10/27/15 CAUSES OF DEATH IN THE WORLD CAUSES OF DEATH IN THE WORLD- LOW INCOME COUNTRIES

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1 Gastrointes*nal infec*ons Flint et al. Principles of Virology, 2:nd ed CAUSES OF DEATH IN THE WORLD CAUSES OF DEATH IN THE WORLD- LOW INCOME COUNTRIES Leading Causes of Global Deaths from Infec8ous Diseases. Infec*ous gastroenteri*s Viruses 50 70% Caliciviruses (Noro) Rotaviruses Adenoviruses Astroviruses Bacteria 15 20% Eschericia coli Campylobacter Salmonella Shigella Yersinia Parasites 10 15% Amoebiasis Giardia Fauci AS, Morens DM. N Engl J Med 2012;366:

2 Viral gastroenteri*s Ø Caused by several unrelated viruses. Ø Symptoms are similar. Ø Transmission: Fecal- oral route. Ø Specific therapy missing supporlve care. Which viruses? Reoviruses - Rotavirus. Caliciviruses Norovirus genus. Sapoviruses (Calicivirus family). Astroviruses. Adenovirus (two serotypes) Aichiviruses (Picornavirus family). RNA viruses that cause gastrointes*nal infec*ons. RNA viruses dsrna ssrna(+) ssrna(- ) DNA viruses that cause gastrointes*nal infec*ons. DNA virus dsdna ssdna Reo Corona Flavi Calici Astro Retro Hepevirus (unclassified) Picorna Toga Rotavirus. Noroviruses Sapovirus Rhabdo Deltavirus (unclassified) Filo Paramyxo Orthomyxo Arena Bunya Papilloma Adeno Herpes Pox Polyoma Hepadna Anello Parvo Aichivirus. Serotypes 40 & 41. Rotavirus ROTA Six groups of rotaviruses: A- F. Rotavirus type A: Humans. Rotavirus type B: Pigs och Humans rare. Rotavirus types B- F: Rare or unclear role in disease. 2

3 Rotavirus infec*on Most common cause of viral gastroenteriks in small children. Fecal- oral route (also respiratory). Person- to- person. Contaminated water and food is less common virions/ml stool. 10 virions can start an infeclon. Good immunity. Rotavirus - symptom IncubaLon Lme: 2 days. Diarrhea in 3-8 days. AssymptomaLc carriers are common. Some children secrete rotavirus without having symptoms. Infected children can secrete rotavirus weeks before onset of symptoms. And for days a[er symptoms ceased. Rotavirus Scandinavia: Affects infants during winter. Approx hospitalized palents/yr. <1 death/yr. Annually and globally : Approx. 2 millions hospitalized palents/yr deaths/yr (low income countries). Vaccine is available. Rotavirus Mild symptoms before age of 3 months, probably due to proteclon by maternal anlbodies. Highest prevalence of rotavirus infeclon is between age 6 to 24 months. Age Have had infeclon < 6 months 17% of children 1 year 40% 2 years 75% Rotaviruses infect cells at the top of villi and impair their func*on. 3

4 Effects of rotavirus NSP4 protein on the gastrointes*nal epithelium Rotavirus NSP4 creates a channel in the ER-membrane thereby releasing Ca 2+. Sascha Kopic and John P. Geibel. Toxins 2010, 2, Hyser J M et al. mbio 2010; doi: /mbio Rotavirus NSP4 protein is an enterotoxin 1) NSP4 inhibits the Na + - Glucose co- transporter that absorbs Na + and Glucose in mucosal cells. 2) This transporter is also used to reabsorb water. 3) NSP4 affects phospholipase C (PLC)- dependent calcium signaling. 4) NSP4 increases intracellular calcium levels that may induce Calcium- dependent export of Cl -. How Rotavirus causes diarrhea: 1) The virus infeclon kills mature mucosal cells in i the small inteslne. These are replaced with new cells that inilally have lower absorplon capacity (salt and water). 2) New, immature cells produce lower levels of di- sackaridases (malabsorplon of carbohydrates). 3) Rotavirus produces an enterotoxin (NSP4): slmulates water and chloride ion Cl - secrelon from the small inteslne. 4) The enteric nerve system is affected. Rotavirus mortality 4

5 10/27/15 Current vaccines to Rotavirus Rotarix (GSK). Afenuated, human reassorted rotavirus licensed RotaTeq (Merck). Afenuated, human- bovine reassorted rotavirus licensed countries* have introduced Rotavirus Vaccine nalonally Rotavirus sample Electron micrograph: - stool filtrate. - child with gastroenterils. Not Gavi- eligible [42] Gavi- eligible [35] Gavi=support ptogram. *As of July 1, 2015 RV = rotavirus vaccine Canada, the Philippines, and Thailand have introduced rotavirus vaccines in pilot or regional introduclons Rotavirus virion is stable Science. 1974;185: ) Rotavirus Linda Stannard University of Cape Town - Icosahedral capsid (70nm). - Several capsids protect from low ph. - Lack of envelope protects from bile acids. Nature Review Microbiology 2007; 5, 529 5

