The word virus was used in medical circles as early as 1790 before the germ theory has been formulated; it then simply meant “poison.” By the end of the 19th century and the climax of the Golden Age of Bacteriology, the causative agent of many infectious diseases had been identified but pathologist realized that there remained some that were not caused by bacteria or protozoa and name this as viruses.
A viroid is a small circular, single stranded RNA molecule that does not apparently code for polypeptides. They cause disease in a variety of plants but not, so far is known in animals.
A virino is the term applied to a hypothetical particle made up of a small, non–coding nucleic acid and molecule associated with a protein of host origin.
A prion is a proteinaceous infectious particle which has no nucleic acid at all. They have been developed in response to very real clinical and laboratory findings that cannot be explained in terms of conventional viruses.
Viroids, virino and prions
are collectively called scrapie–like agents (SLA) after the disease of sheep
that is best studied by this group.
Characteristics of a virus:
1. They are small, usually 0.01 – 0.3 µ in size, retaining infectivity after passage through filters, able to hold back bacteria.
2. They are totally dependent upon living cells (obligate intracellular parasitism), either eukaryotic or prokaryotic, for replication and existence. Some viruses do possess complex enzymes of their own such as RNA or DNA polymerases, but they cannot amplify and reproduce the information in their genomes without assistance.
3. They possess only one species of nucleic acid, either DNA or RNA.
Genome – a viral nucleic acid carrying genetic conformation
Viropexis – is a kind of phagocytosis in which the viral nucleic acid penetrates the parasitized cell.
a. The nucleic acid of all DNA viruses except Parvoviruses is double stranded (but note that hepaDNAvirus DNA is partly single–stranded when not replicating)
b. The nucleic acid of all RNA viruses except REOviruses is single stranded.
(1) Positive stranded – can act directly as messenger RNA (mRNA).
(2) Negative stranded – must be transcribed by a virus–associated RNA transcriptase enzyme to a mirror image positive stranded copy, which is then used as mRNA.
4. They have a component – a receptor binding protein – for attaching to cells so that they can command them as virus production factories.
5. All RNA viruses replicate in cytoplasm, except Orthomyxoviruses and Retroviruses that have replicative stages in nuclei.
6. All DNA viruses require a nucleus, except Poxviruses that can replicate in the cytoplasm.
Structure of virus:
A virion is a complete infectious particle that has the capacity to absorb, penetrate, reproduce and assemble into another complete infectious unit. It has the following components:
1. Nucleocapsid – collective term for capsid together with nucleic acid core.
2. Capsid – a protein shell that encloses the nucleic acid and protects the viral genome from the destructive agents of the environment.
Capsomere – morphologic units on the surface of a virus particle.
3. Envelope – a lipid containing membrane that surrounds some virus particles. It causes fusion of host cells at some stage during their entry.
Classification of viruses:
1. According to the type of nucleic acid present
a. DNA–containing viruses
(1) Parvoviruses
(2) HepaDNAviruses
(3) Papoviruses
(4) Adenoviruses
(5) Herpesviruses
(6) Poxviruses
b. RNA–containing viruses
(1) Picornaviruses
(2) REOviruses
(3) Bunyaviruses
(4) Arboviruses
(5) Togaviruses
(6) Arenaviruses
(7) Coronaviruses
(8) Retroviruses
(9) Orthomyxoviruses
(10) Paramyxovirusus
(11) Rhabdoviruses
(12) Lentiviruses
2. The Baltimore Classification of Viruses
a. Group I (Double-Stranded DNA or dsDNA) – e.g. Adenoviruses, Herpesviruses, Poxviruses
b. Group II (Single-Stranded DNA or ssDNA) – e.g. Parvoviruses
c. Group III (Double-Stranded RNA or dsRNA) – e.g. Reoviruses
d. Group IV (Single-Stranded (+)-Sense or +ssRNA) – e.g. Picornaviruses, Togaviruses
e. Group V (Single-Stranded (–)-Sense RNA or -ssRNA) – e.g. Orthomyxoviruses, Rhabdoviruses
f. Group VI (Single-Stranded RNA with DNA Intermediate or ssRNA-RT) – e.g. Retroviruses
g. Group VII (Double-Stranded DNA with RNA Intermediate or dsDNA-RT) – e.g. Hepadnaviruses
3. According to symptomatology
a. Generalized diseases – smallpox, vaccinia, measles, rubella, chickenpox, yellow fever, dengue, etc.
b. Specific organ disease
(1) Nervous system – poliomyelitis, aseptic meningitis, rabies, anthropod–borne encephalitis, mumps, measles, herpes simplex, etc.
