PATHOGENIC EFFECTS OF VIRUSES H.A MWAKYOMA, MD

I: BASIC CHARACTERISTICS OF A VIRUS. Are smallest infectious agents (human pathogens) known. Majority can only be seen by electron microscopy. Few largest ones are just visible by light microscopy. Each true virus contains only a single nucleic acid as its genome, that is DNA or RNA contained in a protein shell. The type of nucleic acid forms one of the bases for viral classification.

I: BASIC CHARACTERISTICS OF A VIRUS Viruses are incapable of independent metabolism or reproduction and thus are obligate intracellular parasites, requiring living cells in which they replicate (They are incapable of growth and division). After invading cells, these microorganisms divert their biosynthetic and metabolic capacities to the synthesis of viral encoded nucleic acids and proteins. (They make use of the ribosomes of the host cell in the course of replication.)

I: BASIC CHARACTERISTICS OF A VIRUS Viral replication is controlled entirely by nucleic acid. Viruses lack the genetic information required to produce energy generating system. They are specific in action, i.e. they always infect particular organ or organism. They are unaffected by antimicrobial antibiotics They may undergo mutations

II: GENERAL STRUCTURE OF AVIRUS. The nucleic acid is covered by a protein shell (coat) known as CAPSID (NUCLEOCAPSID). The capsid consists of clusters of polypeptides which form what is known as CAPSOMERES. Some viruses also posses an outer envelope (a glycoprotein) derived from host cell. The mature infective virus particle is called a viron.

GENERAL STRUCTURE OF AVIRUS. Most of DNA viruses have NO ENVELOPE with exception of herpes viruses. Most of RNA viruses are ENVELOPED with exception of PICORNA viruses and Reoviruses.

GENERAL STRUCTURE OF AVIRUS

II: GENERAL STRUCTURE OF AVIRUS.

DNA VIRUSES: Poxviruses Herpes viruses:- HSV-1&2 Chickenpox Epstein Barr Virus (EBV) CMV

DNA VIRUSES: Adenoviruses Papovaviruses: Papilloma viruses Polyoma virus Vacuolating virus

RNA VIRUSES: Enteroviruses: Polioviruses Coxsackie virus Rhinoviruses PICORNAviruses Enteroviruses: Polioviruses Coxsackie virus ECHO virus (Entero Cytopathic Human Orphan virus) Rhinoviruses

RNA VIRUSES: ORTHOMYXO viruses – cause influenza. PARAMYXO viruses Parainfluenza virus – cause sore throat Measles virus Mumps virus LTTI (Lower Respiratory Tract Infection) vius

RNA VIRUSES: Rhabdoviruses Rabies virus, etc

III: VIRUSES AND THE TARGET CELL: (Pathogenic mechanism). The functional implications of a viral infection derive from: The changes directly produced by the virus in the host cell. The host tissue reaction to these changes The response of the immune system both to the presence of the virus and to the cellular changes which it has produced.

III: VIRUSES AND THE TARGET CELL: (Pathogenic mechanism). In order to understand how the above changes occur, the knowledge on how the virus enter into a host cell and replicate within it is important. Viruses must gain access to the interior of a host cell because they require many of the cell’s biosynthetic processes for replication. The steps in viral replication are as follows.

The steps in viral replication. Attachment of the virus to the cell surface membrane. Contact between virus and its target cell occurs more or less randomly. Attachment of the virion to the cell surface will NOT take place UNLESS the surface membrane of a cell has a specific viral receptor site which is complimentary to an attachment site on the surface of the virus. Example – poliovirus and influenza virus.

The steps in viral replication. Viral penetration of the host cell membrane. Once attachment to the plasma membrane of the target cell has occurred, the virion becomes engulfed (Viropexis). This is a temperature and energy dependent step. For enveloped viruses, the envelope fuses with the plasma membrane of the cell and nucleocapsid is released directly into the host cytoplasm

The steps in viral replication. Uncoating of the virus particle. This is the time when the protein capsid is removed The viral nucleic acid is uncoated The term uncoating means exposure of the viral nucleic acid NB: Uncoating may never be completed in Reoviruses

The steps in viral replication. Synthesis of nucleic acid and protein. In DNA viruses, this is a two stage process. Synthesis of early proteins (takes place in nucleus) and synthesis of late proteins (which takes place in cytoplasm). OR In RNA viruses, it is a one stage process and takes place in cytoplasm with exception of Orthomyxoviruses which replicate in nucleus.

The steps in viral replication. Assembly of structurally mature viruses Release of viruses from the host cell

VIRAL LATENCY: Certain viruses, especially Herpes virus group, can remain dormant within the host cell for long periods. The viruses remain intergrated with the cell genome until triggered by a variety of stimuli to undergo a period of replication.

THE EFFECTS OF VIRAL REPLICATION: The effects of viruses on host cells may undergo morphological changes. Viruses often cause disease by killing the infected cells (Permissive cells). Many viruses, however, produce disease without killing infected cells,(Non-permissive cells) e.g Rota virus.

THE EFFECTS OF VIRAL REPLICATION: Viruses also produce disease by promoting the release of chemical mediators that incite inflammatory or immunological response e.g symptoms of common cold are due to release of bradykinin

THE EFFECTS OF VIRAL REPLICATION: The effects of viral replication on host cell during replication include the following: No change:- This occurs in the cell in which the viral infection is of LATENT variety and show no structural abnormalities. The virus infect and persist in cells without interfering with normal cellular function, a process known as latency.

