Download College of Medicine Microbiology

College of Medicine
Microbiology
Medical Virology
Control on viral infections:
Dr. Jawad K. AL-Khafaji
----------------------------------------------------------------------------Control on viral infections and diseases by the following main
methods:
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2.
3.
4.
Host defenses.
Viral vaccines.
Antiviral chemotherapy.
Public hygiene (include personal and community).
1-Host defenses:
Host defenses against viruses fall into two major categories:
1. Non specific defenses (innate immunity) , of which the most
important are anatomic barriers, interferon (IFN) and natural
killer(NK)cells.
2. Specific defenses(acquired immunity), including both humoral and
cellular immunity .
A-Non specific host defenses:
1. Anatomic barriers :
Anatomic barriers are located at body surface (skin and mucosa) or
within the body (endothelial cell). They are partly effective in preventing
viral infection.
2. Interferon :
Interferon is glycoprotein produced by any type of cell (all vertebrate
species) after viral infection .
Interferons are produced from infected cell with virus to protect other
cells from viral infection. Interferon does not protect the virus-infected
cell that is produce it.
Interferons are divided into three types based on the cell of origin:
1. IFN-alpha is produced by leukocytes.
2. IFN-beta is produced by fibroblasts.
3. IFN-gamma is produced by lymphocytes .
•IFN-alpha and beta are induced by viruses , whereas IFN-gamma is not
produced in response to most viruses but is induced by mitogen
stimulation. The induction of IFN is not specific to any virus.
•Action of IFN: IFN inhibits replication of widely viruses range. IFN
don’t interact directly with virus but move to other cells , and bind to
receptor on cell surface which induces the cells to activate specific
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signals for synthesis of antiviral proteins (AVP)that are usually result in
an inhibit viral replication. IFN inhibit the growth of virus by blocking
the translation of viral mRNA into proteins without affecting the
translation of cellular mRNA.
3. NK cells and phagocytosis :
NK cells are important parts of the innate defenses against virus-infected
cells. They kill virus-infected cells by secreting some enzymes, which
cause death of the infected cells.
Viruses may be phagocytosed by different PMN leukocytes and
macrophages. The effect of phagocyosis may be virus inactivation ,and
result in clearance of virus.
4. Inflammation and Fever:
Inflammation inhibits viral replication through (i)elevated local
temperature (ii)reduced oxygen tension (iii) metabolic alteration, and
(iv)acid production.
Fever may act in two ways(1)higher body temperature may inactivate the
virus particle , particularly enveloped viruses , which are more heatsensitive than non enveloped viruses.(2)fever may inhibit replication of
some viruses.
B-Specific host defenses:
Specific defenses, including both humoral and cell-mediated immunity
(CMI).
The most important type of host defense is acquired immunity, either
actively acquired by exposure to the virus , or passively acquired by
transfer of immune serum (such as : transfer of IgG from mother to fetus
across placenta, or transfer of IgA from mother to newborn in the
colostrums).
The first exposure to virus stimulates the production of antibodies and
activation of cytotoxic T-cell. The IgM and IgG confer protection against
viruses that enter or are spread through the blood. Secretory IgA is
important in protecting against infection by virus that enters through
mucosa of respiratory and gastrointestinal tracts .
How does Ab inhibit virus? Two main mechanisms for kill virus by
antibodies:
• First; neutralization of infectivity of virus by Abs binding to viral
antigens(proteins on the surface of virus). This binding lead to prevent the
interaction of virus with cellular receptor and inhibit viral replication .
The Ab-coated virus is more rapidly phagocytized than normal virus.
• Second; is lysis of virus-infected cell in presence of Ab and
complement. Ab binds to virus antigens and then binds complement,
which enzymatically degrades the cell membrane of virus-infected cell.
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Because the cell is killed before yield of virus is produced, the spread of
virus is significantly reduced.
Action of cellular immunity : Lyses of virus-infected cell by cytotoxic Tcell. The T-cell recognizes viral antigens only when it is presented in
association with classI MHC. They kill virus-infected cell by three
methods :
(1) releasing perforins ,which make holes in cell membrane of infected
cell .
(2) releasing proteolytic enzymes into infected cell, which degrade the
contents of the cell.
2-Viral vaccines:
Prevention of viral diseases can be achieved by use of vaccines that
induce active immunity.
Main types of viral vaccines are ;
(i) attenuated live-virus vaccine, and (ii) killed-virus vaccine.
Attenuated-virus vaccines: The vaccines contain live virus whose
pathogenicity has been attenuated (weakened) .The pathogenicity of virus
is attenuated either by serial passages in animals or by repeated
subculturing in cell cultures.
The live vaccine is preferred to vaccine containing killed virus because
the live vaccine has several advantages.
1.The virus in such vaccine can be replicate in the host and tend to :
(i)stimulate Ab production (IgG) in longer duration, and induce local Ab
production(IgA) , therefore resistance at portal of entry.
(ii)induce a good cell-mediated response, and stimulate cytotoxic T-cell.
2. In vaccination with live vaccines lead to herd immunity because the
attenuated viruses can replicate in immunized persons and spread to other
members of population, thereby increasing the number of people
protected.
Disadvantages of these vaccines ;
(1) the attenuated virus has risk reversion , the virus can revert to
virulence during vaccine preparation or in immunized person . For this
reason, live vaccine should not be given to immunocompromised peoples
or pregnant women because the fetus may become infected .(2)
Interference may occur with other viruses result in contamination of
vaccine during vaccine preparation.
