Index
They are common pathogens in humans and animals.
Furthermore, several strains have been the subject of intensive research and are used as tools in mammalian molecular biology .
More than 100 serologically distinct types of adenovirus have been identified, including 49 types that infect humans.
The Adenoviridae family is divided into two genera:
- Mammalian adenoviruses ( mastadenoviruses ).
- Los adenovirus aviares (aviadenovirus).
Adenoviruses are named after human adenoids, from which they were first isolated.
Various adenoviruses can cause respiratory and conjunctival diseases. In addition, some types of human adenoviruses induce undifferentiated sarcomas in newborn hamsters and other rodents and can transform certain rodent and human cell cultures.
There is currently no evidence that adenoviruses are oncogenic in humans, but the possibility remains interesting.
Symptoms of adenovirus infection
Symptoms of an adenovirus infection are similar to those associated with a common cold.
Sick children may have:
- Stuffy or runny nose
- Throat pain.
- Infection of the breathing tubes in the lungs.
- Inflammation of the eyelids.
- Fever.
- Middle ear infection
- Pneumonia .
Some children may have a harsh cough similar to whooping cough.
Sometimes, there may be some bleeding from the covering of your swollen eyes. While adenovirus can make a person’s eyes look very sick, their vision is not affected.
Children who are infected with some strains of the adenovirus develop inflammation of their stomach and intestinal tract, something that has the potential to cause abdominal cramps and diarrhea .
Adenovirus can infect a person’s bladder, cause blood in the urine, and pain when urinating. Sometimes the virus causes an infection in or around a person’s brain .
In children who have undergone an organ transplant, or who experience other conditions that result in a weakened immune system, adenovirus infections are something that can be very serious and can lead to an overwhelming infection, or even death. death.
After a child has been exposed to an adenovirus, there is an incubation period of 2 to 14 days before they experience symptoms.
Fortunately, adenoviruses rarely cause serious illness or death in an infected person.
Viruses cause a number of illnesses and symptoms including:
- Colds.
- Fever.
- Pink eye.
- Diarrhea.
- Bronchitis .
- Throat pain.
- Neurological disease.
- Inflammation or infection of the bladder.
- Inflammation of the stomach and intestines.
Some types of adenovirus cause different diseases; it depends on the way a person is infected.
As an example, breathing in adenovirus type 7 can cause severe lower respiratory tract illness. However, swallowing the same type of adenovirus generally does not cause illness or even mild illness.
People can also have persistent adenovirus infections in their tonsils, intestines, or adenoids, without experiencing symptoms. A person who is infected can also “shed” the virus for months or even years.
Structure
The adenovirus particle consists of an icosahedral protein coat that surrounds a protein core containing the linear double-stranded DNA genome.
The shell, which has a diameter of 70 to 100 nm, is made up of 252 structural capsomeres. The 12 vertices of the icosahedron are occupied by units called pentons, each of which has a thin projection called a fiber.
The 240 capsomeres that make up the 20 faces and edges of the isocahedron are called hexons because they form hexagonal matrices. The shell also contains some additional minor polypeptide elements.
The central particle is made up of two main proteins (polypeptide V and polypeptide VII) and a secondary protein rich in arginine (μ). A 55 kDa protein is covalently attached to the 5 ‘ends of DNA.
Classification and antigenic types
Currently, 47 types of human adenovirus have been identified and five additional candidate types are being investigated. The genomes of the different adenoviruses are genetically distinct and vary in size.
Multiplication
Host cells differ in permissiveness for adenovirus types. In permissive cells, the virus multiplies productively and kills the host cell.
Other cells are semipermissive, allowing replication at low efficiency, while in others, replication is blocked and infection is abortive.
As explained below, in some abortifacient infections, all or part of the genome can integrate into the host’s DNA, resulting in latent infection, which can lead to oncogenic transformation.
Productive infection
The virion enters host cells either by binding to the cytoplasmic membrane and then being engulfed in the cytoplasm in a membrane-bound vesicle (viropexis) or by directly penetrating the cytoplasmic membrane.
Viral DNA gradually coats itself and enters the nucleus of the cell, probably as a nucleoprotein complex that still contains proteins from the viral nucleus.
Viral DNA is transcribed and replicated in the nucleus of the host cell. Viral mRNA is processed in the nucleus and / or during transport across the nuclear membrane to the cytoplasm, where it is converted by polysomes into viral proteins.
These proteins return to the nucleus, where the new virions self-assemble. The mass of newly synthesized virus particles can assume crystal arrangements. The bulk of the virions may not be easily released by the nucleus and the cell.
There is evidence that extracellular adenovirus type 12 virions have considerably higher specific infectivity than intracellular virions.
During active viral release, newly synthesized virions can receive properties that confer high infectivity towards host cells.
