Consequences of virus infection in animal & other

organism

• The consequences of a viral infection depend on a number of viral and host factors that affect pathogenesis.

• Viral infection was long thought to produce only acute clinical disease but other host responses are being increasingly recognized.

• These include asymptomatic infections, induction of various cancers, chronic progressive neurological disorders and possible endocrine diseases.

Virulence

• Viral virulence, like bacterial virulence, is under polygenic control.

• The susceptibility of a particular cell to viral infection depends mainly on the presence of cellular receptors. Hence, cells resistant to a virus may be susceptible to its extracted nucleic acid.

• Cultivation may markedly alter the viral susceptibility of cells from that in the original organ. For instance, polioviruses, which multiply in the nervous tissue but not in the kidney of a living monkey, multiply well in culture cells derived from the kidneys, since receptors develop in the cultivated kidneys cells.

• Many viruses are much more virulent in newborn animals than in adults

(e.g. coxsackieviruses, HSV or vice-verse e.g. polioviruses, hepatitis A). • Genetic factors are also thought too play an important role in determining

the susceptibility of an animal to a virus.

Lytic infection

viral nucleic acid initiates destructive replication cycle in which progeny virions are produced and

the host cell is destroyed

Epidemiology

• Acute infections are commonly associated with epidemics (e.g. polio, influenza, measles, common cold)

• Main problem:  by the time symptoms emerge, the host has passed on the infection

• Difficult to control in large populations and environments especially associated with people

• Effective antiviral drug therapy requires early intervention, safe drugs with few side effect (not really practical for acute infections).

• Cost:  90% of outpatient visits due to self-limiting acute viral infections

Destructive replication cycle1. Attachment – occurs as the virus uses its surface proteins to recognize and

bind to host cell surface structures called receptors and co-receptors

2. Penetration – occurs as the virus enters the host cell

- enveloped viruses: enter the host cell by one of two mechanisms:

» receptor-mediated endocytosis » membrane fusion of their envelope and the cytoplasmic

membrane of the host cell, leading to formation of endocytic vesicles containing the virus

- nonenveloped viruses:are generally taken into the host cell by receptor-mediated endocytosis

Pathogenesis

3. Uncoating – occurs in a number of different ways, depending upon the virus,

its structure and its replication requirements, but in all cases it releases the viral nucleic acid, which allows viral gene expression to begin

- nonenveloped viruses:

» attachment to receptor(s) on the surface of the host cell may trigger uncoating

» capsid proteins may be destabilized by the acidic environment and/or digested by proteases inside endocytic vesicles of the host cell

» capsid proteins may be digested by virion-encoded proteases

- enveloped viruses:

» fusion with the host cell membrane uncoats or partially uncoats enveloped viruses

» nucleocapsid(s) must then be removed by destabilization and/or digestion

4. Synthesis – depends upon viral gene expression to generate viral proteins

that are used as new virus structural components (capsomeres, etc.)

– as enzymes participating in viral genome replication using viral

nucleic acid sequences as templates

- gene expression often occurs in more than one stage

(e.g., early and late gene expression)

- mechanisms mediating viral genome replication depend upon factors such as whether the nucleic acid is DNA or RNA, whether it is single- or double-stranded, and whether or not it is segmented

5. Assembly – occurs as viral proteins complex one another to form the capsid

(or its sub-components), then complex with viral nucleic acid molecules to form icosahedral or helical nucleocapsids in the

case of:

- nonenveloped viruses:

these are stable mature infectious viral particles called virions

- enveloped viruses:

these are unstable immature noninfectious nucleocapsids (plus incorporation of viral protein peplomers into the host cell membrane)

6. Release – liberation of mature, infectious virions from the host cell in the

case of:

- nonenveloped viruses, release is generaly mediated by viral lytic enzymes that lyse the host cell membranes

- enveloped viruses, maturation and release of virions is typically mediated by membrane fusion events (referred to as "budding") that enclose individual nucleocapsids within an envelope comprised of host cell membrane containing viral proteins (spikes or peplomers) that were incorporated into it during the synthesis phase of replication

Immunological response

• Most acute infections are rapidly resolved• Limited by the intrinsic and innate immune responses• Localization to the immediate site of infection, Clearance by macrophages, NK cells,

polymorphonuclear cells, complement.• Adaptive immune response provides memory against

subsequent infection.• Virus-specific humoral and cellular responses• If not quickly limited, acute infections are resolved by

host death (e.g. many haemorragic viruses, severely immunocompromised patients)

Persistent infection

host cell remains alive and produces progeny virions at a slow rate, but for a long time

Epidemiology

• Medical science has begun to control a number of virus infections, many by drug treatment and/or immunization, but persistent virus infections are largely uncontrolled.

• Diseases caused by persistent virus infections include: acquired immune deficiency syndrome (AIDS), AIDS-related complexes, chronic hepatitis, subacute sclerosing panencephalitis (chronic measles encephalitis), chronic papovavirus encephalitis (progressive multifocal leukoencephalopathy), spongioform encephalopathies (caused by prions), several herpesvirus-induced diseases, and some neoplasias.