Killed-virus vaccines: The vaccines contain killed virus (killed by
chemicals such as formalin or by UV radiation or by heating).
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The killed vaccines have two advantages,(1) they can not revert to
virulent, and(2) they are more heat-stable (at room temperature) ,
therefore can be used more easily ,especially in tropical climate.
The vaccines have many disadvantages ; (1)cell-mediated immunity is
poor and don’t stimulate cytotoxic T-cells because the virus in the
vaccine does not replicate .(2) stimulate IgG and IgM in shorter duration,
but do not induced local resistance (IgA) therefore not resistance at portal
of entry. Because they induce shorter duration of Ab production are less
protective. The immunity conferred is often brief, and must be boosted.
(3)Some killed vaccines may induce hypersensitivity to subsequent
infection.
Most viral vaccines are usually given before exposure to viral infection
(pre-exposure) except two vaccines , rabies and hepatitis-B vaccines are
effective when given post-exposure because the incubation period of
disease is long enough that the vaccine-induced immunity can prevent the
disease.
3-Antiviral Chemotherapy:
The viruses are unaffected by antibiotic agents but affected by antiviral
chemotherapy agents and interferon .
Number of antiviral drugs(AVD) is very few compared with large
number of antibacterial drugs. The major reasons for these difference and
limitation are due to some problems with viral chemotherapy:
1. All viruses are obligate intracellular parasites.
2. Obligatory dependence upon metabolic of host cell. Therefore , AVD
interfere with cellular processes. Antiviral drugs are difficulty in
obtaining selective toxicity against viruses without normal cell.
3. Some viruses become latent within host cells, and no antiviral drug can
eradicate them.
4. Drug-viral mutants may occur in some viruses , and cause drugresistant viruses.
Mode of action :
Antiviral chemotherapy drugs are available to treat only a few viral
diseases. Antiviral drugs (AVD) specifically inhibit one or more steps of
viral replication , which act as target site for AVD.
1. Inhibition of early events of viral infection(attachment ,penetration,
uncoating).
2. Inhibition of viral N.A replication .
3. Inhibition of viral proteins synthesis.
4. Inhibition of late events (assembly and release).
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Inhibition of early events:
Antiviral drugs inhibit early events of viral life cycle by removal of
binding sites of viruses .
Enfuvirtide(Fuseon) : The drug prevents viral infection by inhibiting
attachment and penetration process. The drug is used to treat HIV
infection. It binds to cellular receptor on cell surface , thereby blocking
the entry of HIV into the cell.
Amantadine(Symmetrel): It prevents viral infection by inhibiting
uncoating of virus by blocking the ion-channel activity of matrix protein
in the virion. The absorption(attachment) and penetration occur normally,
but transcription of viral mRNA by RNA polymerase does not occur
because uncoating can not occur. This drug specifically inhibits influenza
A virus, but not inhibit influenza B and C.
The main side effects of amantadine are CNS alteration such as dizziness,
ataxia, and insomnia.
Inhibition of viral N.A synthesis:
A. Nucleoside inhibitors:
Acyclovir(Zovirax) :Acyclovir is guanosine analogue that active against
DNA polymerase of herpes simplex virus-1(HSV-1) and HSV-2,and
Varicella-zoster virus(VZV) .
Acyclovir must be activated within infected cell by virus-encoded
thymidine kinases that phosphorylate the drug. The drug is not
phosphorylated in uninfected cell, the cellular DNA synthesis is not
inhibited .The drug binds to DNA polymerase, which lead to inhibit viral
replication. Selective toxicity is high and there are very few adverse
effects.
Azidothymidine(AZT, zidovudine, Retrovir) : nucleoside analogue
drug . It is particularly effective against DNA synthesis by inhibits DNA
polymerase (reverse transcriptase )of HIV and inhibits growth of the
virus. The main side effects of AZT are bone marrow suppression and
myopathy.
B. Non-Nucleoside inhibitors:
Foscarnet(Foscavir):is pyrophosphate analogue . It binds to DNA
polymerase at pyrophosphate cleavage site and prevents removal of
phosphate from nucleoside triphosphate (dNTP). This inhibits the
addition of next dNTP to growing DNA chain.
Foscarnet inhibits DNA polymerase of all herpes viruses and HIV . It is
also used to treat patient infected with acyclovir-resistant of HSV-1 and
VZV.
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Inhibition of viral protein synthesis:
Fomivirsen(Vitravene): The drug binds to viral mRNA within infected
cell and prevents it from being translated into viral proteins. This drug
active in blocks the replication of cytomegaloviruses(CMV).
Methisazone: specifically inhibits the protein synthesis of poxviruses by
blocking the translation of viral mRNA.
Interferon(IFN): Synthetic IFN is used in treatment of some viral
viruses. Recombinant alpha-IFN is effective in treatment of patients with
chronic HBV and HCV. IFN inhibits translation of viral mRNA into
proteins.
Inhibition of late events:
Zanamivir (Relenza) and Oseltamivir (Tamiflu): These drugs inhibit
neuraminidase enzyme . This enzyme is located on surface of the
influenza virus and is required for release of the virus from infected cell.
Inhibition of release of influenza virus limits the infection by reducing the
spread of the virus from cell to another. These drugs are effective against
both influenza A and B viruses. Also effective against strains of influenza
virus resistant to amantadine.
N.B
Antibiotic agents are not effected on viruses , therefore it can not used in
treatment of viral infection , but they used in cases of viral infections to
prevent occurring any secondary infection with bacteria.
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