2. VIRAL GENETIC MODIFICATIONS
Viruses show genetic modifications by two principal methods—
(1) mutations
(2) interactions between viral genes or their gene products (proteins).
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3. 1. MUTATION
A mutation is a change that occurs in viral nucleic acid sequence, either due to
mistakes when the viral genome is copied or as the result of environmental factors
Occur during every viral infection, at a frequency of 10-4 to 10-8 mutations per base per generation.
Becomes evident only if it induces some readily observable property or leads to survival or death of the
virus.
Mutants occur spontaneously or may be induced chemically (e.g. 5-fluorouracil) or by physical agents
such as UV light or irradiation.
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B.1.1.7 –UK Strain
30 and 100 per cent more deadly than
previous strains.
4. TYPES OF MUTATIONS
Conditional lethal mutant can grow only in specific conditions called
permissive conditions, but cannot grow in other conditions.
Temperature sensitive mutant
• Type of conditional lethal mutant that can grow at a low
(permissive)temperature (28-31°C), but not at higher (restrictive)
temperature (37°C).
• ts mutants have been used for preparation of live viral vaccines(e.g. ts
influenza vaccine).
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5. INTERACTIONS BETWEEN VIRAL GENES
When two or more virus particles infect the same host cell, there occurs a variety
of interactions, both genetic and non-genetic.
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Genetic Recombination
•Occurs between two different but related viruses of the same family infecting a
host cell simultaneously
•Two viruses exchange segments of nucleic acids between them so that a hybrid
(recombinant virus) results
•Hybrids- possess new genes not found in both the parent viruses, are genetically
stable and able to replicate.
6. REASSORTMENT
Type of recombination seen in segmented RNA viruses such as influenza, rota,
bunya, and arena viruses.
When two strains of influenza virus infect a host cell, gene exchanges take
place between the RNA segments resulting in production of reassortants.
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7. VIRAL INTERFERENCE
When two viruses infect a host cell or a cell line, sometimes it leads to inhibition of
one of the virus, called viral interference
Interference does not occur with all viral combinations; many viruses may infect and
multiply together in a host cell.
Oral Polio Vaccine (OPV) is a classical example where viral interference is seen.
OPV serotypes interfere with the spread of wild poliovirus, thus played a crucial role
in control of polio outbreaks.
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8. PATHOGENESIS OF VIRAL INFECTIONS
Transmission (entry into the body)
Primary Viremia
Secondary Viremia
Manifestations of the disease
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9. TRANSMISSION AND SPREAD OF VIRUSES
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Mode of transmission Produce Local infection at the portal of
entry
Spread to distant sites from the portal of
entry
Respiratory route
(probably the most common
route)
Produce Respiratory infection-
1. Influenza virus
2. Parainfluenzavirus
3. Respiratory syncytial virus
4. Rhinovirus
5. Adenovirus
6. Coronavirus such as SARS-COV2
7. Herpes simplex virus
Measles virus
Mumps virus
Rubella virus
Varicella-zoster virus
Cytomegalovirus
Parvovirus
Small pox virus
Oral route Produce gastroenteritis
1. Rotavirus
2. Adenovirus-40,41
3. Calicivirus
4. Astrovirus
Poliovirus
Coxsackie virus
Hepatitis Virus – A & E
Cytomegalovirus
Epstein-Barr virus (EBV)
10. TRANSMISSION AND SPREAD OF VIRUSES (CONT..)
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Mode of transmission Produce Local infection at the portal of
