WUSM Microbes and Pathogenesis Wiki: Adenovirus Group 9

Spring of 2010

• Note: We think the bolded parts are the most important

Adenovirus is an unenveloped DNA virus responsible for 10% of respiratory tract infections in children. There is an adenovirus vaccine, but it is not given to the general population. Adenovirus is transmitted through direct contact between body surfaces, indirectly through contaminated objects or water droplets, and through organ transplants. Once inside the host cell, adenovirus activates the replication machinery and inhibits the tumor suppressor p53. To exit, Adenovirus Death Protein promotes cell lysis. Common symptoms include conjunctivitis, tonsillitis, ear infection, and croup. Most patients make a full recovery in a week.

Adenovirus Structure

Encounter

Adenovirus is most frequently seen as a mild, self-limiting infection in young children, but adults can also be infected. Outbreaks most commonly occur in crowded institutions such as in daycares and among military recruits. Adenovirus outbreaks often arise between late winter and early summer, and typically present as an upper respiratory tract infection, although virus can present itself in a variety of ways.

Transmission

Adenovirus can be transmitted

• directly, through body surface-to-body surface contact.
• indirectly through contact with a contaminated intermediate object or in contaminated water.
• in droplets (droplets traveling < 3 ft).

Virus is present in the respiratory system (droplet transmission) and the gastrointestitinal tract (fecal-oral transmission).

• Unique modes of direct transmission:
  • At birth, neonates can become infected by cervical secretions from an infected mother who has a severe infection.
  • Recipients of kidney and liver transplants can be infected with adenovirus from healthy donors, suggesting that these two organs can harbor latent virus.

Preventing the encounter

Adenovirus is resistant to lipid disinfectants because the virion is unenveloped. The virus is, however, sensitive to heat, formaldehyde, and bleach.

Entry

Adenovirus Entry

Adenovirus enters the host cell by two coordinated mechanisms. First, the virus adheres to the host cell by binding of adenovirus fiber protein to the host cell receptor. The fiber protein contains three domains: an N-terminal tail that interacts with the penton base, a central shaft domain, and a C-terminal globular domain. Host cell surface receptors include CD46 and CAR (Coxsackievirus Adenovirus Receptor). CD46 acts as the receptor for the group B human adenovirus serotypes, while CAR is the receptor for all other known serotypes. MHC molecules and sialic acid residues may also contribute to adherence.

After initial binding, a motif in the adenovirus penton base protein interacts with an αv integrin co-receptor on the host cell surface. Attachment to the αv integrin induces actin polymerization, resulting in endocytosis of adenovirus into the host cell via clathrin-coated pits. The virus then escapes from the endosome and enters the nuclear pore complex. Viral DNA is then transported to the nucleus, where gene expression, viral replication and assembly can occur.

Sources: Wu and Nemerow (2004). “Virus yoga: the role of flexibility in virus host cell recognition”. Trends Microbiology 12: 162-168.

Spread

Adenoviruses are lytic viruses whose spread is dependent on destroying the integrity of its host cell. As its mechanism of multiplication is dependent on disrupting the host cell cycle. The virus expresses the E1b family of proteins as well as some other gene products to interfere with p53 and prevent early apoptosis. Later in the infection, adenovirus begins to express an E3 protein, also known as the Adenovirus Death Protein. This protein is important for efficient cell lysis and the best delivery of virus particles.

Sources: Tollefson AE, Scaria A, Hermiston TW, Ryerse JS, Wold LJ, Wold WS. The adenovirus death protein (E3-11.6K) is required at very late stages of infection for efficient cell lysis and release of adenovirus from infected cells., J Virol. 1996 Apr;70(4):2296-306. Tollefson AE, Ryerse JS, Scaria A, Hermiston TW, Wold WS., The E3-11.6-kDa adenovirus death protein (ADP) is required for efficient cell death: characterization of cells infected with adp mutants. Virology. 1996 Jun 1;220(1):152-62.

Multiplication

After the viral DNA is uncoated, it travels into the nucleus of the host cell through nuclear pores, where it is replicated and transcribed to initiate the process of making new adenovirus particles.

Adenovirus requires the use of host proteins in order to replicate. To do this the most efficiently, the virus needs to activate the cells from a growing state (the G0 and G1 phases of the cell cycle) to the replicating (S) phase of the cell cycle. The virus has a variety of proteins that facilitate this conversion of the host cell from quiescent to replicating.

The E1 protein is one of the first proteins made from the viral DNA. This protein inactivates pRB (retinoblastoma protein), freeing the transcription factor E2F to facilitate the production of S phase proteins and indirectly initiate nucleotide metabolism and DNA replication. E1 also bind with nucleic acid architecture proteins (such as histone acetyltransferases) and works to remodel the host chromatin to encourage the transcription of many cell cycle genes to further promote the adenovirus’s efforts to keep the cell in replicating mode. The main function of the E1 protein is to deregulate the host cell cycle regulation in the ways listed above as well as by interfering with the formation of the cyclin CDK complexes that would cause the cell to be in another phase of the cell cycle besides S.

