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Influenza Gastrointestinal Infections

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Influenza Gastrointestinal Infections Gastrointestinal Infections Influenza Miranda de Graaf 28 May 2018 [email protected] Viroscience lab, Erasmus MC, Rotterdam, the Netherlands Gastrointestinal infections . Worldwide 3-6 million children die each year from infectious gastroenteritis . Gastrointestinal infections are viral, bacterial or parasitic infections that cause gastroenteritis, an inflammation of the gastrointestinal tract . Symptoms include diarrhea, vomiting, and abdominal pain. Gastrointestinal infections . Which viruses cause gastrointestinal infections . Host defences . Transmission via the fecal-oral route . Tracking transmission . Rotaviruses . Noroviruses . Role of Bacteria . Take home messages Foodborne Illness (USA) Estimated nr FB cases Estimated nr Estimated nr deaths Per 100000 hospitalisations 95% norovirus 95% norovirus 99% norovirus Scallan et al., 2011 Gastrointestinal infections . Norovirus Major outbreaks in children and adults . Rotavirus Major cause of diarrhea in children and infants, Rotavirus is responsible for the most severe cases. Sapovirus Infects children and adults . Astrovirus Infects mainly children <5 years . Adenovirus Infects children much more often. Adenovirus can cause diarrhea. But the most common symptom is respiratory illness Gastrointestinal infections Gastrointestinal infections . Norovirus ssRNA positive strand virus, Non-enveloped . Sapovirus ssRNA positive strand virus, Non-enveloped . Rotavirus dsRNA virus, Non-enveloped . Astrovirus ssRNA positive strand virus, Non-enveloped . Adenovirus dsRNA virus, Non-enveloped . Entrovirus ssRNA positive strand virus, Non-enveloped Gastrointestinal infections . Norovirus Non-enveloped . Sapovirus Capsid viruses . Rotavirus . Astrovirus Naked viruses . Entrovirus Host defenses against gastrointestinal infections . The acidity of the stomach (pH 1.5 to 3.5) inactivates acid labile viruses such as rhinoviruses . Bile salts can destroy the lipid envelopes of many viruses (mainly non-enveloped viruses infect the gastrointestinal tract) . Antiviral defences Proteolytic enzymes and secretory IgA Host defenses against gastrointestinal infections . Intestinal mucus . Gut motility . Normal intestinal flora (microbiome) . Immune mechanisms Phagocytic, humoral, cell mediated . Genetic determinants (presence of receptors) Transmission via the fecal oral route De Graaf et al., 2017 Transmission via the fecal oral route Climate change Fecal oral transmission Fecal oral trasmission Food handler Food production phase High incidence High incidence Human pathogens Human and animal pathogens End of chain Globalisation Local, endemic Mixed infections > risk Early in chain Norovirus, Hepatitis A Widespread Norovirus, rotavirus, Hepatitis A hepatitis E, enterovirus Transmission –tracking the virus Hepatitis A . Pain areas: in the abdomen, joints, or muscles . Gastrointestinal: diarrhea, nausea, or vomiting . Whole body: fatigue, fever, or loss of appetite . Also common: dark urine, itching, weight loss, or yellow skin and eyes Transmission –tracking the virus Hepatitis A Problem for food investigation: Major challenge for people to remember what they ate 30 days ago Transmission –tracking the virus Hepatitis A Institute de Veille Sanitaire http://www.invs.sante.fr/display/?doc=surveillance/hepatite_a/p oint_vha_020310.htm Transmission –tracking the virus Hepatitis A International Network of Food Safety Authorities (INFOSAN) notification: November 2009- Australian multi-jurisdictional outbreak of hepatitis A > 250 people linked to semi-dried tomatoes imported frozen tomatoes tested positive Action: Alert posted on INFOSAN February 2010- France Outbreak of hepatitis A Semi-dried tomatoes were a possible vehicle Transmission –Globalisation Transmission –Globalisation Genetic profiles of enterovirus type 71 in different geographic regions B0 B1 B2 C1 C1 Netherlands B2 C2 C2 C1 C1 UK C2 C2 Europe Austria C1 C4 Bulgaria B1 Hungary B1 Norway C1 USA B1 B2 C1 C2 C2 Australia B2 C1 B3 C2 B4 C4 Vietnam C1/C4/C5 China C3 C4 Singapore B3 Asian B4 Pacific region B3 Malaysia B4 B5/C1 C1 Japan B4 B4 C4 B2 C2 B5 Taiwan B2 C2/C3 B4 C4 B5 C5 1960 1970 1980 1990 2000 2010 Basics Rotavirus Order: Unassigned Family: Reoviridae Genus: Rotavirus Species: Rotavirus A-I Double stranded RNA genome Eight segments Inner and outer capsids Basics Rotavirus Basics Rotavirus . Severe gastroenteritis in children between 6 and 24 months . 2-day incubation period . 