• Successful medical treatment for persistent or chronic virus infections is presently being developed. Attempts to control latent virus reactivation have included vaccination and treatment with interferon and various antiviral compounds.

• Suppression of latent HSV, VZV and CMV reactivation has been achieved in many immunocompromised patients receiving acyclovir and/or ganciclovir treatment.

• Health education is an important component in preventing the spread of infections that tend to persist.

Pathogenesis

Immune modulation• Many viruses that cause persistent infection avoid the

specific and nonspecific immune defenses in several ways. Example:

a. Limitation of recognition molecules on infected cells: > Restricted expression of viral antigens (e.g., HIV,

measles virus in subacute sclerosing panencephalitis).

> Antiviral antibody-induced internalization and

modulation of viral antigens (e.g., measles virus).

> Viral antigenic variation (e.g., HIV).

> Blocking antibody that prevents the binding of

neutralizing antibody (e.g., measles virus).

> Decreased expression of cell major histocompatibility complex recognition molecules (e.g., CMV, adenoviruses).

> Restricted expression of the cell adhesion molecules LFA-3 and ICAM-1 (e.g., EBV, CMV).

b. Altered lymphocyte and macrophage functions, including modified production of cytokines and immunosuppression (e.g., HIV-1, HIV-2, EBV).

c. Infection in immunologically privileged anatomic sites (e.g., HSV-1, HSV-2, VZV in the central nervous system).

d. Compromised nonspecific defenses (e.g., interferon).

Modulation of viral gene expression• Examples include down regulation of some viral genes

by viral or cellular regulatory gene products (e.g., HIV, HPVs), specific latency-associated proteins (e.g., EBNA-1) and possibly by synthesis of latency-associated transcripts (e.g., HSV-1, HSV-2) and viral variants (e.g., HIV, measles).

Immunological response• Autoimmune injury and other forms of cell damage may occur

during persistent infections. • Budding virions and viral peptides associated with the cell

membrane change the antigenic characteristics of the cell so that the immune system may recognize it as foreign.

• The cell then may be attacked by the humoral and cellular immune systems of the host and may die, even if it was infected by a noncytocidal virus.

Latent infection

there is a delay between infection of the host cell and generation of progeny virions

Epidemiology

• Hepatitis B virus is prevalent in Southeast Asia and Africa. Tumors are associated with primary infection at an early age, with viral persistence and chronic infection. The virus can be sexually transmitted particularly among homosexuals.

• Control of the development of hepatocellular carcinoma is being tried by vaccination to control HBV infection. Safe and effective vaccines have been available since 1982 but infant vaccination is not yet universal in high risk countries. That universal vaccination should be implemented by 1997 is a World Health Assembly recommendation.

• African Burkitt's lymphoma (BL), the most frequent childhood tumor in Africa, arises in areas where malaria is endemic and infection with EBV occurs very early in life when the immune system may be depressed by malaria or not yet mature.

• Preventive measures should be considered in individuals at risk of serious disseminated varicella infection ie. the immunocompromised and neonates.

• Immunocompromised individuals should be advised to avoid contact with people with varicella or zoster. If contact has been made, prophylaxis with passive immunization or antiviral chemotherapy should be considered.

Pathogenesis

Generation of cells that escape a cell-mediated immune response

Down regulation of MHC production in infected cells so that they are not recognized and destroyed by T cells

Infection of cells in immunoprivileged sites such as the brain

Examples of latent infection include:

> Chronic Congenital Rubella, CMV, EBV, hepatitis B, HIV

> Latent HSV, VZV, adenovirus and some retroviral infections

> SSPE, PML, Kuru, CJD, progressive rubella

panencephalitis

Transformation

the viral nucleic acid triggers neoplastic changes in the host cell which "immortalilze" it

and cause uncontrolled growth, which can lead to tumors (cancer) in the host

Epidemiology

• Current data indicate that transformation of a cell involves at least two components: first, the cell gains the capacity for unlimited cell division (immortalization), and second, the immortalized cells acquire the ability to produce a tumor in an appropriate host.

• In vivo, the history of malignancies also suggests a multiple process of cellular evolution, involving cumulative genetic changes, selection of rare cells that have the ability to invade, metastasize, and avoid

immune surveillance.

PathogenesisBenign tumor• Noninvasive; tumor cells, often enclosed in a "capsule" of host

tissue, do not spread to other tissues Malignant (metastatic) tumor• Invasive; tumor cells spread to other tissues and proliferates there

Immunological response• May cause formation of circulating antigen-antibody complexes

involving viral antigens. • Complexes may deposit (e.g., in the glomeruli) and elicit

inflammation by activating the classical pathway of complement. • The long-term association of the virus with specific target cells may

lead to altered function or responses; this type of mechanism is thought to be responsible for the progressive neurologic disease associated with slow virus infections