The initiation of adenovirus DNA replication is atypical because the β-hydroxyl group of a serine residue in the terminal protein precursor (pTP), an 80 to 87 kDa polypeptide, acts as a primer in DNA replication.
Viral DNA replication can proceed bi-directionally and by single-stranded displacement from either end of the DNA duplex.
Adenovirus-encoded DNA polymerase, pTP, the adenovirus E2A protein, and various host proteins catalyze viral DNA replication.
Most adenovirus genes are transcribed by host DNA-dependent RNA polymerase II in a complex transcriptional program.
This program is regulated by the nucleotide sequences and structure of viral promoters and by a series of cell-encoded transcription factors that recognize specific nucleotide sequence motifs upstream and downstream in promoters.
Genes in the E1A region of the adenovirus genome are the first to be transcribed. A protein product of this region of the gene is a transactivator that is essential for the activation of all other viral genes.
This immediate early viral function can also turn certain cellular genes on or off.
The jointly controlled E2A and E2B regions encode proteins that are essential for viral DNA replication.
Among the encoded functions of E3, one is a 25,000 (19,000) molecular weight glycoprotein responsible for interaction with cell membrane associated proteins (major histocompatibility complex).
The functions encoded in the E3 region may be unnecessary for viral replication in cell culture, but are essential for interaction with the intact defense system of an organism and for modulation of host functions.
The late viral L1 region can also be transcribed early in the infection cycle, probably to a limited degree. The genes encoded in the L1 region of Ad5 DNA are essential for virion assembly.
All late viral functions are under the control of major components of the late promoter (MLP), which are found at approximately 17, 20, and 27 map units in the viral genome.
The gene encoding the fiber structural protein can also be controlled by the x, y, and z leaders.
Regulation of promoter activity in all biological systems is dominated by the interaction of promoter sequence motifs with specific factors.
These factors (proteins) in turn bind to a large number of additional proteins, cofactors, which determine the structure of the transcription complexes. Viral promoters are conditioned by factors present in specific host cells.
Enhancers and silencers are quantitative modulators of promoter function. Both act independently of position and orientation and can exert their influence over relatively long distances.
Enhancers reinforce the activity of the promoter, while silencers have a negative effect, nullifying or decreasing the function of the promoter. The boosting and silencing elements are species specific.
VAI and VAII RNAs (Fig. 67-3) are transcribed by RNA polymerase III. VAI RNA is an important activator of host cell translation and viral messenger RNAs (mRNAs) late after infection.
It prevents the activation of a protein kinase that is responsible for phosphorylation and consequent inhibition of the translation factor eIF-2. This kinase can be induced by interferon. VAI RNA, therefore, can be seen as a viral defense mechanism against interferon.
Abortive infection
The virus’s interaction with a host cell can be blocked in many different steps, leading to an incomplete or abortive cycle.
Depending on the permissiveness of the host cell, different types of adenovirus host cell interactions can be distinguished. Many cultured human epithelioid cell lines are productively infected with human adenoviruses.
Rat cells are semipermissive (eg for Ad5), and allow viral replication only with low efficiency. The outcome of an adenovirus infection depends on the animal species, the cell type, and the type of virus involved.
For example, hamster cells are abortively infected with human Ad12. Viral DNA is transported to the nucleus, where part of it is integrated into the genome of the host cell.
In both productive cells and abortifaciently infected cells, viral DNA gravitates to and transiently associates with host cell chromosomes as evidenced by in situ fluorescence.
Most early viral genes are transcribed, but late genes remain silent in host cells. Ad12 DNA replication in hamster cells cannot be detected with the most sensitive techniques.
The major late promoter of Ad12 DNA is inactive in both uninfected and Ad12-infected hamster cells, whereas it functions in infected human cells.
Ad2 cannot replicate in monkey cells; in this case, the translation of some of the late viral mRNAs is incorrect.
The adenovirus genome persists, perhaps for a long time, in human tonsil cells. It is not known how adenovirus replication is restricted in this human organ.
Pathogenesis
Adenovirus disease results from localized multiplication of viruses at portals of entry.
Integration of adenovirus DNA into the host genome
Latency and persistence of, as well as oncogenicity by, DNA viruses are frequently associated with the integration of all or part of the viral genome into the host cell’s DNA.
Integration of adenovirus DNA has been demonstrated in abortifaciently infected cells, adenovirus-transformed cells, and Ad12-induced tumor cells.
In productively infected human cells, recombination between adenovirus DNA and host cell DNA has also been observed.
However, it is not known whether this recombination can lead to stable integration, because in the productive cycle of infection, host cells eventually die.
There is evidence that in productively infected human cells, Ad12 DNA preferentially integrates into human chromosome 1.