entry
Spread to distant sites from the portal of
entry
Cutaneous route Produce skin lesions
Herpes simplex virus
Human papilloma virus
Molluscum contagiosum virus
1. Herpes simplex virus
Vector bite - Arboviruses such as-
1. Dengue virus (Aedes)
2. Chikungunya virus(Aedes)
3. Japanese encephalitis virus (Culex)
4. Yellow fever and Zika virus(Aedes)
5. Kyasanur Forest disease virus (Tick)
Animal bite - 1. Rabies virus
11. TRANSMISSION AND SPREAD OF VIRUSES (CONT..)
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Mode of transmission Produce Local infection at the portal of entry Spread to distant sites from the portal of
entry
Sexual route Produce genital lesions-
1. Herpes simplex virus
2. Human papilloma virus
Hepatitis B, C& rarely D
HIV
Blood transfusion - 1. Hepatitis B, C & rarely D
2. HIV
3. Parvovirus
Injection - Hepatitis B, C & rarely D
HIV
Transplacental
route
Produce congenital manifestations in fetus
1. Rubella virus
2. Cytomegalovirus (CMV)
3. Herpes simplex virus
4. Varicella-zoster virus
5. Parvovirus
Transmitted through placenta to fetus, without congenital
manifestations
1. Measles virus
2. Mumps virus
3. Hepatitis B virus
4. Hepatitis C virus
5. Hepatitis D virus
6. HIV
Conjunctival route 1. Adenovirus
2. Enterovirus70
3. Coxsackie virus A-24
4. Herpes simplex virus
12. PRIMARY SITE OF REPLICATION
Some viruses are restricted to the portal of entry where they multiply and
produce local diseases.
They spread locally over the epithelial surfaces, but there is no viremia
or spread to distant sites.
They have a shorter incubation period and shorter duration of immunity.
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13. PRIMARY SITE OF REPLICATION (CONT..)
On the other hand, most viruses multiply locally to initiate a silent local
infection which is followed by the spread via lymphatics to regional
lymph nodes (most viruses) or via blood (e.g. polio virus) or via neuronal
spread to reach CNS (e.g. rabies virus).
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14. MANIFESTATIONS OF VIRAL INFECTIONS
1. lncubation Period:
Time interval between entry of the virus into the body and appearance of first
clinical manifestation.
Depends on the distance between site of entry and the target organ.
Shorter - if the virus produces lesions near to the site of entry e.g. influenza
Longer - if the target organ is much far from the site of entry; e.g. polio virus and
rabies virus
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Exception- For e.g. Hepatitis B virus, IP 30-180days.
Other factors that depends on the incubation period such as host immune response,
nature of the virus etc.
15. 2. Clinical Manifestations:
Inapparent (subclinical) infection
Apparent (clinical) infection- may be acute, subacute or chronic in nature
depending upon onset of illness.
Respiratory viruses such as influenza and coronaviruses produce upper and lower
respiratory tract infections
Gastroenteritis may be produced by viruses such as Rotavirus and Norwalk virus
Hemorrhagic fever may be a manifestation of viruses such as Dengue, Ebola
virus etc
Neurotropic viruses can produce meningitis (Enteroviruses) or encephalitis
(Rabies, Japanese encephalitis)
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16. VIRAL PATHOGENESIS AT CELLULAR LEVEL
Three types of infections in a host cell which in turn depends on the nature
of the virus and the cell infected.
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Types of Infection
1.Failed Infection (Abortive
Infection)
Occurs if the virus infects the host
cells which are non permissive (i.e.
absence of surface receptors or
machineries to support viral
replication)
2. Cell Death (Cytocidal or lytic
Infection)
1. Viruses adopt different mechanisms to induce
host cell death such as:
2. Inhibition of host cell DNA by herpesvirus
3. Inhibition of host cell protein synthesis by
poliovirus
4. Fusion (syncytia formation)
5. Immune mediated lysis
3. Infection without Cell
Death
Steady state infection -
The virus and host cell enter into a
peaceful coexistence, both
replicating independently
1. Latent infection E.g Herpes, HIV,
Slow virus infection
2. Cell Transformation E.g
Oncogenic viruses –HBV, EBV,
HPV
3. Persistent tolerant infection
(Lymphocytic Choriomeningitis
Virus infecting mice)
17. MORPHOLOGICAL CHANGES IN THE HOST CELLS
1. Certain viruses induce characteristic changes in the host cells (e.g. inclusion body), which can be
detected by histopathological staining.
2. Aggregates of virions or viral proteins & other products of viral replication that confer altered staining
property to the host cell.