THE EFFECTS OF VIRAL REPLICATION: No change:- Viruses that establish latent infection can emerge to produce disease or transmit infection long after primary infection Opportunistic infections are frequently caused by viruses that have established latent infections (CMV, HSV) are among most frequent opportunistic pathogens, which emerge in persons with impaired cell-mediated immunity.

THE EFFECTS OF VIRAL REPLICATION: Cell death:- Cell death is an extremely common outcome of viral infections and the type of cell affected may play a dominant role in determining the clinical pattern of disease e.g. Poliomyelitis (anterior motor neuron destruction – motor paralysis)

THE EFFECTS OF VIRAL REPLICATION: Alteration of cell surface membrane: Some viruses, especially the Paramyxovirus group cause fusion to take place between infected and non-infected cells with the formation of Multinucleated Giant Cells. This is not uncommon in the tissues of patients suffering from MEASLES, giant cells being found chiefly (but not exclusively), in lymphoid tissues.

MEASLES, giant cells cont-- The giant cells are highly characteristic mulberry-like giant cells known as WARTHIN-FINKELDY CELLS and may be useful in the diagnosis of measles in tissue sections from patients who may have died from measles pneumonia.

WARTHIN-FINKELDY GIANT CELL in a lymphnode

THE EFFECTS OF VIRAL REPLICATION: The formation of inclusion bodies: These bodies are strongly eosinophilic in tissue sections stained with H&E. There are 2 types of inclusion bodies;

Types of inclusion bodies; Intracytoplasmic inclusions: - are found in the cytoplasm in cells infected by:- Poxviruses – (Guarnieri body) Paramyxoviruses Reoviruses Rhabdoviruses (Nigri bodies in the brain and spinal cord) in rabies.

Types of inclusion bodies; Intracytoplasmic inclusions:- are found in the cytoplasm in cells infected by; Herps viruses Adenoviruses

Viral Intranuclear inclusion bodies -liver

Viral intranuclear inclusion bodies - liver

Viral intranuclear inclusion bodies- liver

Viral intranuclear inclusion bodies- spleen

INTRANUCLEAR INCl u.bladder

Cytoplasmic viral inclusion bodies-HSV2

Cytoplasmic inclusion bodies- rabies (Nigri bodies) in neurons

THE EFFECTS OF VIRAL REPLICATION: Cell proliferation:- Independent of any oncogenic effect, some viral infections can cause cells to proliferate. This is commonly seen in self-limiting disorders e.g. Infectious Mononucleosis caused by Herpes virus, the EBV of the targent cell in the B lymphocytes. The B lymphocytes proliferate.

Infectious Mononucleosis

Peripheral blood in infectious mononucleosis (glandular fever)- atypical lymphocytes

lymphocytes (cellular response) Antibody production:- PROTECTIVE RESPONSE OF HOST CELLS AGAINST VIRAL INFECTIONS (Host Response to viral infection): Inflammation:- lymphocytes (cellular response) Antibody production:- humoral response (Immunoglobulins, IgG, IgM, IgA) Interferon production:- These are glycoproteins

Interferon production:- They are produced by the host cell especially of the macrophage system in response to viral infections. They are not antibodies They are specific of the species in which they are produced (Species specific BUT not virus specific)

TYPES OF INTERFERON They are 3 distinct types of interferon known; Alpha(ά) interferon:- released chiefly by leucocytes. Beta(β) interferon:- released chiefly from fibroblasts Gamma(γ) interferon:- released by activated T lymphocytes.

TYPES OF INTERFERON NB: Most important inducers of Alpha and Beta interferon release are viral infections, but the production can also be triggered by:- Rickettsiae, Protozoa, Bacterial endotoxins.

ACTIONS OF INTERFERON interferon act by interfering with viral synthesis the protective effect of interferon is not limited to a single virus because, unlike antibody, it does NOT interact directly with the virus the interferon secreted by an infected cell diffuses from that cell and binds to a membrane receptor on the surface on neighbouring non-infected cell.

ACTIONS OF INTERFERON cont- There is NO inhibition of viral attachment or penetration of the cell to which interferon has bound The protective effect is mediated through blocking the translation of viral mRNA in the host cell Polyribosomes.

FAILURE OF VIRAL ELIMINATION: Failure to eliminate the virus from the host cell may lead to a number of situations. Such infectios can be; LATENT:- the virus is not normally detected the infection persists in occult, quiescent from the episode of reactivation in the form of acute, self-limiting illness.

LATENT:examples Examples are;- HSV, Herpes zoster virus(HZV-which causes Shingles or herpes zoster), Chicken pox which causes vericella

FAILURE OF VIRAL ELIMINATION: cont-- PERSISTENT AND SLOW INFECTION:- The infection persists and causes a prolonged disease which is slow to develop (CARRIERS) Examples are:- HBV, HCV, CMV

FAILURE OF VIRAL ELIMINATION: cont-- ONCOGENIC:- An infection in which part of the viral genome is incorporated into the host genome, resulting in MALIGNANT TRANSFORMATION (CANCER) Examples are:- DNA viruses: Papilloma viruses:- squamous cell papilloma, condyloma accuminatum, Carcinoma of the cervix (HPV)

ONCOGENIC DNA viruses :- Examples Herpes viruses:- Burkitt’s lymphoma and Nasopharyngeal carcinoma (EBV), Hepatitis B virus (HBV): – Hepatocellular carcinoma etc

RNA oncogenic viruses:- Hepatitis C virus (HCV):- Hepatocellular carcinoma Human T cell Lymphotropic Virus-1 (HTLV-1):- Adult T cell leukaemia etc