3-8 days watery diarrhea . Can cause chronic infections in immunocompromised patients . Fever and abdominal cramps are common Rotavirus Pathology Ciarlet et al., 2002 Rotavirus diarrhea . Infections leads to shorting and atrophy of the villi . Mature absorptive cells are replaced with immature cells Ramig et al., 2004 Rotavirus diarrhea . Immature cells have reduced capacity to absorb salt and water . Reduced capacity to absorb carbohydrates . NS4 functions as a enterotoxin . The enteric nervous system is activated Ramig et al., 2004 Rotavirus Vaccination . A vaccine is available . Started in 1980s with a “Jennerian” approach with a attenuated bovine rotavirus . Rotateq -bovine backbone, with human rotavirus glycoproteins . Rotarix -attenuated human rotavirus Ramig et al., 2004 Rotavirus Vaccination Gastañaduy et al., 2013 Basics Norovirus Basics Order: Unassigned Family: Caliciviridae Genus: Norovirus Species: Norwalk Norovirus Basics . RNA virus, capsid, no lipids . Low infectious dose . High levels of shedding (up to 1011 viral copies/ml) . Very stable outside host . Little immunity, lasting short . Asymptomatic infections . Transmission via contact, food, water, droplets produced by vomiting (Larry) . NO CULTURE MODEL UNTIL RECENTLY ORF1 ORF3 Norovirus Replication p48 NTPase p22 VPg Pro RdRp VP2 3’ VPg AAAAAAAAAAAn NS1/2 NS3 NS4 NS5 NS6 NS7 VP1 N-term 2C-Like 3A-Like 3C-Like Binding to histobloodgroup antigens 1. Atttachment (determine your bloodtype) 2. Internalisation 4. Translation 3. Uncoating and disassembly VPg (+)vRNA VP2 VP1 p48 NTPase p22 VPg 3CLpro RdRp 6. Replication VPg (+)vRNA (-) vRNA 5. Post-translational cleavage p48 p22 NTPase VPg RdRp (+)vRNA 3CLpro VP2 (-) vRNA VP1 VPg genomic VPg vRNA 7. Encapsidation VPg VPg subgenomic VPg vRNA VPg 8. Release De graaf et al., 2017 Diversity De graaf et al., 2016 Norovirus -transmission and settings- Food then person to person Foodborne Other Person to person Unknown Waterborne Norovirus -transmission and settings- Foodborne GI Person to Person GI NoV I.1 NoV I.1 NoV I.2 NoV I.2 NoV I.3 NoV I.3 NoV I.4 NoV I.4 NoV I.5 NoV I.5 NoV I.6 NoV I.6 Foodborne GII Person to person GII NoV II.1 NoV II.2 NoV II.3 NoV II.4 NoV II.5 NoV II.6 NoV II.7 Norovirus -transmission and settings- Country (source) Samples analyzed % positive Reference China 128 19% NoV Kou et al., 2006 Netherlands 42 17% NoV Boxman et al., 2006 Italy 235 6% HAV, 14% NoV, 2 % both Groci et al., 2007 Italy 170 14% HAV Macaluso et al., 2006 Netherlands 64 22% EV Lodder et al., 2005 France 52 40% EV Dubois et al., 2004 Spain 60 47% AdV,19% EV, 24% HAV Muniain-Mujika et al., 2003 France, Netherlands, 87 9% NoV,5% EV Beuret et al., 2003 Ireland Spain ? 27% HAV, 44% EV Romalde et al., 2002 Italy 100 market 23% HAV Chironna et al., 2002 Italy 142 35% (13%) De Medici et al., 2001 France 108 17% AV, 23% NoV, 19% EV, 27% RV LeGyader et al., 2000 Brazil 27 22% HAV Coelho et al., 2003 South America 17 24% HAV Romalde et al., 2001 Norovirus Pathogenesis Pathogenesis is not clear . Lesions in the small bowel Broadening and blunting of intestinal villa . Transient malabsorption of sugar and fats . Decreased activity in brush border enzymes Norovirus Tropism Karst et al., 2016 Norovirus Tropism Karst et al., 2015 Norovirus Tropism . Enterocytes in biopsies of immunocompromised patients . Macrophages, Dendritic cells and B cells in mice (murine norovirus) . Cells in the lamina propria in chimpanzees (human norovirus) . Enterocytes in pigs (human norovirus) Norovirus culture model A breakthrough in the norovirus field is the development of a cell culture system for testing the infectivity of norovirus . Replication occurs in stem-cell derived human organoids (mini-gut) in enterocytes (Ettayebi et al, Science 2016, Karandikar et al J. Gen. Virol 2016) . Successful replication of several norovirus strains . In humans and the norovirus culture model susceptibility to norovirus infection is dependent on the expression histobloodgroup antigens Norovirus culture model The influence of bacteria on enteric viruses Attachment factor Karst et al., 2016 Attachment factor Karst et al., 2016 Stability The release of lipopolysaccharide by gram negative bacteria Karst et al., 2016 -Immune modulation- . Mouse norovirus can cause persistent infections . Bacteria suppress antiviral IFNλ . Without IFNλ there is viral persistence Karst et al., 2016 Take home messages . Gastrointestinal infections pose significant public health impact . Noroviruses most common foodborne disease . Fecal-oral transmission can occur via person-to-person, water and food, vomites . Globalisation of the food chain leads to globalisation of exposures and potential for large scale and diffuse outbreaks . The microbiome can play an important role in viral gastroenteritis Questions???? Norovirus group -Nele Villabruna -Claudia Schapendonk -Mark de Jong -Jeroen van Kampen -Annemiek van van der Eijk -Marion Koopmans .
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