Virology - Coronaviruses Flashcards
Outline coronaviruses.
- Family: Coronaviridae, Sub-family: Coronovirinae, Genus: Alpha (group 1)/Beta (group 2)/Gamma (group 3) Coronavirus
- Spherical, enveloped, ~100nm diameter
- ssRNA +ve sense genome, non-segmented, 30kb long (longest RNA genome)
- Coronaviruses are recognized in a range of species causing respiratory, gastrointestinal, neurological and systemic diseases
- Mainly infect the upper respiratory tract, classical coronaviruses cause the common cold
- Club-shaped surface projections or peplomers (composed of trimers of spike (S) protein) of approximately 20 nm in length are seen in all species
Outline the structure of coronaviruses.
Contain the structural proteins S, M, E, N, and HE (not all contain).
Coronaviruses have a non-segmented single-stranded positive-sense RNA genome of approximately 30 kb, making these the largest known RNA virus genomes. In the virion, viral RNA is complexed with nucleoprotein (N) in an extended helical nucleocapsid 9–11 nm in diameter. This is enclosed within a lipid-bilayer membrane envelope in association with a transmembrane protein (M), which is the most abundant virus structural protein. The spike (S) glycoprotein, smaller amounts of a non glycosylated envelope (E) protein, and in some group 2 viruses, also the haemagglutinin-esterase (HE) protein, are also found on the virus envelope.
Six coronaviruses are known to infect humans. Name some them.
- Classical HCoV-229E and HCoV-OC43 (cause common cold), isolated in the 1960s
- SARS-CoV (causes severe acute respiratory syndrome) identified in 2003
- HCoV-NL63 and HCoV-HKU1 identified in 2004, 2005
- MERS-CoV identified in 2012
How are coronaviruses grouped?
Coronaviruses are classified into three groups based on antigenic relationships of the spike (S), membrane (M) and nucleocapsid (N) proteins, and now re-enforced by viral genetic phylogeny. The HCoVs 229E and NL63 are group 1 coronaviruses, while OC43, HKU-1 and SARS coronaviruses are classified in group 2. Group 3 coronaviruses are found in avian species. Genetic recombination readily occurs between members of the same and different coronavirus groups providing opportunity for increased genetic diversity.
Outline the replication cycle of coronaviruses.
- Attachment: Coronaviruses attach to their glycoprotein receptors on host cells via their S (and when present, the HE) proteins. Group 1 coronaviruses 229E and NL63 bind to the metalloproteases, human aminopeptidase N and angiotensin converting enzyme 2 (ACE-2) respectively. Group 2 coronaviruses bind to 9-O-acetylated neuraminic acid molecules on the cell surface. SARS coronavirus also uses ACE-2 as the receptor for virus binding and entry. The receptors for OC43 and HKU-1 have not been yet identified.
- Penetration: The fusion of the viral and cell membranes (either at the cell surface or within the endocytic vesicle) is mediated by the S2 portion of the virus spike protein.
- Replication: RNA polymerase translates -ve RNA from the +ve RNA to make +ve mRNA. Viruses replicate in the cytoplasm every 10-12 h. An increased synthesis of viral components triggers the expansion of ERGIC and Golgi organelles into large virion-containing vacuoles (LVCVs), which are an additional site where complete virions are produced.
- Assembly and Release: Newly formed virions bud into the RER (where M protein localises) and accumulate into endoplasmic vesicles. These newly formed virions are transported to the Golgi apparatus to the plasma membrane where they are released by exocytosis.
Outline the pathogenesis of coronaviruses.
Infection with the common-cold coronaviruses leads to loss of ciliary action (ciliostasis) and degenerative changes affecting the cilia of epithelial cells of the respiratory tract.
SARS CoV targets type 1 and type 2 alveolar epithelial cells of the lung and also differentiated bronchial epithelial cells. The desquamation of alveolar epithelial cells leads to hyaline membrane formation within the alveoli and diffuse alveolar damage, the histological hallmark of acute respiratory distress syndrome (ARDS). Patients with SARS have elevated levels of pro-inflammatory cytokines (IL-6, IL-12) and chemokines (IL-8, CCL-2, CXCL10) in the plasma but whether these mediators drive disease pathogenesis or are simply the consequence of the lung pathology remains unresolved. Oedema, hyaline membrane formation, squamous metaplasia. Can lead to multinucleated giant cells upon cytolysis. High viral load in lung, bowel, lymph nodes, and spleen, kidney, and liver.
The severity of SARS infection in humans increased with age.`The SARS CoV also infects the intestinal epithelium and virus is shed in the faeces. The diarrhoea associated with SARS infection may be related in part to direct infection of the intestinal tract.
Outline the clinical features of SARS CoV.
- acute onset, fever, myalgia (muscle pain), malaise
- dry cough is common (1/3 patient improve)
- shortness of breath (tachypnoea), oxygen desaturation, worsening of chest signs, onset of diarrhoea (20-30% patients need intensive care, mechanical ventilation)
- watery diarrhea in some patients typically associated with clinical deterioration
- lymphopenia (low T cell count)
- terminal events: severe respiratory failure, multiple organ failure, sepsis
- 10% fatal case
Outline a SARS CoV outbreak.
- Originated from Guang Dong Province, China
- Outbreak started around November 2002 and ended in mid 2003
- One infected patient from Guangdong travelled to Hong Kong and stayed one day at a hotel there leading to the infection of 15 other guests who travelled onwards to Toronto, Singapore, Hanoi and elsewhere, seeding chains of secondary transmission in different parts of the world
- Within months, the outbreak had spread to 29 countries and regions
- Approximately 8000 cases
- 10% case fatality rate
The SARS-CoV outbreak has demonstrated the capacity of coronaviruses:
- To induce serious pathology in humans
- To “jump” from different animal hosts
- To spread efficiently (high transmission rate)
The primary route of transmission of human coronaviruses is via the respiratory tract.
What receptor recognises SARS CoV?
ACE-2
What interactions occur during early SARS CoV infection?
-
C-type Lectins: L-SIGN, DC-SIGN, L-SECtin
- Attachment factors bind high-mannose oligosaccharides on S
-
Pattern recognition receptors (PRRs):
- Innate immune response
- Mannose-binding lectin (enhance phagocytosis)
- Toll-like receptors (cytokine expression)
Outline MERS-CoV.
Newly discovered HCov (2012). Middle-East Respiratory Syndrome-coronavirus
- Initially isolated from the respiratory tract of a patient from Bisha, Saudi Arabia
- The patient developed severe pneumonia and acute renal failure in June 2012
- In February 2013, MERS-CoV infection was confirmed in an adult male in the UK (developed severe respiratory tract infection 10 days after travelling to Pakistan and Saudi Arabia)
- 135 contacts were traced. Among them 2 family members were identified with MERS-CoV infection. One developed severe respiratory illness and died; the other had a flu-like illness.
- Severe disease in the majority of patients
- Symptoms may vary from mild illness, influenza-like symptoms, fever, diarrhoea, renal failure, to death.
- Exact mode of transmission is unknown (zoonotic exposure is suspected as the source of human infection: Camels?)
Human Infection with MERS Coronavirus after Exposure to Infected Camels, Saudi Arabia, 2013 (Emerg Infect Dis. June 2014)
What are the WHO recommendations for MERS-CoV.
Urgent epidemiologic investigations are required to better understand the transmission patterns of MERS-CoV.
How are coronavirus infections diagnosed and treated?
Diagnosis: RT-PCR screening from respiratory tract samples
Treatment: no approved vaccine, no anti-viral drug available
