Overview_of_the_Respiratory_Viruses_of_Upper_Respiratory-2023_Leo_final.pptx
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Overview of the Respiratory Viruses of Upper Respiratory Tract: The Common Cold Debra Bramblett, PhD Burrell College of Osteopathic Medicine, 2023 Entry Objective • List the most common viral etiological agents of the common cold: Adenovirus, Rhinovirus (Picornaviridae), Coronavirus (Coronaviridae...
Overview of the Respiratory Viruses of Upper Respiratory Tract: The Common Cold Debra Bramblett, PhD Burrell College of Osteopathic Medicine, 2023 Entry Objective • List the most common viral etiological agents of the common cold: Adenovirus, Rhinovirus (Picornaviridae), Coronavirus (Coronaviridae), Influenza (Orthomyxoviridae), Metapneumovirus, Parainfluenza and Respiratory Syncytial Virus (Paramyxoviridae) The common cold • Clinical manifestations: • • • • Starts with nasal stuffiness, sneezing and headache. Rhinorrhea then occurs with increasing severity General malaise lacrimation, sore throat, slight (low grade) fever. There may be a cough (more likely with viral URI) • Most common causes • Rhinovirus and Human Corona virus • There are several other viral causes of cold like symptoms • Pathogenesis • Virus enters by inhalation • Infects cells lining nasal passages and the pharynx following attachment to cell receptor like ICAM-1 • Inflammatory changes occur with hyperemia, edema and leukocyte inflammation. The ciliated columnar epithelial cells are destroyed and slough off. • Secondary bacterial infections by normal flora can cause secretions to become mucopurulent. If severe, blockage of the Sinus ostia or the Eustachian tube occurs, paranasal sinusitis or otitis media results. Comparison of Common Viral Causes of Sore Throat and/or Upper Respiratory Tract Disease Family Name Genome Morphology Cellular Receptor Adenoviridae Adenovirus 1-7 Ds DNA Not Enveloped Icosahedral CAR Orthomyxovirid ae Influenza A, B, C ss (-) RNA segmente d Enveloped, Helical nucleocapsi d Sialic Acid Coronaviridae Coronavirus HCoV-OC43 HCoV-229E ss(+) RNA Enveloped Helical ACE Angiotensin converting enzyme 2; APN aminopeptidase N, Sialic acid Paramyxovirida e Subfamily: Paramyxovirina e Parainfluenza 1,2,3,4 ss(-) RNA No segments Enveloped, Helical nucleocapsi d Sialic acid Respiratory Syncytial virus ( RSV)1 ss(-) RNA Enveloped, Helical nucleocapsi d Glycosaminoglycans (GAGs) such as Heparin sulfate and chondroitin sulfate B also CX3CR1. IGF1R binds to RSV-F Human metapneumovirus ss(-) RNA Enveloped, Helical nucleocapsi d Glycosaminoglycans (GAGs) Coxsackie A group ss(+)RNA Not Enveloped ICAM-1 used by A21, A13, A18 Paramyxovirida e Subfamily: Pneumovirin ae Genus Pneumovirus Picornaviridae Part I Objectives • Recognize the Adenovirus based on the virion structure, replication and genomic architecture. • Know the Adenovirus types associated with respiratory disease and recognize signs of Adenovirus infection. • Explain how Rhinovirus and Adenovirus interfere with the host anti-viral response. Human Adenovirus (HAdV) • Adenovirus types 1-7 are upper respiratory, • Types 40, 41 attack the GI system • Receptors for HAdV. • Types 1, 2, 4, 5, 6 bind adenovirus-coxsackie virus receptor –CAR in respiratory system. • Types 3, 7 bind to CD46, CD80/86 and HSPG, MHC-I in respiratory system • Non-enveloped, capsid virus (70-90 nm) • Icosahedral with 12 pentons over 12 vertices and fiber protrusions with ligands for cellular receptors at the ends. • Genome is a single ds DNA • It has early genes and late genes.Transforming • Latent vs Lytic infection • Type-specific, Life-long protective immunity • Gene therapy and oncolytic viral therapy • Respiratory Disease: acute febrile pharyngitis, characterized by a cough, sore throat nasal congestion and fever. Adenovirus Replication 1. Adsorption: The viral fiber protein interacts with glycoprotein receptor CAR a. Adenovirus uses the same receptor is used by any Coxsackie B virus, which gave it the name coxsackie-adenovirus receptor CAR 2. Endocytosis: after attachment to the cell it is internalized by receptor-mediated endocytosis in a clathrin –coated vesicle. 