(2) Respiratory tract – influenza, respiratory syncytial virus pneumonia, bronchiolitis, adenovirus, common cold
(3) Skin or mucous membrane – herpes simplex type 1 (oral) and type 2 (genital), molluscum contagiosum, warts, herpangina, herpes zoster
(4) Eye – adenovirus conjunctivitis, keratoconjunctivitis and epidemic hemorrhagic conjunctivitis
(5) Liver – hepatitis, yellow fever, in newborns – enteroviruses, herpesvirus and rubella virus
(6) Salivary glands – mumps and cytomegalovirus
(7) Gastrointestinal tract – rotavirus and Norwalk virus.
(8) Sexually–transmitted disease – herpes simplex, hepatitis B, papilloma, molluscum contagiosum, retrovirus associated with AIDS and cytomegalovirus.
4. According to shape
a. With icosahedral symmetry – all DNA–containing viruses except poxviruses.
b. With helical symmetry – single–stranded RNA viruses
c. Complex – poxviruses
5. According to anatomic areas in the body
a. Dermotropic (skin) – smallpox, measles, chickenpox and herpes simplex
b. Pneumotropic (respiratory tract) – common cold, influenza and viral pneumonia
c. Neurotropic (central nervous system) – rabies, poliomyelitis and encephalitis
d. Viscerotropic (visceral organ) – hepatitis (liver), mumps (salivary
glands)
VIRAL REPRODUCTION
Two phases of viral growth:
1. Eclipse phase – a stage wherein viruses lose its physical identity and most or all their infectivity during the initial stage of replication.
2. Productive phase – new virus particles are produced and released from the cell.
The seven stages of virus replication are categorized as follows:
1. Attachment
Viruses make initial contact with cells at the plasma membrane. The binding of a virion is a specific process that involves the virus attachment protein binding to a cell surface receptor, which will vary depending upon the virus. This determines the tropism of the virus. Some viruses require coreceptors for entry.
All viruses have on their outsides a glycoprotein or glycolipids containing a receptor–binding site which often takes the form of a pocket or a protuberance that reacts specifically with a corresponding receptor on a cell surface.
The binding of a virus attachment protein to a cell surface receptor involves electrostatic forces. Virus attachment proteins will be located on the outermost surface of the virion, whether that is the envelope or capsid (for nonenveloped viruses).
2. Penetration
Penetration refers to the crossing of the plasma membrane by the virus. In contrast to virus attachment, penetration requires energy, although this is contributed by the host cell, not the virus.
A method of penetration that is used exclusively by enveloped viruses is fusion. Fusion of the viral envelope can occur at the cell membrane or within endocytosed vesicles, such as the endosome, and is mediated by the same viral protein that is used by the virus for attachment or by a different viral protein, depending upon the virus.
Viropexis is a kind of phagocytosis in which viral nucleic acid penetrates the parasitized cell. The host cell membrane has the protein clathrin which forms a so-called coated pit and once the virus has attached, inversion of the cellular membrane through which it must negotiate a route to the true internal fusion mediated by viral haemagglutinin (HA) protein. A further requirement of internal fusion is a low pH in the cytoplasmic vacuole which triggers a movement of the three–dimensional structure of the HA protein, so allowing juxtaposition of the fusion sequence with lipid membranes.
|
Method of Penetration of some Human Viruses |
|
|
Type of Penetration |
Virus Examples |
|
Clathrin–mediated
endocytosis |
Dengue virus, hepatitis C
virus, reovirus, adenovirus, parvovirus B19, West Nile virus |
|
Caveolin–mediated
endocytosis |
Human papillomavirus,
SV40, hepatitis B virus |
|
Fusion |
HIV, influenza,
respiratory syncytial virus, herpes simplex viruses, dengue virus, Ebola
virus |
3. Uncoating
Uncoating refers to the breakdown or removal of the capsid, causing the release of the virus genome into the cell to wherever genome replication and transcription will take place.