6 10/27/15 Rotavirus protec*ve capsid layers Rotavirus genome & virion Reovirus- family. dsrna, 18-30kb. Segmented genome: 11 segments. Lacks lipid envelope. Double capsids provide stability. Rotavirus Segment Rotavirus Protein FuncKon 1 VP1 Polymerase 2 VP2 Transcriptase component 3 VP3 mrna capping 4 VP4 Viral afachment 5 NSP1 RNA binding 6 VP6 Maior inner capsid protein 7 NSP3 RNA binding 8 NSP2 RNA binding (replicalon and packing). 9 VP7 Maior outer capsid protein 10 NSP4 Enterotoxin 11 NSP5 och 6 NSP5 binds RNA and NSP6. Rotavirus replica*on cycle Arnold, MM., et al PLOS Pathogens 9(1):e

7 VP8 binds sialic acid. Rotavirus replica*on Taken up by endocytosis, then to endosome. Transcrip*on of the rotavirus dsrna genome mrna: 123'*'F*5='&#EN;OH1#'(FDG"##############################P8Q###################################H23'*'F*5='&#EOR;OS1#'(FD"G ///? Release of DLPs (lack outer capsid) into the cytosol aclvates pol..etu:getu:gttetu:g:e:utge:utg E:UTGTEUTGETUGEUTGE:UG.. TranscripLon of capped, non- polyadenyated +ssrnas. These +ssrna are used as mrnas or for synthesis of new genomic dsrna. NSP2 + NSP5 form the inclusion bodies (viroplasms) where replicalon takes place and DLPs assemble. Outer capsid is added at the ER surface and parlcles bud into ER. Removal of ER envelope from parlcles and subsequent proteolylc cleavage of VP4 generate fully infeclous virions. TranscripLon: > #.%/#%0#1234'5 6#)07%'5#89: ;#)07%'5#89: <7*04=' B*(CD43)07%'5#&4'*?4 E4'F%/)=5%045G > H2 12 >?89:#)@'0A4)=) H2 12 is added by rotavirus protein VP3. Transla*on of Rotavirus mrnas Transcrip*on and replica*on of the rotavirus dsrna genome Translation of +RNA (mrna) * Encapsidation of +RNA * +RNA synthesis Secondary +RNA synthesis BRNA synthesis In addilon, rotavirus NS3 inhibits translalon of cellular mrnas. Double-stranded RNA genome 5@ * 3@ 3@ 5@ * * Cap at 5@-end + strand RNA B strand RNA Protein G. Magnusson 200 Rotavirus genomic RNA is abached to the inside of the capsid, at pores through which de novo synthesized +ssrna can exit the capsid. Trask, SD. et al Nat Rev MiBi., 10:165. 7

8 10/27/15 RNA viruses that cause gastrointes*nal infec*ons. RNA viruses dsrna Re Calicivirus VIRIONEN - Non- enveloped. - Icosahedral capsid. - 38nm. ssrna(- ) ssrna(+) o He R C A pe etr oro stro na vir o us (u nc Rotavirus. las si fi ed ) C a Fl P T lic avi ico oga rn i a De Rh Fil Pa O lta ab o ra rth Aren Bun m vir do yx omy a ya us o xo (u nc Aichivirus. las si fi ed ) Norovirus. Sapovirus Calicivirus genome Calicivirus Ø Ø Ø Ø ViralZone Swiss Ins*tute of Bioinform*cs (SIB). +ssrna, (8 kb). Transcribed to two mrnas. Subgenomic mrna produces capsid proteins. Viral polyproteins are cleaved by proteases. Hyde, F., et al J.Virol. 83:9709. Norovirus transmission Transmission: Fecal oral: Aerosol? Norovirus epidemics Meet VomiLng Larry : The Fake VomiLng Head ScienLsts Are Using To Study The Norovirus Epidemic. TIME. By Melissa Locker Jan. 28, 2013 Typical scenario: schools, day care centers, home for elderly, cruise ships, military exercises, restaurants and hospitals. Explosive outbreaks o[en from one source. food water Contact: person person environment person hbp:// gov/handwashing/ Hand washing Diagram from EastDevon.gov.UK Hotellrevyn Bild: Istockphoto 8