3. Endosome lysis: The virus lyses the endosomal vesicle 4. Microtubule transport: The capsid travels to the nucleus by way of microtubules and thereby delivers viral DNA to the nucleus 5. Capsid delivery of DNA to the nucleus a. DNA replication occurs in the nucleus via viral encoded DNA pol H+ Capsid disassembly Microtubule Nuclear Por DNA is injected into the Adenovirus Replication continued 6. Transcription and translation • Transcription occurs in two phases early and late by Cellular RNA Pol II Early gene expression- E1, E2, E3, E4 The early genes are transcribed from four promoter sequences, and each generates several messenger RNAs by processing the primary RNA transcripts (Splicing) E1A • E1A gene codes for the E1A transactivator, which is required for all early gene transcription, including the DNA polymerase • E1A also binds cellular pRB, blocking its activity and promoting the cell cycle • • pRB is the “Gatekeeper” – cell cycle inhibition E1A has oncogenic potential in animal cells because of its interaction with the tumor suppressor pRB E1B • E1B blocks apoptosis by binding to cellular p53 • P53 is the “Genome Guardian” – apoptosis promotion after DNA damage • E2 proteins are involved in viral DNA replication and include a DNA polymerase, a ssDNA binding protein and a precursor to the terminal protein (found at each end of the genome) • E3 is not essential for Adenovirus replication in cell culture and can be deleted or replaced with out disrupting viral replication in vitro • It is therefore favored as an insertion site for foreign DNA when constructing adenovirus vectors. • E3 modulates the host response to adenovirus infection • by inhibiting Class I MHC in infected cells and inhibition of TNF • E4 inhibits the cellular DNA damage response 7. Viral DNA replication occurs in the nucleus • there are inverted repeats at each end of the genome that serve as initiation sites • the terminal protein (TP linked to the 5’ ends serve as primer for viral polymerase instead of the 3’ OH) 8. Late gene transcription (L1 to L5). a. Starts only after DNA replication. b. All of the late genes are transcribed from one promoter sequence c. Capsid proteins (L) are produced in the cytoplasm and then transported to the nucleus for viral assembly. 9. Virus remains in the cell and is released when the cell degenerates and lyses. Adenovirus can produce lytic, Latent and transforming infections In non-permissive cells, there is viral latency and the genome remains in the nucleus but doesn’t replicate (this tends to occur in the adenoids and tonsils) In permissive cells the virus stimulates cell growth, which promotes virus production and then cell death ensues. The initial port of entry can be the eye or upper respiratory track. Dissemination can occur from here. Adenovirus does tend to become latent in the adenoids, tonsils and Peyer’s patches. The only cells known to be transformed by Adenovirus are hamster cells. • The histological hallmark of Adenovirus infection is a dense, central, intranuclear inclusion ( that consists of viral DNA and protein) within an infected epithelial cell. Dense central intranuclear inclusions Adenovirus and the innate antiviral response See figure on next slide • Viral capsid or genomic DNA activates innate immunity, leading to production of interferons (IFNs) and inflammatory cytokines. • Adenovirus adsorption and penetration induces type I IFNs by activation of RIG-1, TLR9 and TLR2. • INF /β bind to a common interferon receptor which leads to signaling cascades (JAK/Stat) to induce an antiviral state (there are many interferon responsive genes than contribute the antiviral state) • Protein kinase PKR is responsible for the phosphorylation of elongation initiation factor eIF-2therefore inhibiting protein synthesis. • PKR enzyme expression is induced in a latent form but binding to dsRNA or to RNAs containing duplex regions to undergo autophosphorylation activating it. • Dimerization plays a key role in PKR activation. PKR dimerizes weakly in solution and dimerization is sufficient to activate PKR in the absence of RNA. • Adenovirus encodes RNA decoys (VA RNA) that bind PKR but do not activate it, thereby serving to block the antiviral response. How Adenovirus Blocks the Antiviral response 1 . Adenovirus infection 1. Interferon binds receptor to activate Jak-STAT pathway 2. Phospho STAT activates Interferon stimulated genes including PKR (ISGs) 5 2. 