PATHOLOGY/ DISEASE: MECHANISMS OF CELL AND TISSUE DAMAGE
PART 1 INTRODUCTION AND DISEASE PRODUCTION BY VIRUSES
Reading Assignments: (1) Text: Chapter 7, pp. 101-104 (Review of Hypersensitivity Reactions)
(2) HANDOUTS: (A) Brooks, G.F., J.S. Butel, and S.A. Morse. 1998. “Pathogenesis and Control of Viral Diseases”, pp. 345-355. In: Jawetz, Melnick, and Adelberg's Medical Microbiology (21st ed.), Appleton and Lange, Stamford, CT., (B) White, D.O. and F.J. Fenner. 1994. “Mechanisms of Disease Production”, pp. 136-146. In Medical Virology (4th ed.), Academic Press, New York.
I. INTRODUCTION
Review Steps in the Infectious Process and Glossary of Terms from Lecture 1
A. Infection
B. Disease,
C. Infectious Disease,
D. Patho-
E. Pathogen
F. Pathogenesis,
G. Pathogenicity (Virulence)
H. Pathology
THERE IS A DISTINCTION BETWEEN INFECTION AND DISEASE; INFECTIONS DO NOT ALWAYS RESULT IN DISEASE.
THE ICEBERG CONCEPT OF INFECTIOUS DISEASES
Whether disease develops depends on variables associated with:
1. The Host (review lecture 1)
2. The Pathogen
Many infections with pathogens will not result in disease. They will be asymptomatic.
(Below the water in the iceberg) Why?
a. The pathogen may enter and fail to establish an infection.
b. The pathogen may enter and be taken out by either the nonspecific or specific
immune systems (or both). How do you know this has happened?
c. The pathogen may enter, colonize a body surface, and take up temporary
residence for a period of time – carriage – duration may be short or long.
These asymptomatic individuals that are infected with a pathogen can
play an important part in disease transmission.
But if the pathogen causes demonstrable damage to the host – resulting in either mild or severe symptoms (above the water in the iceberg) –then disease (pathology) is the result.
II. GENERAL REMARKS ABOUT MICROBIAL DAMAGE AND DISEASE PRODUCTION:
A. The impact of microbial damage depends on the tissue involved.
1. Heart
2. Brain
3. Lungs
4. Endothelial cells of the blood vessels
5. Other organs
B. The potential for disease production can depend on the rate that the microbes multiply in vivo.
III. DISEASE PRODUCTION CAN RESULT FROM THE DIRECT EFFECTS OF THE MICROORGANISM (OR ITS TOXINS), OR INDIRECTLY FROM THE OVERACTIVATION OF IMMUNE RESPONSES (IMMUNOPATHOLOGY) - EITHER NONSPECIFIC, SPECIFIC, OR BOTH. (See Mims Fig. 12.1)
Review Hypersensitivity Reactions Types I, II, III, and IV.
IV. DISEASE PRODUCTION BY VIRUSES
The ability of viruses to cause disease can be viewed at 2 distinct levels: (1) the changes that occur within individual cells, and (2) the process that takes place in the infected patient. (see Reading Assignment (A): Fig. 30-1)
A. How Viral Infections Affect Individual Cells
1. No apparent morphologic or functional change ( = disease).
2. Cytocidal Infection – an infection that results in cell death either from cell lysis, apoptosis, or the accumulation of cytopathic effects.
a. Cell lysis- viral replication causes dissolution of the cell. What viruses depend on lysis of the cell to be released?
b. Apoptosis – viral infections can trigger premature programmed cell death.
c. Cytopathic effects – cellular injury caused by virus infection. (2nd meaning: the effects of virus infection on cultured cells, visible by microscopic or direct visual examination).
Mechanisms of cell injury include:
1. Inhibition of macromolecular synthesis (DNA, RNA, protein synthesis)
2. Damage to cell lysosomes.
3. Alteration of cell membranes, including the formation of multinucleated giant cells – virus induced membrane fusion of infected cells (50-100 may fuse together).
