Respiratory viruses.pdf

Respiratory viruses Dr. Marine Petit [email protected] Respiratory viruses-Learning Outcomes • Appreciate the burden of respiratory viruses • Learn about a few important respiratory viruses • Understand key facts including: • • • • Burden History & epi Virology Pathogenesis • Similarities and...

Respiratory viruses Dr. Marine Petit [email protected] Respiratory viruses-Learning Outcomes • Appreciate the burden of respiratory viruses • Learn about a few important respiratory viruses • Understand key facts including: • • • • Burden History & epi Virology Pathogenesis • Similarities and differences between respiratory viruses Respiratory viral infection Respiratory viral infection Upper Runny nose Cough Sore throat Rhinitis Pharyngitis Laryngitis Respiratory viral infection Upper Runny nose Cough Sore throat Rhinitis Pharyngitis Laryngitis Influenza virus Respiratory Syncytial Virus RSV Respiratory viral infection Upper Runny nose Cough Sore throat Rhinitis Pharyngitis Laryngitis Croup -kids -stridor Bronchiolitis Pneumonia Lower Respiratory failure Respiratory viral infection Upper Runny nose Cough Sore throat Rhinitis Pharyngitis Laryngitis Influenza virus Respiratory Syncytial Virus RSV Croup -kids -stridor Bronchiolitis Pneumonia Important info! Lower Respiratory failure Respiratory viruses' seasonality July Oct Dec June Transmission of Respiratory Viruses Important info! https://www.nature.com/articles/s41579-021-00535-6 Respiratory Syncytial Virus RSV-history & epidemiology • RSV first discovered in 1956 • RSV is the most common cause of respiratory infection in infants and young children • Virtually all infected by age 2 • Reinfected throughout life • Very young, very old and immunocompromised most at risk • 33 million infections worldwide each year • 3.4 million hospitalisations • Up to 199,000 deaths/year RSV-virology Classification: Enveloped, negative-sense ssRNA virus Mononeavirales-pneumoviridae-orthopneumovirus Viral strains: Divided into 2 subtypes A and B (based on the F and G proteins) 16 RSV A and 22 RSV B clades identified Description: Virions are pleomorphic 10 genes encoding 11 proteins Important info! RSV-virology Classification: Enveloped, negative-sense ssRNA virus Mononeavirales-pneumoviridae-orthopneumovirus Viral strains: Divided into 2 subtypes A and B (based on the F and G proteins) 16 RSV A and 22 RSV B clades identified Description: Virions are pleomorphic 10 genes encoding 11 proteins RSV genome Glycoprotein Viral attachment to cells Phosphoprotein Nucleoprotein RNA binding Small hydrophobic protein Viroporin; ion channel. Delays apoptosis Evasion of the immune response. Inhibiting apoptosis and IFN signalling Important info! Matrix protein Assembly Fusion protein. Fusion of viral & host cell membranes M2-1 Transcription M2-2 Regulation of transcription Large protein RNA dependent RNA polymerase RSV-diagnosis & treatment • Diagnosis is usually by PCR as part of a respiratory panel. Rapid antigen tests are available. • Diagnosis is about patient management & isolation, does not impact treatment • No vaccine, no treatment • One prophylactic option: palivizumab, a humanised monoclonal antibody requiring monthly administration. £££ reserved for high risk children Important info! RSV-pathogenesis RSV-pathogenesis Incubation of 2-8 days RSV causes syncytia (mostly observed in cell culture) More serious disease: atelectasis, respiratory failure Infection results in inflammation, infiltration of inflammatory cells (neutrophils, monocytes), increased mucous production, sloughed cells. A link to the development of asthma right upper lobe atelectasis Innate antiviral mechanisms RSV replication can be limited by: • Cell apoptosis • Extrinsic: TRAIL binding to death receptor 4/5 • Intrinsic: BCL-2 proteins localising to mitochondria • Cell Stress • ER stress • Transcriptional stress • Oxidative stress • Innate immune responses • Virus recognised through NOD-like receptors (NLRs), Toll-like receptors (TLRs), RIG-I-like receptors (RLRs) • Signal through adapter proteins to activate interferon regulatory factors (IRFs) and NF-kB • Type I and type III Interferon and other cytokines produced The development of an RSV vaccine 1st Vaccine developed with Inactivated virus Maternal immunization against RSV antibody treatment: an injectable shot known as palivizumab, or Synagis. Injected infants during trials developed Vaccine-associated enhances respiratory disease 80% vaccinated children were hospitalized 2 children died Capella C, et al. J Infect Dis. 2017;216(11):1398–1406. The development of an RSV vaccine Maternal immunization against RSV antibody treatment: an injectable shot known as palivizumab, or Synagis. Glycoprotein conformation post-attachment Use for the 1st vaccine trial Capella C, et al. J Infect Dis. 2017;216(11):1398–1406. The development of an RSV vaccine Glycoprotein conformation pre-attachment Use in other respiratory vaccine trial This led to the recent development of the RSV vaccine Maternal immunization against RSV antibody treatment: an injectable shot known as palivizumab, or Synagis. Important info! The antibody generated against the pre-fusion glycoprotein are more stable and create a good immunization Glycoprotein conformation post-attachment Use for the 1st vaccine trial Capella C, et al. J Infect Dis. 2017;216(11):1398–1406. The Good News!!! Our RSV specialist at Surrey: Lindsay Broadbent! Rhinovirus Rhinovirus-Virology Classification: Non-enveloped positive-sense ssRNA Picornavirales-picornaviridae-enterovirus-Rhinovirus Virus strains: 3 groups/species of Rhinovirus: A, B & C Approx 160 serotypes identified Nomenclature: HRV-(Species) (index number). A and B use the same index numbers, HRV C has different index numbers • HRV-A1; HRV-B6; HRV-C16 Rhinovirus-history & epi Virus isolated from samples taken from healthcare workers with a cold in 1953 Primary cause of the ‘common cold’ Responsible for over 50% of Upper Respiratory TI Symptoms: runny nose, sneezing, coughing, sore throat, headache, fatigue, aches. Symptoms apparent ~2 days post infection Commonly asymptomatic Co-morbidity: One of the major causes of asthma exacerbations Due to different serotypes reinfection is common in short intervals. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632063/ https://www.theguardian.com/news/2017/oct/06/why-cant-wecure-the-common-cold Rhinovirus Rhinovirus A & B predominantly use ICAM1 as a receptor RV-C uses CDHR3 receptor Transmitted through aerosols/microdroplets and fomites Rhinoviruses like it a bit colder! They prefer 32oC No vaccine currently available Important info! RV-Innate Immunity • Like RSV, Type I and III IFNs play important role • Similar cytokine production from RV-A, B or C • RV disrupts the junctions between cells (mechanisms unclear) • Immune response to RV infection results in pro-inflammatory cytokines and increased airway responsiveness https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067602/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8794520/ 5 minute break Coronavirus Coronaviruses We know Hundreds of coronaviruses! Coronavirus infect pigs, cows, bats, horses, camels, cats, dogs, rodents, birds…. Potential for zoonotic spillover 7 coronavirus (so far!) can infect humans: Including 4 ‘common cold’ endemic strains: 229E, OC43, NL63, HKU1 Coronaviruses are responsible for 10-15% of common colds 3 more severe strains: SARS (2002), MERS (2012), SARS-CoV-2 (2019) Coronaviruses: virology Classification: enveloped +ssRNA viruses Nidovirales-Coronaviridae-Coronavirus Virus strains: Coronavirus virion Alphacoronaviruses include: 229E, NL63 common cold Betacoronaviruses include: SARS1, MERS, SARS-CoV-2, OC43, HKU-1, severe and common coronavirus Description: Coronavirus are the largest RNA viruses known 4 Structural proteins SARS-CoV2 genome 16 Non-Structural proteins ViralZone.expasy.org Pandemic Potential • Ecological distribution • Genetic diversity • Interspecies transmission • “we…highlight the diversity and potential of spillover of bat-borne coronaviruses” 2018; Pre Sars-CoV-2! https://www.nature.com/articles/s41579-018-0118-9 Different coronaviruses, different receptors! **9-O-acetylneuraminic acid receptor also known as Neu5Ac** Pathogenesis-MERS, SARS, SARS-CoV-2: AKI: Acute kidney injury https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-020-01479-w#:~:text=Morphology%20and%20genome%20organization,Transmission%20electron%20microscopy&text=Of%20these%20deadly%20hCoVs%2C%20MERS,kb%2C%20respectively%20%5B47%5D. Pathogenesis-MERS, SARS, SARS-CoV-2: Respiratory infections that cause multiple organ dysfunction https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-020-01479-w#:~:text=Morphology%20and%20genome%20organization,Transmission%20electron%20microscopy&text=Of%20these%20deadly%20hCoVs%2C%20MERS,kb%2C%20respectively%20%5B47%5D. Exploring SARS-Cov-2 genome evolution Try the nextStrain website Nextstrain / ncov / open / global / all-time Influenza Influenza pandemics th 20 Century and on…. Influenza Classification: enveloped negative sense RNA virus Influenza genetic material is segmented into 7 or 8 segments Virus strains: 4 subtypes A, B, C & D Description: Influenza is pleomorphic Each segment of the genome bound to nucleoproteins in a ribonucleoprotein complex (RNP) Influenza replicate in the nucleus of the cell https://www.biorxiv.org/content/10.1101/2021.12.09.472010v1.full Influenza Influenza A has the largest host range. Important info! Influenza A & B are responsible for most human influenza infections. Naming Influenza Virus type Isolate number Virus subtype A/Fujia n/411/2002 (H3N2) Geographic origin Year of isolation NA: 11 subtypes known HA: 18 subtypes known Influenza symptoms Influenza symptoms Important info! Viral life cycle Binding: HA proteins bind to sialic acid receptors (except HA17 & HA18!) Internalisation: endocytosis. Low endosomal pH triggers fusion of viral envelope and endosomal membrane Uncoating: RNPs are released into host cytosol. RNPs transported to the nucleus where mRNA is transcribed Translation: Viral mRNA exported out of the nucleus and translated by host ribosomes. Viral polymerase subunits and NP proteins move to the nucleus to form RNPs Assembly & budding: HA, NA and M2 proteins trafficked to the cell membrane. RNPs in the nucleus and move to the cytosol then the cell membrane. Virions bud from the cell membrane Influenza replication cycle Important info! Antigenic drift vs shift • Drift: Accumulation of mutations in antigens (particularly HA, also NA)) • Occurs most frequently in Influenza A, then B • Shift: Different strains infecting the same host cells can undergo ’reassortment’ • Occurs among influenza viruses of the same genus. Most common in IAV (particularly avian influenza) Important info! Reassortment & pandemic potential https://pubmed.ncbi.nlm.nih.gov/29322273/ Influenza During COVID-19 Key Points: Learn key facts about: RSV Coronaviruses Rhinovirus Influenza Including the history, disease burden, virus structure, differences in strains, pathogenesis Respiratory viruses in the news! https://time.com/6275289/rsv-vaccine-history/ https://www.forbes.com/sites/stevensalzberg/2013/08/08/scientists-will-create-a-deadly-new-flu-strainjust-to-prove-they-can/?sh=16ae45234391 Scientific literature to go further https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-020-01479-w https://www.nature.com/articles/nature04239 Good videos: Universal flu vaccine https://www.youtube.com/watch?v=mXzgOa3cSeE