Pathogenesis of viruses

PRINCIPLES OF VIRAL DISEASES

• The fundamental process of viral infection is the viral replicative cycle.

The cellular response to that infection may range from no apparent
effect to cytopathology with accompanying cell death to hyperplasia
or cancer.
• Viral disease is some harmful abnormality that results from viral
infection of the host organism.
• Clinical disease, syndrome, subclinical
PRINCIPLES OF VIRAL DISEASES
• Important principles that pertain to viral disease include the
following:
Many viral infections are subclinical;
The same disease syndrome may be produced by a variety of viruses;
The same virus may produce a variety of diseases; and
The outcome in any particular case is determined by both viral and
host factors and is influenced by the environmental context and
genetics of each.
PRINCIPLES OF VIRAL DISEASES
• Viral pathogenesis is the process that occurs when a virus infects a cell and
causes cellular changes.
• Disease pathogenesis is a subset of events during an infection that results in
disease manifestation in the host.
• A virus is pathogenic for a particular host if it can infect and cause signs of
disease in that host.
• A strain of a certain virus is more virulent than another strain if it commonly
produces more severe disease in a susceptible host.
• Viral virulence in intact animals is not necessarily related to cytopathogenicity
for cultured cells; viruses highly cytocidal in vitro may be harmless in vivo,
and, conversely, noncytocidal viruses may cause severe disease.
PATHOGENESIS OF VIRAL DISEASES
• To produce disease, viruses must enter a host, come in contact with
susceptible cells, replicate, and produce cellular injury.
• Steps in Viral Pathogenesis:
• Specific steps involved in viral pathogenesis are the following:
viral entry into the host,
primary viral replication,
viral spread,
cellular injury,
host immune response,
viral clearance or establishment of persistent infection, and
viral shedding.
PATHOGENESIS OF VIRAL DISEASES
• The ability of viruses to cause disease can be viewed on two distinct
levels:
• (1) the changes that occur within individual cells and
• (2) the process that takes place in the infected patient
THE INFECTED CELL
There are four main effects of virus infection on the cell:
• (1) death,
• (2) fusion of cells to form multinucleated cells,
• (3) malignant transformation, and
• (4) no apparent morphologic or functional change
Cell death
• Death of the cell is probably due to inhibition of macromolecular
synthesis.
• Inhibition of host cell protein synthesis frequently occurs first and is
probably the most important effect.
• Inhibition of DNA and RNA synthesis may be a secondary effect. It is
important to note that synthesis of cellular proteins is inhibited but viral
protein synthesis still occurs. For example, poliovirus inactivates an
initiation factor (IF) required for cellular mRNA to be translated into
cellular proteins, but poliovirus mRNA has a special ribosome-initiating
site that allows it to bypass the IF so that viral proteins can be
synthesized.
Fusion of cells to form multinucleated cells
• Fusion occurs as a result of cell membrane changes, which are
probably caused by the insertion of viral proteins into the membrane.
• Example- herpesviruses and paramyxoviruses.
• The clinical diagnosis of herpesvirus skin infections is aided by the
finding of multinucleated giant cells with eosinophilic intranuclear
inclusions in skin scrapings.
Fusion of cells to form multinucleated cells
• A hallmark of viral infection of the cell is the cytopathic effect (CPE).
• This change in the appearance of the infected cell usually begins with
a rounding and darkening of the cell and culminates in either lysis
(disintegration) or giant cell formation.
• Detection of virus in a clinical specimen frequently is based on the
appearance of CPE in cell culture. In addition, CPE is the basis for the
plaque assay, an important method for quantifying the amount of
virus in a sample.
Malignant transformation
• Infection with certain viruses causes malignant transformation, which
is characterized by unrestrained growth, prolonged survival, and
morphologic changes such as focal areas of rounded, piled-up cells.
The infected patient
• The stages of a typical viral infection are the same as those for a
bacterial infection including:
• an incubation period during which the patient is asymptomatic,
• a prodromal period during which nonspecific symptoms occur,
• a specific-illness period during which the characteristic symptoms and
signs occur, and
• a recovery period during which the illness wanes and the patient
regains good health.
• In some patients, the infection persists and a chronic carrier state or a
latent infection occurs
Transmission & Portal of Entry
• Viruses are transmitted to the individual by many different routes,
and their portals of entry are varied.
• Can have:
• Respiratory tract
• GIT
• Skin
• Genital tract
• Blood
• Transplacental- at birth- breastfeeding
Localized or Disseminated Infections
• Most viral infections are either localized to the portal of entry or
spread systemically through the body.