3. Characteristic of specific viral infections.
4. They have distinct size, shape, location and staining properties by which they can be demonstrated in
virus infected cells under the light microscope
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18. 18
Types of Inclusion Bodies
1. Intracytoplasmic inclusion bodies –
generally acidophilic -pink structures
with Giemsa or Eosin Methylene blue
stains.
2. Intranuclear inclusion bodies are
basophilic
Cowdry type A inclusions are variable
in size and have granular appearance
Cowdry type B inclusions are more
circumscribed and multiple
3. Both intracytoplasmic &
intranuclear inclusions.
Negri bodies –Rabies virus
Paschen body- Variola virus
Guarnieri bodies - Vaccinia virus
Bollinger bodies - Fowl pox virus
Molluscum bodies - Molluscum contagiosum
virus
Perinuclear cytoplasmic body- Reovirus
A)Cowdry type A inclusions
1. Torres body- seen in Yellow fever
2. Lipschultz body - seen in Herpes simplex
B)Cowdry type B inclusions - seen in
1. Poliovirus
2. Adenovirus
Owl’s eye appearance- seen in
Cytomegalovirus
Measles
19. INTERFERONS
The term interferon derives from the ability of these cytokines to interfere with viral replication
Interferons (IFNs) are family of a host coded glycoprotein produced by a variety of host cells on induction by viral or non viral inducers
during cellular transcription and protein synthesis .
Clinical Uses:-
Antiviral – Induces resistance to viral infections, High dose local application shows some benefits in URTI, Herpetic
keratitis, genital warts, imitated use in Hepatitis B, Hepatitis C infection and lymphoma.
Antimicrobial- resistance to intracellular infections e.x Toxoplasma, Malaria and Chlamydia
Cellular effects- a. inhibition of cell growth and proliferation
b. Inhibition of DNA and Protein synthesis
c. increased expression of MHC antigens on cell surface
Immunoregulatory effects- a. incresead cytotoxic activity of Nk cells, K cells and T cells(Tsupressor cell)
b. activation of macrophage cytocidal activity
c. modify the antibody formation
d. Supressive DTH
Research suggests that IFNs may also be beneficial in the treatment of other viral, autoimmune, and neoplastic
conditions of the nervous system like multiple sclerosis
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20. PROPERTIES OF INTERFERONS
• It is a natural defence mechanism possessed by vertebrate cells against viral infections
• IFN are species specific
• They are not virus specific
• IFN production can be increased by increasing temperature to 40C
• Inhibited by steroids and high oxygen tension
• Inactived by Proteolytic enzyme but not by lipases and nucleases
• Resist heating at 56-60C for one hour
• Mol.wt – 17,000
• Non dialysable, non sedimentable
• Poorly antigenic so no serological test.
•Non toxic, diffusible freely in the body
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Types of Interferons
IFN-I
1. IFN-α (further classified into 13
different subtypes IFN-α1, -α2, -α4, -
α5, -α6, -α7, -α8, -α10, -α13, -α14, -
α16, -α17 and -α21), IFNα- produced
by leukocytes
2. IFN-β. produced by fibroblasts
IFN-II
Only one sub type IFN-γ produced
by lymphocytes
IFN-III
denoted IL-28/29,
Important role in host defense against
viral infections
Biological effects are like IFN-I
22. MECHANISMS OF ACTION
1. IFNs, besides being first line of defence and part of innate immunity against viral infections,
2. Play important roles in immunosurveillance for malignant cells.
3. On exposure to IFN cells produce TIP (Translation Inhibitory Protein) which selectively
inhibits the translation of viral mRNA without affecting cellular mRNA
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Stimulate resistance to
viral replication in all
cells through cellular
genes activation, with
the consequent
Destruction of the viral
mRNA and
Inhibition of the viral
proteins translation
NK cells mediated lysis
of virus-infected cells
23. QUESTIONS:
Q1. All of the following viruses are transmitted by respiratory
route, except:
a. Influenza virus
b. Rotavirus
c. RSV
d. Rhinovirus
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