Shortly after infection, the viral genome can insert into selective sites in the cell genome. The initial steps of viral malignant transformation could involve insertional mutagenesis at a number of selective cell sites.
From the geneticist’s point of view, this model of viral oncogenesis remains one of the most attractive possibilities.
Furthermore, after initially inserting itself into a limited number of sites and causing decisive mutagenic events (eg, deletions), the viral DNA could perhaps be transposed to other loci in the host genome or could be lost.
Recently, an interesting alternative mechanism of insertional mutagenesis in tumor cells induced by Adenovirus or Ad12 was discovered.
Insertion of Ad12, plasmid, or bacteriophage lambda DNA into established mammalian genomes can lead to extensive changes in cellular DNA methylation patterns away from and on chromosomes other than those of the viral DNA integration site.
Since DNA methylation patterns are related to expression patterns and genome organization, alterations in DNA methylation patterns can affect many cellular functions whose altered expression may play a role in insertional mutagenesis and oncogenesis. viral.
Analyzes of several different integration sites in transformed cell lines suggest that transcriptionally active regions of the host cell genome, which have a characteristic chromatin structure, are best suited to recombine with foreign (viral) DNA.
Adenovirus DNA frequently recombines with cellular DNA through its terminals, and terminal viral nucleotides are often removed from the integrated viral DNA molecule.
In general, considerable variability is observed in the structure of the integration site. No specific cellular DNA sequence has been found at the viral DNA insertion site in established cell lines.
Cellular DNA can be removed at the insertion site, or the cell site can be retained to the last nucleotide. Ad12 DNA frequently integrates almost intact into the DNA of non-permissive hamster cells.
However, the adenovirus system has also served as a model to study the function of sequence-specific promoter methylations in mammalian cells.
Upon integration of the adenovirus genome into the host cell genome, a highly specific methylation pattern is imposed de novo on the integrated viral genome over many cell generations. This de novo methylation is not primarily dependent on nucleotide sequence.
The site of integration, the structure of integration, and the genetics of the host cell are contributing factors.
There is evidence from analyzes in many different biological systems that sequence-specific promoter methylations can cause long-term gene inactivation.
Ad12-transformed hamster cells or Ad12-induced hamster tumor cells kept in culture may eventually lose integrated copies of viral DNA. This loss suggests that adenoviruses could cause transformation by a “hit and run” mechanism.
Malignant transformation and oncogenesis
Cells from a number of rodent and human species can be transformed in culture by adenovirus.
The frequency of malignant transformation is extremely low, and this has prohibited quantitative studies in this system.
Transformed human cell lines have also been described. Some adenoviruses, such as Ad2 and Ad5, are not oncogenic in animals.
The tumorigenic potential has been attributed to the ability of some adenoviruses (eg, Ad12) to disable the expression of major histocompatibility complex genes and thus allow transformed cells to overcome host defenses and become solid tumors.
Most adenovirus-induced tumors, tumor cell lines, and transformed cell lines carry one or more copies of the viral genome integrated into the chromosomes.
The tumor or transformed state is also associated with differential expression of integrated viral genes. Early viral genes are often the predominant genes expressed. The E1 region of the viral genome is believed to be particularly important in causing the transformed state.
However, the continued presence of the viral genome, or parts of it, may not be essential for the maintenance of the transformed state.
The so-called oncogenes represent a set of cellular genes that participate in many different ways in the control of growth.
Oncogenes in adenovirus-induced tumors or transformed cells have received surprisingly little attention.
The few studies on this topic have reported occasional changes in oncogene activity, particularly for mycgene. Additionally, E1 proteins can bind strongly to the retinoblastoma (RB) product or the p53 gene, which are considered anti-oncogenes.
It has been suggested that the binding of anti-oncogenic products by E1 proteins could contribute to the transformation of cells.
The interaction of various viral and cellular factors can eventually alter the control of cell growth and weaken or defeat host defenses such that an adenovirus-transformed rodent cell can become a solid tumor.
Since many human tumors do not contain traces of adenovirus genes or gene products, the possibility that adenoviruses cause human tumors is low. New more sensitive techniques are now available.
On the other hand, the “hit and run” hypothesis has not been ruled out. Since even experimentally induced tumors can lose the viral genome and retain oncogenicity, this possible mechanism of transformation of human cells is still being studied.
Persistence of adenovirus in human tonsils
Adenoviruses were first isolated from human adenoids, and the persistence of these viruses or their DNA in human adenoids has been studied.
It is not known whether adenoviruses or their genomes can persist in other human organ systems. When adenoids are removed during acute adenovirus infection, intact viral genomes are present.
In contrast, when adenoid tissue obtained during a symptom-free interval or from a chronically infected carrier is analyzed, only a small number of cells appear to harbor the viral genome, which may not be intact.