• Local spreed e.g respiratory viruses- rhonovirus
• Systemic-Blood e.g. poliomyelitis, measles
Neural e.g rabies, herpes virus
Pathogenesis & Immunopathogenesis
• The signs and symptoms of most viral diseases undoubtedly are the
result of cell killing by virus-induced inhibition of macromolecular
synthesis.
• Death of the virus-infected cells results in a loss of function and in the
symptoms of disease.
• Example:
• The hemorrhages caused by Ebola virus are due to the damage to the
vascular endothelial cells caused by the envelope glycoprotein of the
virus.
Virulence
• Strains of viruses differ greatly in their ability to cause disease. For
example, there are strains of poliovirus that have mutated sufficiently
such that they have lost the ability to cause polio in
immunocompetent individuals (i.e., they are attenuated). These
strains are used in vaccines.
• The viral genes that control the virulence of the virus are poorly
characterized, and the process of virulence is poorly understood.
Evasion of Host Defenses
• Viruses have several ways by which they evade our host defenses
• These processes are often called immune evasion.
• Two very important processes are:
Synthesis of receptors for immune mediators and
Reduction of expression of class I MHC proteins
Persistent Viral Infections
• In most viral infections, the virus does not remain in the body for a significant
period after clinical recovery. However, in certain instances, the virus persists
for long periods either intact or in the form of a subviral component (e.g., the
genome).
• The mechanisms that may play a role in the persistence of viruses include:
Integration of a DNA provirus into host cell DNA, as occurs with retroviruses;
Immune tolerance, because neutralizing antibodies are not formed;
Formation of virus–antibody complexes, which remain infectious;
Location within an immunologically sheltered “sanctuary” (e.g., the brain);
Rapid antigenic variation;
Spread from cell to cell without an extracellular phase, so that virus is not
exposed to antibody;
Immunosuppression, as in acquired immunodeficiency syndrome
Persistent Viral Infections
• There are three types of persistent viral infections of clinical
importance.
• They are distinguished primarily by whether virus is usually produced
by the infected cells and by the timing of the appearance both of the
virus and of the symptoms of disease.
Chronic-Carrier Infections
Latent Infections
Slow Virus Infections
Laboratory Diagnosis
• There are five approaches to the diagnosis of viral diseases by the use
of clinical specimens:
identification of the virus in cell culture,
microscopic identification directly in the specimen,
serologic procedures to detect a rise in antibody titer or the presence
of IgM antibody,
detection of viral antigens in blood or body fluids, and
detection of viral nucleic acids in blood or the patient’s cells
IDENTIFICATION IN CELL CULTURE
• The growth of viruses requires cell cultures because viruses replicate
only in living cells, not on cell-free media the way most bacteria can.
• Because many viruses are inactivated at room temperature, it is
important to inoculate the specimen into the cell culture as soon as
possible; brief transport or storage at 4°C is acceptable
IDENTIFICATION IN CELL CULTURE
• Virus growth in cell culture frequently produces a characteristic
cytopathic effect (CPE) that can provide a presumptive identification.
CPE is a change in the appearance of the virus-infected cells.
• This change can be in such features as size, shape, and the fusion of
cells to form multinucleated giant cells (syncytia).
• CPE is usually a manifestation of virus-infected cells that are dying or
dead.
• The time taken for the CPE to appear and the type of cell in which the
virus produces the CPE are important clues in the presumptive
identification.
IDENTIFICATION IN CELL CULTURE
• If the virus does not produce a CPE, its presence can be detected by several other
techniques:
• (1) Hemadsorption (i.e., attachment of erythrocytes to the surface of virus-infected
cells). This technique is limited to viruses with a hemagglutinin protein on their
envelope, such as mumps, parainfluenza, and influenza viruses.
• (2) Interference with the formation of a CPE by a second virus. For example, rubella
virus, which does not cause a CPE, can be detected by interference with the
formation of a CPE by certain enteroviruses, such as echovirus or Coxsackie virus.
• (3) A decrease in acid production by infected, dying cells. This can be detected
visually by a color change in the phenol red (a pH indicator) in the culture medium.
The indicator remains red (alkaline) in the presence of virus infected cells but turns
yellow in the presence of metabolizing normal cells as a result of the acid
produced. This technique can be used to detect certain enteroviruses.
