two components involved, the direct effect of virus components involved, the direct effect of virus replication and the effects of bodily responses replication and the effects of bodily responses to the infection.to the infection.

The course of any virus infection is determined The course of any virus infection is determined by a delicate and dynamic balance between the by a delicate and dynamic balance between the host and the virus. host and the virus.

In some viral infections, most of the In some viral infections, most of the pathologic symptoms observed are pathologic symptoms observed are attributable to the side effects of the attributable to the side effects of the immune response.immune response.

Inflammation, fever, headache and skin Inflammation, fever, headache and skin rashes are usually caused by the cells of rashes are usually caused by the cells of the immune system due to the release of the immune system due to the release of potent chemicals such as interferon and potent chemicals such as interferon and interleukins.interleukins.

The vast majority of virus infections are The vast majority of virus infections are silent and do not result in outward signs of silent and do not result in outward signs of disease. disease.

With many virulent viruses, subclinical or With many virulent viruses, subclinical or unapparent infections often outnumber cases of unapparent infections often outnumber cases of symptomatic illness. symptomatic illness.

However, for certain classic viral infections, However, for certain classic viral infections, such as measles, smallpox, rabies, and such as measles, smallpox, rabies, and influenza almost all infected individuals develop influenza almost all infected individuals develop disease.disease.

It is perfectly possible to envisage viruses with It is perfectly possible to envisage viruses with a hit- and-run strategy, moving quickly form a hit- and-run strategy, moving quickly form one host to the next and relying on continuing one host to the next and relying on continuing circulation for their survival.circulation for their survival.

Nevertheless, there is a clear tendency for Nevertheless, there is a clear tendency for viruses not to injure their hosts if possible.viruses not to injure their hosts if possible.

Mechanisms of cellular injuryMechanisms of cellular injury

In general terms, a number of common In general terms, a number of common phenotypic changes can be recognized in phenotypic changes can be recognized in virus-infected cells. These are often referred virus-infected cells. These are often referred to as CPE and include:-to as CPE and include:-

Altered shape (rounding).Altered shape (rounding). Detachment from the substrate.Detachment from the substrate. Membrane fusion (giant cells, syncytium).Membrane fusion (giant cells, syncytium). Increased membrane permeability.Increased membrane permeability. Inclusion body formation.Inclusion body formation. Lysis.Lysis. Apoptosis.Apoptosis.

Pathogenic mechanisms include Pathogenic mechanisms include implantation of the virus at a body site implantation of the virus at a body site (the portal of entry), replication at that (the portal of entry), replication at that site, and then spread to and site, and then spread to and multiplication within sites (target multiplication within sites (target organs) where disease or shedding of organs) where disease or shedding of virus into the environment occurs.virus into the environment occurs.

Most viral infections are subclinical, Most viral infections are subclinical, suggesting that body defense against suggesting that body defense against viruses arrest most infections before viruses arrest most infections before disease symptoms become manifest.disease symptoms become manifest.

Knowledge of subclinical infections comes Knowledge of subclinical infections comes from serologic studies showing that from serologic studies showing that sizeable portions of the population have sizeable portions of the population have specific antibodies to viruses even though specific antibodies to viruses even though the individuals have no history of disease.the individuals have no history of disease.

Unapparent infections have great Unapparent infections have great epidemiologic importance; they epidemiologic importance; they constitute major sources for constitute major sources for dissemination of virus through the dissemination of virus through the population and they confer immunity.population and they confer immunity.

HOST factors which modify viral pathogenesis

• Virus receptors - genetically determined or due to the state of differentiation.

• Age - certain infections are more severe in

different age groups. - less severe before puberty, e.g. EBV

infections and mononucleosis, measles, VZV (chickenpox) and poliomyelitis.

• Metabolic state Generalized malnutrition or Vitamin A

deficiency increase susceptibility to, and severity of, measles infection.

Pregnancy (with its associated change in hormonal balance) can also lead to altered susceptibility to certain viruses.

• “Altered” immune responses - Impaired (Congenital or Acquired) - Enhanced (Auto-immunity)

Routes of entry

• Skin

• Respiratory tract

• Gastrointestinal tract

• Genitourinary tract

• Conjunctiva

Skin May be penetrated by viruses as a result of - mechanical trauma (HPV,HIV, HSV, HBV,

poxvirus) - by injection (HBV, HIV) - by the bite of an infected mosquito

(arboviruses) - by the bite of an infected animal (rabies)

Generally, viruses do not multiply locally but are carried away from site of infection:

- by bloodstream (HBV, arboviruses) - or migration along nerves (rabies)

Respiratory Tract Major route of invasion: For viruses causing local respiratory

infections - influenza, RSV, rhinoviruses

Others causing asymptomatic initial infection then generalized spread

- measles, mumps, chickenpox, enteroviruses

Transmission usually by droplet infection in aerosols

Gastrointestinal Tract Entry via GI tract may involve • local infection (rotavirus, coronavirus, adenovirus)

or • invasion of the host to produce systemic illness (enteroviruses, hepatitis A)

Virus survival depends on: - acid stability - resistance to bile salts - inactivation by proteolytic enzymes, in some cases

a requirement!

Mostly non-enveloped

Genitourinary Tract Tears or abrasions of mucosa allow viral

entry

Sexually transmitted viruses • HIV • herpes simplex (mostly HSV II) • papillomaviruses (genital warts) • hepatitis B virus

Nature of cervical mucus, the pH of vaginal secretions and the chemical composition of urine all play a role in host defense.