Many viruses achieve uncoating by escaping from the endosome that they used to enter the cell. Other viruses do not completely uncoat and use the remaining capsid as a home base for replication processes.
Some viruses uncoat at the nuclear envelope immediately before transporting the genome into the nucleus. A few viruses are small enough to pass through the nuclear pores and uncoat in the nucleus.
4. Replication
The viral proteins and messages are expressed. Intermediates such as viral complementary RNA or integrated proviral DNA are needed as described below:
a. Group I: Double-Stranded DNA
This class can be further subdivided into two as follows:
(1) Replication is exclusively nuclear or associated with the nucleoid of prokaryotes. The replication of these viruses is relatively dependent on cellular factors. In some cases, no virus-encoded enzymes are packaged within these virus particles as this is not necessary, whereas in more complex viruses’ numerous enzymatic activities may be present within the particles.
(2) Replication occurs in cytoplasm. These viruses have evolved (or acquired from their hosts) all the necessary factors for transcription and replication of their genomes and are therefore largely independent of the cellular apparatus for DNA replication and transcription. Because of this independence from cellular functions, these viruses have some of the largest and most complex particles known, containing many different enzymes.
b. Group II: Single-Stranded DNA
The replication of these virus genomes occurs in the nucleus, involving the formation of a double-stranded intermediate which serves as a template for the synthesis of new single-stranded genomes. In general, no virus-encoded enzymes are packaged within the virus particle since most of the functions necessary for replication are provided by the host cell.
c. Group III: Double-Stranded RNA
These viruses all have segmented genomes, as each segment is transcribed separately to produce individual monocistronic messenger RNAs. Replication occurs in the cytoplasm and is largely independent of cellular machinery, as the particles contain many virus-encoded enzymes essential for RNA replication and transcription since these processes (involving copying RNA to make further RNA molecules) do not normally occur in cellular organisms.
d. Group IV: Single-Stranded (+)-Sense RNA
These viruses can be subdivided into two groups.
(1) Viruses with polycistronic mRNA such as flaviviruses and picornaviruses. As with all the viruses in this group, the genome RNA represents mRNA which is translated after infection, resulting in the synthesis of a polyprotein product, which is subsequently cleaved to form the mature proteins.
(2) Viruses with complex transcription such as coronaviruses and togaviruses. In this subgroup, two rounds of translation are required to produce subgenomic RNAs which serve as mRNAs in addition to the full-length RNA transcript which forms progeny virus genomes. Although the replication of these viruses involves copying RNA from an RNA template, no virus-encoded enzymes are packaged within the genome since the ability to express genetic information directly from the genome without prior transcription allows the virus replicase to be synthesized after infection has occurred.
e. Group V: Single-Stranded (–)-Sense RNA
The genomes of these viruses can also be divided into two types.
(1) Segmented. The first step in the replication of these viruses (e.g., orthomyxoviruses) is transcription of the (–)-sense RNA genome by the virion RNA-dependent RNA polymerase packaged in virus particles to produce monocistronic mRNAs, which also serve as the template for subsequent genome replication.
(2) Nonsegmented. Monocistronic mRNAs for each of the virus genes are produced by the virus transcriptase in the virus particle from the full-length virus genome. Subsequently, a full-length (+)-sense copy of the genome is synthesized which serves as a template for (–)-sense progeny virus genomes (e.g., paramyxoviruses and rhabdoviruses).
f. Group VI: Single-Stranded RNA with DNA Intermediate
Retrovirus genomes are composed of (+)-sense RNA but are unique in that they are diploid and do not serve directly as mRNA but as a template for reverse transcription into DNA. A complete replication cycle involves conversion of the RNA form of the virus genetic material into a DNA form, the provirus, which is integrated into the host cell chromatin. The enzyme reverse transcriptase needs to be packaged into virus particles to achieve this conversion, as virus genes are only expressed from the DNA provirus and not from the RNA genome found in retrovirus particles of retroviruses.
g. Group VII: Double-Stranded DNA with RNA Intermediate
This group of viruses also relies on reverse transcription, but unlike the retroviruses, this occurs inside the virus particle during maturation. On infection of a new cell, the first event to occur is repair of the gapped genome, followed by transcription. As with group VI viruses, a reverse transcriptase enzyme activity is present inside virus particles, but in this case, the enzyme carries out the conversion of virus RNA into the DNA genome of the virus inside the virus particle. This contrasts with retroviruses where reverse transcription occurs after the RNA genome has been released from the virus particle into the host cell.