IDENTIFICATION IN CELL CULTURE
• A definitive identification of the virus grown in cell culture is made by
using known antibody in one of several tests. Complement fixation,
hemagglutination inhibition, and neutralization of the CPE are the
most frequently used tests.
• Other procedures such as fluorescent antibody, radioimmunoassay,
enzyme-linked immunosorbent assay (ELISA), and immunoelectron
microscopy are also used in special instances.
MICROSCOPIC IDENTIFICATION
• Viruses can be detected and identified by direct microscopic
examination of clinical specimens such as biopsy material or skin
lesions.
• Three different procedures can be used.
• (1) Light microscopy can reveal characteristic inclusion bodies or
multinucleated giant cells. The Tzanck smear, which shows
herpesvirus-induced multinucleated giant cells in vesicular skin
lesions, is a good example.
• (2) UV microscopy is used for fluorescent antibody staining of the
virus in infected cells.
• (3) Electron microscopy detects virus particles, which can be
characterized by their size and morphology.
SEROLOGIC PROCEDURES
• A rise in the titer of antibody to the virus can be used to diagnose
current infection. Seroconversion is the term used to describe the
finding of antibody to a virus (or any microbe) in a patient’s serum
when the patient previously had no antibody.
• Stated another way, the patient’s serum has converted from antibody-
negative to antibody-positive.
• A serum sample is obtained as soon as a viral etiology is suspected
(acute-phase), and a second sample is obtained 10 to 14 days later
(convalescent-phase).
• If the antibody titer in the convalescent-phase serum sample is at least
fourfold higher than the titer in the acute-phase serum sample, the
patient is considered to be infected.
SEROLOGIC PROCEDURES
• It is important to realize that an antibody titer on a single sample does
not distinguish between a previous infection and a current one. The
antibody titer can be determined by many of the immunologic tests
mentioned previously.
• These serologic diagnoses are usually made retrospectively because
the disease has frequently run its course by the time the results are
obtained.
• In certain viral diseases, the presence of IgM antibody is used to
diagnose current infection.
DETECTION OF VIRAL ANTIGENS
• Viral antigens can be detected in the patient’s blood or body fluids by
various tests, but most often by an ELISA.
• Tests for the p24 antigen of human immunodeficiency virus (HIV) and
the surface antigen of hepatitis B virus are common examples of this
approach.
DETECTION OF VIRAL NUCLEIC ACIDS
• Viral nucleic acids (i.e., either the viral genome or viral mRNA) can be
detected in the patient’s blood or tissues with complementary DNA or
RNA (cDNA or cRNA) as a probe.
Clinical presentation for viral infection
• Symptoms of a viral infection depend on where infection occurs, and
this can include:
• General symptoms: fever, muscle ache, headache, joint pains, fatigue
• Upper respiratory symptoms: Flu-like symptoms, sore throat, cough,
sneezing.
• Digestive symptoms: nausea, vomiting, diarrhea.
• Skin conditions: rashes, sores, blisters, warts.
• CNS
• Many viral infections don’t cause any symptoms
General approach to management of viral
infection
• Treatment of symptoms
• Antiviral drug use
General Complications of viral infection- not exhaustive- look
for more
• Inflammation in your lungs (pneumonia). Respiratory illnesses can infect your lungs and
cause swelling that can make it hard to breathe. You may have to be treated in the
hospital for severe pneumonia.
• Inflammation in your brain or its lining (encephalitis or meningitis). If a virus moves to
your brain from another part of your body, it can cause swelling. This can be life-
threatening.
• Severe bleeding. Hemorrhagic illnesses, like severe dengue, can cause life-threatening
bleeding.
• Reactivation. Some viral infections can stay in your body for a long time, even if you no
longer have symptoms — or you never had symptoms at all. A virus that’s not
reproducing or causing symptoms in your body is called dormant. Viruses like Epstein-
Barr (EBV), HPV, herpes simplex and varicella can reactivate in your body and cause
symptoms years later.
• Paralysis- e.g polio etc
• Cancer. Some viruses that stay in your body for long periods of time can cause cancer
(oncoviruses). HPV, Epstein-Barr, hepatitis B and C, human T-lymphotropic virus 1 (HTLV-
Prevention of viral infection
• Hygienic factors such as efficient sanitation facilities, effective waste
disposal, clean water, and personal cleanliness, avoiding overcrowded
areas, minimizing contact etc ( stop the transmission)
• Active immunization by vaccines (antigen-containing preparations
that elicit the synthesis of antibodies and thus immunity) has been
useful in preventing common epidemics caused by acutely infectious
viruses.