Localization vs systemic spread

Many viruses multiply in epithelial cells at site of entry, produce a spreading infection then are

shed directly to the exterior

• Respiratory infections – influenza, rhinoviruses and RSV

• Gastrointestinal infections caused by rotaviruses

• Dermatologic infections of the papillomaviruses

Targeting of viral budding to apical or basal surfaces of polarized cells may define subsequent spread

Baso -lateral budding (Rhabdo and Retroviruses)

Apical budding (Orthomyxo and paramyxoviruses)

SpreadSpread

Cell-to-cellCell-to-cell..

Blood streamBlood stream:- free or cell associated :- free or cell associated viremia.viremia.

Primary Vs secondary viremia.Primary Vs secondary viremia.

Neural spreadNeural spread: - usually preceded by : - usually preceded by primary viremia but may be direct (rabies). primary viremia but may be direct (rabies).

Cell and tissues tropism is a major Cell and tissues tropism is a major determinant of spread.determinant of spread.

After traversing the epithelium and its basement membrane at the body surface, invading viruses face multiple tissue and cellular defenses

• enter directly into blood stream (arboviruses) • initially taken up by the lymphatic system

Viruses may also enter directly into peripheral nerves (rabies)

Invasion of mucosal tissue and subsequent spread by the bloodstream results ultimately in the infection of particular target organs

Incubation period ends with the onset of symptoms

• from a few days (localized infections – paramyxoviruses

• to a few weeks (systemic infections - chickenpox, hepatitis A)

• or years (chronic, persistent and “slow”

viruses)

VIRUS SHEDDING AND TRANSMISSION

Horizontal: From host to host of the same generation

1. Direct: host to host by contact • skin lesions – papillomavirus • saliva – rabies, mumps, CMV, EBV, HIV • mechanical trauma – HIV, HSV • aerosols - influenza, measles, rhinoviruses

2. Indirect: host to fomites (food, water, needles,

vector-mediated) to host - hepatitis A, polio, hepatitis B and yellow fever

Vertical: From host to progeny - Congenital transmission (Rubella, Cytomegalovirus,

HIV) 1. Transplacental: CMV, parvovirus B19 cross the placenta and can cause fetal infections

2. Perinatal: infection with HIV or HSV can occur during birth (during passage of infant through birth

canal)

3. Via breast milk: breast milk can serve as a vehicle for transmission of HIV1 and HTLV1

The course of viral infectionsThe course of viral infections Abortive InfectionAbortive Infection A virus infects a cell but cannot complete the full replication

cycle (non- productive). May result in transformation Acute infectionAcute infection

The virus is usually eliminated by the immune system. Brief infection but may have a lasting effect (VZV). Recovery with no residual effects Recovery with residual effects e.g. acute viral encephalitis

leading to neurological sequelae. Death Proceed to chronic infection

ACUTE INFECTIONS ACUTE INFECTIONS • Acute viral infections are severe public health Acute viral infections are severe public health

problems.problems.• They are usually associated with epidemics.They are usually associated with epidemics.• The main problem is the short incubation period.The main problem is the short incubation period.• This causes a delay in identifiable symptoms until This causes a delay in identifiable symptoms until

the virus has already spread.the virus has already spread.• Acute infection epidemics are often seen in crowded Acute infection epidemics are often seen in crowded

populations.populations.• SchoolsSchools• Military bases and Nursing homesMilitary bases and Nursing homes

Chronic InfectionChronic Infection The converse of acute infection (prolonged and The converse of acute infection (prolonged and

stubborn).stubborn).

To cause this type of infection, the virus must To cause this type of infection, the virus must persist in the host for a significant period. persist in the host for a significant period.

In chronic infections, a limited number of cells are In chronic infections, a limited number of cells are infected. infected.

These infected cells may demonstrate a cytopathic These infected cells may demonstrate a cytopathic effect, synthesize virus macromolecules, and release effect, synthesize virus macromolecules, and release infectious virus.infectious virus.

Persistent infectionPersistent infection Continuous production of virus particles.Continuous production of virus particles.

This infection results from a delicate balance between This infection results from a delicate balance between the virus and the host organism, in which ongoing the virus and the host organism, in which ongoing virus replication occurs, but the virus adjusts its virus replication occurs, but the virus adjusts its replication and pathogenicity to avoid killing the host. replication and pathogenicity to avoid killing the host.

It differs form chronic infection in that in chronic It differs form chronic infection in that in chronic infection the virus is usually eventually cleared by the infection the virus is usually eventually cleared by the host (unless infection proves fatal), whereas in host (unless infection proves fatal), whereas in persistent infection the virus may continue to be persistent infection the virus may continue to be present and to replicate in the host for its entire present and to replicate in the host for its entire lifetime. lifetime.

May trigger autoimmune injury.May trigger autoimmune injury.

Latent infectionLatent infection Existing but not exhibited.Existing but not exhibited.

This is The ultimate infection. This is The ultimate infection.

In a latent infection, the virus is able to down regulate its In a latent infection, the virus is able to down regulate its gene expression and establish an inactive state (strictly gene expression and establish an inactive state (strictly limited gene expression without ongoing virus replication). limited gene expression without ongoing virus replication).

They typically persist for the entire life of the host. They typically persist for the entire life of the host.

Can be reactivated.Can be reactivated.

Infectious progeny

Cell death Signs/ symptoms

Duration of infection

Acute + + + S <3 wks

Inapparent + + - S

Chronic + + +/- L

Persistent <<+ - - L

Latent - - - L

Slowly progressive

+ + Eventually +

L

Tumorigenic +/- - + L

Clinical latency

Questions?