5. Assembly
Assembly refers to the packaging of the copied viral genome with newly manufactured viral proteins to create a virion. This can occur in the nucleus, within an organelle like the rER or Golgi complex, or in the cytosol, depending upon the virus.
6. Maturation
Maturation refers to the final changes that must occur within the virion to create an infectious virion rather than an inert particle. This can involve the modification of cell surface receptors, the cleavage of viral polyproteins, or changes to the viral capsid. Maturation is often tightly linked with assembly and/or release.
7. Release
Release refers to the exit of the virion from the cell. This most often occurs through the budding of enveloped viruses or via cell lysis.
Although the range of cytopathic effects (extent of damage to host cells) varies significantly between strains, there are two main modes of viral release: budding (nonlytic) and bursting (lytic).
A virus is budding if it exits the cell via exocytosis with progeny gradually budding out of the plasma membrane until the cell death. The budding mechanism is characteristic of enveloped viruses.
On the other hand, a virus is lytic if it ruptures and kills the host
cell, releasing progeny in one big burst. Naked viruses are often characterized
by a lytic exit strategy.
PATHOGENESIS OF VIRAL INFECTIONS
Pathogenicity compares the severity of disease caused by different microorganisms while virulence compares the severity of the disease caused by different strains of the same microorganisms.
Important events in pathogenesis:
1. Virus must invade the host.
2. Establish a bridgehead by replicating susceptible cells at the site of inoculation.
3. Overcome the local defenses (e.g., lymphocytes, macrophages, interferon)
4. Spread from the site of inoculation to other areas, often via the bloodstream.
5. Undergo further replication in its target area, whether this be localized or generalized
6. Exit from the host in numbers large enough to infect other susceptible hosts and thus ensure its own survival.
Invasion routes of viruses:
1. Entry via abrasions
a. Papillomaviruses
b. Poxviruses
c. Herpes simplex virus
2. Entry via abrasions or inoculation with contaminated needle
a. HepaDNAvirus
b. Lentivirus
3. Entry via insect or animal bites
a. Arboviruses
b. Lyssaviruses
4. Entry via respiratory tract
a. Orthomyxoviruses
b. Paramyxoviruses
c. Rhinoviruses
d. Varicella–zoster
5. Entry via gastrointestinal tract
a. Poliovirus
b. Other Enterovirus
c. Rotavirus
6. Entry via conjunctiva
a. Enterovirus type 70
b. Adenovirus type 8
7. Entry via genital tract
a. Lentivirus
b. HepaDNAvirus
c. Herpes–simplex
d. Papillomavirus
Classification of incubation period exhibited by viruses:
1. Short – means less than a week and primarily applied to viruses causing localized infection that spread rapidly on mucous surfaces. Some viruses injected by an anthropod vector also have short incubation period.
e.g., influenza, common cold
2. Medium – incubation periods range from 7–21 days and is seen in generalized infections.
e.g., poliomyelitis, measles, rubella, varicella, mumps
3. Long – refers to periods measured in weeks or months
e.g., hepatitis A & B, infectious mononucleosis
4. Very long – incubation periods are measured in years, which is why some of the agents involved are known as “slow” viruses.
e.g., Subacute Sclerosing Panencephalitis (SSP), Creutzfeldt–Jakob Disease
ANTIVIRALS
Antiviral drugs are therapeutic agents which inhibits replication or reproduction of viruses. Most of these drugs are administered intramuscularly although a few orally.
Prophylaxes on the other hand are solutions with chemical antiviral which has immediate action usually one hour after administration.
Inhibitory actions of antiviral drugs:
1. Binding to the free virus particle.
2. Interference adsorption or attachment to the receptor binding site on the cell, e.g. soluble CD4
3. Inhibition of virus uncoating and release of nucleic acid.
4. Inhibition of viral nucleic acid transcription and replication.
a. Influenza – RNA transcriptase
b. Herpes – thymidine kinase; DNA polymerase
c. HIV – Reverse transcriptase; Integrase, Protease
5. Interference with cellular processing of viral polypeptides by preventing addition of sugar or acyl groups.
6. Prevention of budding.
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