4. Formation of inclusion bodies – clustering of viral components in the nucleus or cytoplasm.
5. Chromosomal disruptions
3. Persistent or chronic infections – ongoing virus replication occurs without killing the cell. What viruses characteristically cause persistent infections?
4. Latent Infections – after the initial infection of the cell, the virus stops reproducing and remains dormant for a period of time before being reactivated. What happens to the viral genome during latency?
a. genome is integrated into the host cell DNA (HIV)
b. genome survives as a free plasmid (episome) in the cytoplasm or nucleus.
During latency, the expression of the viral genome is repressed wholly or partially. All genes are derepressed during reactivation.
5. Malignant transformation – viruses transform individual cells, resulting in unrestrained growth and prolonged survival.
B. How Viral Infections Affect the Host (the Patient).
1. Entry Followed by Primary Replication in the Host:
a. Local Damage at the Primary Site of Entry After entering the body, viruses replicate at the primary site of entry, resulting in spread to nearby epithelial cell surfaces (Ex.s rhinoviruses, papilloma viruses, rotaviruses)
b. Systemic Spread – invasion of underlying tissues and spread to distant sites.
2. Cell Injury, Tissue Damage, and Clinical Illness:
SEE READING ASSIGNMENT B FOR A DISCUSSION OF VIRAL DAMAGE TO TISSUES AND ORGANS
Just as there is a range of responses at the cellular level, there is a spectrum of responses in the host from subclinical to severe clinical disease.
3. SUBCLINICAL INFECTIONS:
a. Exposure to the virus without infection
b. Inapparent (Subclinical) infections – patient is asymptomatic; this is common with viral infections.
4. CLINICAL INFECTIONS:
a. Acute Infections – the host runs a clinically apparent course, either recovering or succumbing to the disease; antibodies and cell mediated responses are made; immunity may be life long. The Stages of an Infectious Disease Apply to Acute Infections (review with Prescott p.724):
1. Incubation
2. Prodromal
3. Specific Illness
4. Recovery
b. Persistent (Chronic Infections)- unlike an acute infection, a persistent infection is not cleared quickly and virus particles are produced for long periods of time; antibodies can be detected in the blood. The immune system fails to clear the infection!
1. Persistent Infection with Shedding - After an initial acute infection, the virus persists in an infectious form with continuous or intermittent shedding at low levels (Hepatitis B, EBV virus)
2. Persistent Slow Infection following Acute Infection After an initial acute infection, the microbe continues to grow – sometimes in a privileged site and years later, disease may be manifested. (SSPE, HIV)
A DIFFERENT PATTERN OF PERSISTENCE: NO ACUTE STAGE AND NO IMMUNE RESPONSE
3. Persistent Slow Infection Without an Acute Stage- The host is infected, and years go by before disease is manifested (Creutzfeld-Jakob Disease – Prions)
c. Latent Infections (a form of persistence) – the virus persists in a dormant or occult form. It cannot be detected in the blood; there is no immune response during latency. Years later, there may be reactivation with viral replication, symptoms, the ability to infect others, and an immune response. (Herpesviruses HSV, VZV)
CONSIDER THIS: PERSISTENCE IS OF SURVIVAL VALUE FOR THE MICROBE (Taken from: Mims, C., J. Playfair, I. Roitt, D. Wakelin, and R. Williams. 1998. Medical Microbiology (2nd ed.) Mosby International, London)
d. Malignancy as the result of cell transformation –
Viruses associated with cancer:
1. Human T cell lymphotropic viruses – lymphomas and leukemias
2. Epstein Barr virus – nasopharyngeal carcinoma and Burkitt's lymphoma
3. Human Papillomaviruses – cervical, penile, and rectal cancers; skin cancers
4. Hepatitis B virus – liver cancer