BMS2037 - Viral Gastroenteritis Lecture combined.pptx

[email protected] www.maluquerlab.org @maluquerlab BMS2037: Viral Gastroenteritis Dr Carlos Maluquer de Motes Reader in Molecular Virology Learning objectives • Understand the properties of the viruses causing gastroenteritis and their impact on human health. • Identify and describe...

[email protected] www.maluquerlab.org @maluquerlab BMS2037: Viral Gastroenteritis Dr Carlos Maluquer de Motes Reader in Molecular Virology Learning objectives • Understand the properties of the viruses causing gastroenteritis and their impact on human health. • Identify and describe the main viral groups causing human gastroenteritis • Understand the strategies that these viruses exploit to establish infection and pathogenesis. Lecture Outline • PART I – Introduction to viral gastroenteritis • Impact on global human health • Definitions • Detection methods • PART II – Main viral groups causing human gastroenteritis • Disease profile • Transmission and distribution • Key molecular properties contributing to pathogenesis Gastroenteritis • One of the most common disease in mankind • 200M people suffer from diarrhoea every day! • Worldwide mortality = 3-5M people pa • 11K per day (compare to pneumonia [6K], malaria [2K] …) Agents that commonly cause gastrointestinal illness Salmonella Shigella Bacteria Campylobacter Escherichia coli O157:H7 Clostridium difficile Adenovirus Astrovirus Viruses Rotavirus Norovirus Giardia Protozoa Cryptosporidium Entamoeba histolytica Gastroenteritis • Lower respiratory infections remained the world’s most deadly communicable disease, ranked as the 4th leading cause of death • One of the largest declines in the number of deaths is from diarrhoeal diseases, with global deaths falling from 2.6 million in 2000 to 1.5 million in 2019. Gastroenteritis • Low-income countries suffer far more from transmissible diseases. • Diarrhoeal diseases remain in the top 5 causes of death together with malaria, TB, HIV/AIDS… • Nonetheless, diarrhoeal diseases are decreasing their incidence as cause of death. Gastroenteritis viruses • Viral gastroenteritis = inflammation of the lining of the stomach, small and large intestine. • ‘Stomach flu’ => misnomer • Most people recover without problems, but complications derive from dehydration. • Highly contagious and extremely common. Gastroenteritis viruses • Many viruses infect via the gastrointestinal tract, but disseminate elsewhere. • They do not cause gastroenteritis. • Cause pathology elsewhere in the body (eg poliomyelitis) • For gastroenteritis viruses, the gut has to be BOTH the portal of entry and the target tissue. • Replicate in the gut and remain in the gut. • Induce symptoms in the gut, usually diarrhoea and/or vomiting. Gastroenteritis viruses • All gastroenteritis viruses transmit via the oral-faecal route, … but not all the viruses that transmit via the oral-faecal route are gastroenteritis viruses. Gastroenteritis viruses • GE viruses spread via the oral-faecal route. • Usually enter via food and water => food poisoning • Excreted in faeces • Poor hygiene, sanitation, clean water availability • Can cause severe outbreaks. • Highly transmissible => fast replication and highly resistant. • These are not normally serious as long as fresh drinking water is available (developing countries!) • Fluid intake needs to be higher than that lost through vomiting and diarrhoea Diagnostic of GE viruses • Most GE viruses remain poorly characterised. • Most GE viruses do not grow well in laboratory settings. • Very small amounts (10-100 vp) are sufficient to cause infection, so highly transmissible. • GE viruses are rarely detectable in food (only exception are the Bivalbia shellfish). • Routine food screening is not feasible and most food contaminations are identified retrospectively from patients’ clinical samples. Diagnostic of GE viruses • Current available methods result in underestimation of GE infections. • None of the current available methods informs of infectivity. • Best approach is to prevent: HACCP guidelines for handling and safe management of food. Lecture Outline • PART I – Introduction to viral gastroenteritis • Impact on global human health • Definitions • Detection methods • PART II – Main viral groups causing human gastroenteritis • Disease profile • Transmission and distribution • Key molecular properties contributing to pathogenesis Gastroenteritis viruses Gastroenteritis viruses Rotaviruses • Members of the Reoviridae family. • Non-enveloped, dsRNA viruses protected by 3 protein capsid layers. • 70nm icosahedral viruses with spikes radiating from central hubs (like a wheel). • ‘Hit-and-run’ virus. Rotavirus genome and capsid • 18kB dsRNA genome divided into 11 segments (codes for 12 proteins: 1 in each segment and 2 in segment 11). • 3 capsid layers protecting the genome. • Proteolytic cleavage of VP4 by host proteases. • Key determinant of virus tropism. Rotavirus genome and capsid • dsRNA is a potent PAMP triggering host inflammatory response • Virus immune evasion mechanism • Maximises transcription and replication of virus genome. Rotavirus genome and capsid Uninfected tissue RtV-infected tissue Villus layer Mucosal layer Muscularis mucosae • Virus infects