In some cases, in situ hybridization is necessary to show that individual cells in the adenoids contain the viral DNA and / or the adenovirus-specific RNA. These cells do not produce infectious viruses.
It is not known to what extent adenovirus virions continue to replicate in adenoids throughout adult life.
Host defenses
In adolescents and adults, a high prevalence of circulating neutralizing antibodies contributes to generalized immunity against adenovirus infections. Cytotoxic T lymphocytes also recognize and destroy adenovirus-infected cells.
Interferon is induced by adenoviruses in vitro but does not inhibit many types of adenoviruses, perhaps due to the function of VA RNA. However, some preliminary studies have reported that interferon is effective in treating adenovirus conjunctivitis.
epidemiology
Adenovirus infections are widely distributed in human populations. The highest susceptibility is found among children 6 months to 2 years of age and extends to the group of children 5 to 9 years.
Types 2, 1, 3, 5, 7, and 6 (in that order) are most frequently isolated from adenovirus-infected children, and types 1 and 2 make up about 60 percent of all isolates.
However, adenovirus infections are responsible for only 2 to 5 percent of acute respiratory infections in children.
Adenovirus also infects military recruits in the United States, where this infection has been well studied, and most likely in other countries as well. Adenovirus types 4, 7, and 3 cause acute respiratory illnesses, including pneumonia, in this population.
Adenoviruses have been isolated from severely immunocompromised patients, such as those with acquired immunodeficiency syndrome (AIDS). Many of these isolates, including adenovirus types 42 to 47, are found in the urine of AIDS patients.
Diagnosis
Infection with an adenovirus can be suspected on the basis of a characteristic clinical presentation, eg, respiratory disease, conjunctivitis.
The diagnosis can be confirmed by demonstrating an increase in antibody titer between the acute phase and the convalescent phase sera or by virus detection or isolation.
Control
Since adenoviruses are excellent antigens, vaccination could be very effective. However, viral vaccines have not generally been used because adenoviruses are involved in tumorigenesis in animals and in cell cultures.
Also, adenovirus infections rarely cause serious complications.
However, efforts are underway to produce vaccines using recombinant DNA technology. Purified fiber or hexon preparations induce high levels of neutralizing antibodies, and vaccines based on these proteins have been successfully tested.
Vector in human somatic gene therapy
Adenoviruses have been used as vector systems in approaches to human somatic gene therapy.
The early E3 region of the viral genome is not essential for viral replication in cell culture and can be removed to make room in the genome for the insertion of foreign genes constructed for therapeutic purposes.
Furthermore, the E1 region of the adenoviral genome can be excised to disable viral replication in human tissues, thus offering additional space for insertions of foreign genes.
E1-deficient, engineered adenovirions can be propagated in the human cell line 293 which contains in an integrated form and constitutively expresses the E1 region of Ad5.
Results adduced to date indicate that adenoviral genomes engineered, for example, with the test gene for β-galactosidase under the control of the inserted eukaryotic promoter, persists and continues to express this test gene in different rodent organs for periods of up to months.
It is not known whether these viral genomes can integrate into the host genome under these conditions.
In the genetic disease of cystic fibrosis, mutations in the human gene for the cystic fibrosis transmembrane conductance regulator (CFTR) cause severe symptoms in the respiratory and gastrointestinal tracts, mainly due to a drastic increase in the viscosity of the cells. secretions.
This disease can lead to death early in life for those affected. Recombinant adenoviruses carrying the c-DNA for the CFTR gene have been shown to facilitate the synthesis of the CFTR gene product in infected human cells.
Recent clinical trials in human cystic fibrosis patients have shown that recombinant adenovirus infection of the CFTR gene can lead to better lung function in these patients.
An increase in antibody titer against adenoviruses and bronchial irritations has also been reported, probably due to adenovirus toxicity.
Prevention and treatment
The adenovirus types 4 and 7 vaccine was developed and approved by the US Food and Drug Administration in March 2011, but its use was only for US military personnel. The vaccine is not available to people in the general public.
Exist; however, there are steps you can take to protect yourself and others from adenovirus infection.
These steps include:
- Staying home when you are sick.
- Do not touch your eyes, nose or mouth.
- Wash your hands often with soap and water.
- Avoid close contact with sick people.
- Maintain adequate levels of chlorine in swimming pools.
- Cover your mouth and nose when coughing or sneezing.
- Frequent hand washing is especially important in daycare.
Unfortunately, there is no specific form of treatment to treat adenoviruses. The good news is that most adenovirus infections are mild and generally only require treatment of the symptoms a person is experiencing.
Adenovirus infections that are serious can only be treated by treating the symptoms the person is experiencing, as well as any health complications they have from the infection.
Important Disclaimer: The information provided on this page is for informational and educational purposes only, is not offered and does not constitute medical advice.