The viral protein E4 also contributes to the disregulation of the cycle by interfering with other regulators. This disregulation leads to an accumulation of the tumor suppressor p53 protein which would normally lead to halting of the cell cycle. The adenovirus expresses E1B and E4orc6 proteins to combat this accumulation and allow the host cell to continue to replicate unchecked.

Once the cell is in a replicating mode, the virus employs a few other factors to get its DNA and proteins synthesized and make new particles.

• The E2A protein is a DNA binding protein essential for viral DNA replication.
• The E2B protein is the viral DNA polymerase and is also referred to as the precursor terminal protein. The precursor terminal protein, in addition to its polymerase activity, also acts as the primer for DNA synthesis with the projection of the hydroxyl group of its beta serine residue. This protein is of the utmost importance to adenovirus multiplication.
• The E3, the other early gene product, interacts with the host MHC molecules to help the virus evade the host immune system. Viral RNA is made from the viral DNA by the host RNA polymerase II.

These proteins are all important in getting the host cell into a state so that the building blocks of new virus can be made more efficiently. After these proteins are established, the late gene products, aptly named L1-L5, are made. These proteins are all either capsid proteins or proteins otherwise involved in the assembly of the virus coat so as to facilitate the spread of the virus to its next host. The transcription of these genes is controlled by the Major Late Promoter, a sequence motif that regulates mRNA production based on the binding of transcription factors from the host. Transcribed after these late genes are the VAI and VAII RNA molecules. These untranslated gene products act as translational activators for both host and viral mRNA molecules. VAI also inhibits the actions of interferon and helps adenovirus avoid the host immune system.

Sources: http://www.ncbi.nlm.nih.gov/gene/; http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mmed&part=A3538; [Frontiers in Bioscience 7, d1369-1395, May 1, 2002] ADENOVIRUS AND CELL CYCLE CONTROL Haggit Ben-Israel and Tamar Kleinberger

Damage

• Viral proliferation within bronchiolar epithelial cells, alveolar macrophages, and lymph nodes
• Cell-mediated immunity is the major immune response
  • E3 reduces MHC I on infected cells, inhibits CTL recognition
• Viral capsid/particle induces innate immunity and inflammation (cytokines, chemokines, leukocyte adhesion molecules)

Symptoms

The most common symptoms of infection include conjunctivitis, tonsillitis, ear infection, and croup. Other symptoms that occur in more severe infections can be divided into two major classes: respiratory infections and intestinal tract infections. Respiratory infections typically occur between 2 and 14 days after exposure to the virus and symptoms include those of the common cold (runny nose, sore throat) along with fever, severe cough and headache. Small children are particularly at risk of developing bronchiolitis or pneumonia. Intestinal tract infections (gastroenteritis) can also develop 3 to 10 days after exposure and symptoms include abrupt onset diarrhea, abdominal tenderness and vomiting. Other more severe symptoms include viral meningitis, encephalitis, and hemorrhagic cystitis (a form of urinary tract infection)

Symptoms/Diseases: (major serotypes associated with the symptom)

Infants	Children	Adults	Immunocompromised
Pneumonia	Pneumonia		Pneumonia
Otitis Media	Respiratory infection	Acute respiratory disease (4, 7, 14)	Meningoencephalitis
Pharyngitis	Gastroenteritis (40, 41)	Pharyngitis, sometimes purulent	Gastroenteritis (40,41)
Hemorrhagic cystitis	Conjunctivitis, sometimes causing epidemic keratoconjunctivitis	Hemorrhagic cystitis
Diarrhea	Diarrhea
	Tonsillitis

Causes ~10% of upper respiratory tract infections in children (Note: different serotypes cause different diseases)

Ad-14 – “new emerging disease”

• Outbreak in Wales Island, 4 states in U.S. (Alaska is the most recent)
• Can be a severe, sometimes fatal; respiratory illness in all ages

See News Video

Sources: Rosman FC, Mistchenko AS, Ladenheim HS, do Nascimento JP, Outani HN, Madi K, Lenzi HL. Acute and chronic human adenovirus pneumonia: cellular and extracellular matrix components.Pediatr Pathol Lab Med. 1996 May-Jun;16(3):521-41. Ginsberg HS, Prince GA. The molecular basis of adenovirus pathogenesis. Infect Agents Dis. 1994 Feb;3(1):1-8. Liu Q., Muruve D. A. Molecular basis of the inflammatory response to adenovirus vectors. Gene Therapy. 2003;10:935-940.

Outcome

Treatment

• No antiviral exists that is specific for adenovirus. Therefore, the only way to treat the illness is to try to alleviate the symptoms.
• Vaccines are available for serotypes 4 and 7, but only for specific populations (mostly military recruits)

Outcome

Most patients make a full recovery. Infection usually lasts about a week, but in cases of more severe respiratory infections (such as pneumonia), symptoms can persist for 2-4 weeks. However, adenoviruses can be lethal in immunodeficient patients.

Sources: CDC: http://www.cdc.gov/ncidod/dvrd/revb/respiratory/eadfeat.htm; UVA Health System: http://www.healthsystem.virginia.edu/UVaHealth/peds_infectious/adenov.cfm. McLaughlin et al. Outbreak of Adenovirus 14 Respiratory Illness – Prince of Wales Island, Alaska, 2008. Centers for Disease Control and Prevention MMWR 2010;59 (1); 6-10.