9 10/27/15 Paramedics dressed in proteclve aqre enter a German cruise ship quaranlned in December a[er an outbreak suspected to be norovirus. A new strain is making people miserable around the world this year (Jan 28, 2013). By Maggie Fox, Senior Writer, NBC News Noroviruses appear during the winter C alicivirus veckorapport vecka 7 Folkhälsomyndighetens rapport för vecka 7 visar att antalet rapporterade fall av norovirus ligger på samma nivå som veckan innan medan antalet sapovirusfall har ökat. Totalt rapporterades 209 fall av norovirus och 39 fall av sapovirus. Antalet sapovirusfall är det högsta antalet som rapporterats under de senaste fem säsongerna. Ökningen ses framför allt i Stockholm och Skånes län. Bland de smittade ses både barn och vuxna. Till skillnad från norovirus har sapovirus tidigare framför allt ansetts infektera små barn. Under senare år har dock denna skillnad i åldersfördelning hos de smittade inte varit lika tydlig. REUTERS/Lisi Niesner A har återigen ökat något. Det viktigaste rådet för att skydda sig från vinterkräksjukan är att vara noga med handhygienen. Tvätta alltid händerna efter toalettbesök och innan du äter eller hanterar mat. För att undvika att sprida smittan vidare är det viktigt att stanna hemma när man är sjuk samt ytterligare ett par dagar efter tillfrisknandet. Man kan sprida smitta under flera dygn även om man inte längre har några symtom v7 Norovirus is very contagious Cases of laboratory confirmed norovirus infec*ons per eek in Sweden Fyndwav norovirus per vecka Norovirus(2009, Norovirus(2010,11 Antal patienter Virus transmifed during symptomalc phase + days. Transmission requires virus parlcles. High secondary afack rate. Folkhälsomyndighetens rapport för vecka 7 visar att antalet rapporterade fall av norovirus ligger på samma nivå som veckan innan medan antalet sapovirusfall har ökat. Totalt rapporterades 209 fall av norovirus och 39 fall av sapovirus. Antalet sapovirusfall är det högsta antalet som rapporterats under de senaste fem säsongerna. Ökningen ses framför allt i Stockholm och Skånes län. Bland de smittade ses både barn och vuxna. Norovirus(2011, Millions billions virions per gram womit. C alicivirus veckorapport vecka 7 Norovirus(2012,13 Norovirus(2013, Till skillnad från norovirus har sapovirus tidigare framför allt ansetts infektera små barn. Under senare år har dock denna skillnad i åldersfördelning hos de smittade inte varit lika tydlig A har återigen ökat något. Det viktigaste rådet för att skydda sig från vinterkräksjukan är att vara noga med handhygienen. Tvätta alltid händerna efter toalettbesök och innan du äter eller hanterar mat. För att undvika att sprida smittan vidare är det viktigt att stanna hemma när man är sjuk samt ytterligare ett par dagar efter tillfrisknandet. Man kan sprida smitta under flera dygn även om man inte längre har några symtom. 7 Remains in the environment for a long Lme. Stable Vecka Fynd av norovirus per vecka Norovirus(2009, Norovirus(2010,11 Norovirus(2011,12 Antal patienter 450 Norovirus(2012, Norovirus(2013, SolnaFolkhälsomyndigheten,SE417182Solna.Besök:Nobelsväg18.ÖstersundFolkhälsomyndigheten,SE483140Östersund.Besök:Forskarensväg Telefon E1postinfo@folkhalsomyndigheten.sewww.folkhalsomyndigheten.se Vecka Immunity ajer calicivirus infec*on Norovirus virions are stable Resistant to healng to 60 C. SolnaFolkhälsomyndigheten,SE417182Solna.Besök:Nobelsväg18.ÖstersundFolkhälsomyndigheten,SE483140Östersund.Besök:Forskarensväg3. Telefon E1postinfo@folkhalsomyndigheten.sewww.folkhalsomyndigheten.se Survives ph=3. Survives clorine in drinking water. Resistant to detergents. Same calicivirus Short- lived YES immunity Short- lived NO immunity (2 3 years) Another calicivirus NO NO Results from experimental infec*on of volonteers. 9

10 Experimental infec*on of volonteers with nororvirus: Some individuals are resistant to some noroviruses 82% infected 68% clinical infeclon 32% subclinical infeclon Why do some individuals in the populalon not contract norovirus GII.4? 18% not infected Graham DY. et al J. Infect. Dis. 170; Homozygous point muta*on (G428A) in the fucosyltransferase- 2 gene (FUT2(- /- ) protects against infec*on with the most common Norovirus. - 20% of Europeans are homozygo. Hutson AM., et al Trends in microbiology. 12:279. Lack of FUT2 enzyme: No expression of ABH an*gens in intes*ne or saliva. 10