3& 4 3. PKR recognizes dsRNA and dimerizes 4. PKR autophosphorylates 5. Phospho-PKR phosphorylates eIF-2a to block translation Adenoviral VAI-RNAs act as decoys to prevent activation of PKR Clinical Adenovirus Upper Respiratory Syndromes o Acute Febrile Pharyngitis (HAdV-1-7) o Pharyngoconjunctival fever (HAdV-3 and -7) o Occurs in young children under 3 looks like Strep. Mild flulike symptoms with nasal congestion, cough, coryza, malaise, fever, chills myalgia and headache. o accompanied by conjunctivitis o Acute Respiratory disease (HAdV-1,2,3,5) o Fever, runny nose, cough, and pharyngitis o Military recruits Conjunctivitis and Ep (HAdV 4 and 7) o Epidemic Keratoconjunctivitis (HAdV-4, HAdV-8, HAdV-19, HAdV-37) o Causes follicular conjunctivitis (pinkeye) o Pneumonia, severe and complicated particularly in infants (HAdV- 3,7,14 and 21) EXTREMELY infectious!!! Spread in aerosols and by the fecal-oral route, by fingers, by fomites ( including towels and medical instruments) and in ponds or poorly chlorinated swimming pools. Associated with close quarters like schools and military barracks Part II. Learning Objectives • Compare and contrast the virion structure, and genomic architecture and replication cycle of the two most common causes of the common cold, Rhinovirus and Coronavirus. • Describe the mechanism of action of drugs that target the Picornaviruses [ Arildone, dioxaril, Pleconarile and other mythylisoxazole compounds that block penetration and uncoating]l • as compared to viruses that enter the cell by the acidification of endocytic vesicles. • Compare and contrast the upper respiratory syndromes caused by the Picornavirus family and the viruses of the Paramyxovirus family and know the cellular receptors and viral proteins important to viral entry and replication for these viruses. Objective: Define the Picornaviridae in regards to the virion architecture, genome composition, replication and other biological properties that all the members of this family share. FAMILY: PICORNAVIRIDAE Small (30nm) (+) RNA, non-enveloped icosahedral capsid (Vp1-Vp4) Genome structures and translation processes are highly conserved. The two most important Genera are Enterovirus Rhinovirus These two genera are easily differentiated by the fact that the Enteroviruses are acid stable, in that they can survive the GI tract acid and are transmitted through an oral-fecal route. In contrast, the Rhinovirus is highly acid labile and is not transmitted in this fashion. Review 22 Review Slide The Picornavirus Genomic RNA • Genome length 7.0 – 8.5 kb • One open reading frame that encodes a single poly protein comprising a structural protein ( Capsid) P1 region and non-structural proteins encoded by the P2 and P3 regions. • Rather than cap dependent initiation of translation, the 5’ end is linked to VPg viral protein and there is an IRES • Release of mature and functional proteins is primarily mediated by the viral proteinase 3Cpro and its precursor 3CD RNA Translate Poly protein Mature proteins Primary VP0 VP3 VP2 P 1 VP4 VP1 P3 P 2 2A 2 B 2 C Vp G 3A, 3B, 3Cpro RdRp Secondary Stage Rhinovirus (+ RNA) Binding Binding to ICAM or LDL Replication is Capsid conformation change VP1entirely in the Uncoating Transmission of RNA across the cell most RNA viruses except membrane and vesicle association Translation cytoplasm like influenza a Immediately after un-coating to notable generate a poly-protein that mustexception. be cleaved into VP1, VP2, VP3, VP4, 2A, 3D Transcription Requires translation of viral RNA polymerase to generate template Genome Replication (-)RNA to (+) RNA by viral polymerase Release from Cell Encapsidation -Provirion Virion formation Cell lysis Fields Virology fifth edition, Vol I Section II Chapter 24 Eds. Knipe and Griffin Lippincot Williams & Wilikins, 530 Walnut Street, Philadelphia, PA 19106 USA Compare and contrast the replication cycle of Rhinovirus with Human Coronavirus. Rhinovirus pathogenesis • Rhinovirus rapidly kills relatively a few cells in the upper airways and quickly surrenders to the innate immune system • Runny nose: Capillaries of the upper respiratory tract are very near the surface and are targets of cytokines and other inflammatory mediators given off. • Causes capillaries to leak and fluid to escape causing running nose. Cytokine production increases mucus production. • Constricted airways is due the fluid that leaks out to get trapped in tissues. • Normal drainage from the nasopharyngeal areas can result in middle ear and sinus infections. • Low grade fever is triggered by IL -1 . • It interferes with the production of interferon. Little interferon production results in milder symptoms than the “flu”. • Because Rhinovirus reproduces best at temps below the core body temperature, rhinovirus infection usually are confined to the upper respiratory tract and as a result almost never results in pneumonia Explain how Rhinovirus and Adenovirus interfere with the host anti-viral response. Review Diseases of Coxsackie A virus another Picornavirus Family: Picornavirus Genome Composition: (+) RNA Coxsackie A group o A21, A13, A18-common cold o A10, A16 -HFM disease in US o E71 -HFM and encephalitis outbreaks in Asia Capsid Shape: naked, small (25 to 30 nm) icosahedral Diseases: Herpangina Hand -foot and mouth disease (HFMD) Aseptic Meningitis Meningoencephalitis in neonates and those with agammaglobulinemia Purpuric macules and papules in a 4-year-old girl with enteroviral infection. Anti – Viral Drug mechanisms of action • Arildone, dioxarile, Pleconaril and other methylisoxazole compounds block uncoating of Picornaviruses by binding into a cleft in the receptorbinding canyon of the capsid and prevent disassembly of the capsid. • Amantadine and rimantadine are hydrophobic amines (weak organic bases) that can neutralize the pH of endocytic vesicle and prevent virion uncoating. • effective against influenza A • Ribavirin inhibits RNA synthesis. It resembles a riboguanosine and promotes mutations, inhibits nucleoside biosynthesis, RNA synthesis, and mRNA capping all important for viral and cellular processes. • Approved for RSV and Lassa virus but not a lot of other RNA viruses • Zanamivir (Relenza) and oseltaminvir (Tamiflu) act as inhibitors of virion assembly and release by inhibiting the viral protein Neuraminidase • Effective against both Influenza A and B Part III Objective • Compare and contrast the virion structure, and genomic architecture and replication cycle of the two most common causes of the common cold, Rhinovirus and Coronavirus. Human Coronaviruses (Hcov) • Genome Composition: ss (+) RNA • Capsid Shape: Spherical virion with petal shaped spikes, helical nucleocapsid • Major Viral proteins /antigens: M (Matrix), E (Envelope protein), S (Spike), N (nucleocapsid) • Enveloped Receptor(s): ACE Angiotensin converting enzyme 2 (for SARS-CoV); APN aminopeptidase N ( cat, pig and human corona virus), Sialic acid certain differences in glycosylation between APN coronavirus receptors from different species are critical determinants in the species specificity of infection. • Disease: The common cold • Interaction with the host: Non-lytic, released by exocytosis • Replication Strategies: Similar to other ss(+) RNA viruses but it synthesizes 6 individual mRNAs from a minus strand template. Also, virions are assembled in the rough endoplasmic reticulum. Has early and late protein synthesis • Host cell range: strict species specificity of each strain but Phylogenetic tree for Coronavirus Common Cold Viruses: HCoV-229E HCoV-NL43 HCoV-OC43 HCoV-HKU1 Receptors: APN ACE2 glycan-based receptors carrying 9-O-acetylated sialic acid. Viruses that cause severe respiratory disease Receptors: Severe acute respiratory syndrome coronavirus SARS-CoV Middle East respiratory syndrome coronavirus ACE2 DPP4 ACE2 Corona virus replication 1. The E2 glycoprotein (S spike) interacts with the receptors on epithelial cells. 