the tips if the microvilli in the intestine • Massive change in the host ability to reabsorb water. • Most effective treatment is re-hydration (avoid de-hydration). Rotavirus transmission Reasons for high transmission High stability to inactivation Quick infection (2-4 days) High production of viral particles in stools Target Children Seasonality All year round (but annual RtV epidemic exist) Treatment i.v. fluid therapy for children Rehydration for adults Rotavirus burden • RtV are the major cause of viral gastroenteritis in infants and young children worldwide. • 1M deaths pa (mainly in developing countries). • Major cause of hospitalisations for acute gastroenteritis in developed countries. • $1B pa in the US alone • ~75K hospitalisation pa in under 5yo in the EU Rotavirus immunity • Poor immunity that does not protect against future infections (hit’n’run). • Maternal passive immunity can protect for few months, but children become then susceptible. • Live attenuated vaccines approved for use in the US and UK: routine vaccination with 3 doses at ages of 2, 4 and 6 months. Cost-effectiveness analysis by NHS: • Rota Teq (Sanofi) £25 per dose • Rotarix (GSK) £35! Noroviruses • NoV are the single major cause of nonbacterial GE. • ~45% GE cases UK • ~25% of all GE cases in US • Very high transmissibility => implications for child care settings, hospital wards, food handlers, cruise ships… • Highly contagious. Noroviruses Norovirus incidence • True incidence has been underestimated for long time. • Increase of cases until 2010. • Stabilised after that. • Control measures? • General awareness? • Public campaigns Source: PHE Norovirus incidence • Marked seasonality. • Winter months • ‘Winter vomiting bug’ • Human behaviour. • Health authorities guidelines: • ‘Stay at home for at least 48 hours after symptoms have stopped to avoid further spread’ Source: PHE Norovirus - Classification • NoV belong to the Caliciviridae family, which contains 4 genera: Vesivirus, Lagovirus, Sapovirus and Norovirus. • Those infecting man lay within the Sapovirus and Norovirus groups, and cause “winter vomiting disease”. • Non-enveloped, 7.5kB +ve ssRNA genome (Baltimore’s group IV). • True ‘hit-and-run’ viruses (~12 hours). Kapikian et al., JVI, 1972 Norovirus – Molecular features • 3 Open-reading frames: Non-structural proteins => ORF1 Structural proteins => subgenomic RNA • VP1 self-assembly to form viral capsid • Priming strategy: 5’ VPg (13-15kDa) Norovirus transmission • Symptoms appear 12-48h post-infection and last between 2-3 days • Transmitted via oral-faecal route: • Consumption of contaminated food • Person-to-person or fomite-to-person contact • Airborne droplets (vomit) • Symptoms include nausea, vomiting, diarrhoea, abdominal cramps and pain. Norovirus transmission • https://www.youtube.com/watch?v=DueeDf9Uprg Norovirus transmission • In the UK, norovirus infections cost the NHS ~£80M pa. • No effective treatment available; prevention remains best treatment (eg isolation of affected individuals, disinfection…) • Drugs against protein synthesis, protease and polymerase are in the pipeline. • Vaccines: - antigenic drift and number of serotypes circulating are a concern - transient immunity that wanes quickly - recombinant capsid protein vaccines (eg VLP) are under development. Astroviruses • Non-enveloped, 30nm icosahedral virus with a peculiar 56 pointed, star-like appearance. • 7kB, +ve ssRNA => group IV • Worldwide distribution. • Transmitted through the oral-faecal route (winter) • Infects epithelial cells of the intestinal tract (small intestine), inducing mostly diarrhoea Astroviruses • Affects mostly 2 groups: young children and elderly, institutionalised patients. • Determinants of immunity not well understood, but generated immunity is longlasting (although wanes with age). • >80% 5-10yo children have antibodies against AstV. • Diagnosis by EM, ELISA or NAAT (sequence variability). Adenoviruses • Non-enveloped, icosahedral viruses with large • dsDNA genome (~36-38kB) => Group I Baltimore classification • Very distinctive morphology that facilitates diagnostic by EM. • More than 50 serotypes, some with strong links to respiratory and eye infections • Serotypes 40 and 41 specialise in infecting cells in the intestine: enteric AdV. • Affects mostly children (mainly <2yo). Up to 50% seroprevalence that then decreases. • Transmitted through oral-faecal route and found robustly and universally in water • Waterborne rather than foodborne • Indicators of faecal contamination Summary Virus Adenovirus ID (particles) Not known Incubation period (days) 5-7 Astrovirus <1000 3-4 Rotavirus 10-100 2-4 Norovirus <10 0.5-1 Symptoms Watery Diarrhoea Diarrhoea & Vomiting (mainly D) Diarrhoea & Vomiting Diarrhoea & Vomiting (mainly V) Duration (days) 5-7 4-7 4-7 2-4 Further reading • Desselberger et al. (2009) Rotaviruses and rotavirus vaccines. British Medical Bulletin 90:37-51 • Caddy et al. (2021) Rotavirus research 2014-2021. Virus Research 304:198499 • Thorne & Goodfellow (2013) Norovirus gene expression and replication. Journal of General Virology 95:278-291. • Donaldson et al. (2010) Viral shape-shifting: norovirus evasion of the human immune system. Nature Reviews Microbiology 8:231-241.