2. Once it binds to the cell and is adsorbed, the genome is released and translated into a polyprotein which is cleaved to produce some other proteins including the RNA polymerase L. (Early protein synthesis) 3. Transcription and replication of the genome occurs in the cytoplasm associated with membrane vesicles created by viral protein 4. It uses a negative-sense template RNA to replicate new genomes and to produce about 6 -8 individual messenger ribonucleic acids (mRNA). 5. Late-stage translation from the mRNAs produces the structural proteins 6. The genome associated with rough ER membrane and buds into the lumen of the ER. 7. The virus is then released by exocytosis Compare and contrast the virion structure, and genomic architecture and replication cycle of the two most common causes of the common cold, Rhinovirus and Coronavirus. HCov Replication • Attachment (S1) to ACE2 or APN • Entry/fusion from endosomes requires S2. • Translation of nonstructural proteins • NS proteins (pp1a pp1ab) that rearrange cell membranes to form double membrane vesicles where viral replication takes place. • RNA polymerase (RDRP) • Proteases (PLPpro and Mpro) • Genome transcription and replication • Translation of structural proteins • Virion assembly in the ER-Golgi and release via secretory pathway. Compare and contrast the virion structure, and genomic architecture and replication cycle of the two most common causes of the common cold, Rhinovirus and Coronavirus. Coronavirus pathogenesis and transmission Due to the “corona” formed by the halo of glycoproteins this virus , although enveloped, can endure the conditions in the gastrointestinal tract!!!!! can be spread by fecal-oral route (very unique for an enveloped virus). Most often acquired by respiratory route Human Coronaviruses (HCoV) have an optimum temperature of the growth of 33 °C-35°C and therefore infection remains localized to the upper respiratory tract (like rhinovirus). Zoonotic coronaviruses SARS-CoV and MERS-CoV can replicate at 37° C and these cause systemic disease. we will discuss the zoonotic corona viruses like SARS-COV2 in greater detail next year Human Coronavirus Disease and Epidemiology Disease due to HCoV occurs mainly in infants and children because antibodies to coronavirus are usually present in adults but reinfection is common even with the presence of antibodies. The typical disease caused by human corona virus is identical to the “cold” caused by rhinovirus. Most often occurs in the winter and spring. Incubation is about 3 days and the illness lasts between 2 and 18 days The cold causing human corona virus is pretty much ubiquitous and causes about 10% to 15 % of all upper respiratory tract infections. Part IV Objectives: Paramyxoviridae: Metapneumovirus, Parainfluenza and Respiratory Syncytial virus (RSV) • Describe the replication cycle of the Paramyxoviridae •Compare and contrast the upper respiratory syndromes caused by the Picornavirus family and the viruses of the Paramyxovirus family and know the cellular receptors and viral proteins important to viral entry and replication for these viruses. •Describe how there are other viruses that cause the common cold, which are frequently associated with lower respiratory symptoms including RSV, Influenza, Parainfluenza and Adenovirus and Metapneumovirus • Describe the action of the drug Palivizumab used for RSV Prophylaxis in premature babies. • Compare the transmission, genomic structure and virion structure of some less common viral causes of pharyngitis (herpes, Epstein-Barr virus, human immunodeficiency virus (HIV)) to the most common viral causes of sore throat. Parainfluenza (HPIV) • A negative sense (-)RNA, • Virion is enveloped with helical capsid containing the single stranded genome • Viral proteins and/or antigens: • HN, F, M, N , P (H and N are part of the same glycoprotein spike) • Receptor(s): Sialic acid • Interaction with the host: Non-lytic (Buds) • Transmission: Spread by respiratory droplets Parainfluenza • Disease: • Mainly upper respiratory tract disease “cold” with fever. In about 25% of case it can spread to LRT to cause bronchiolits and pneumonia • Croup is parainfluenza infection of larynx (wheezing and barking cough). • HPIV-1 and HPIV-2 are more likely to cause Croup and pharyngitis. • HPIV-3 can cause pneumonia (LRT) in children, elderly and immuno-compromised and URT infections in adults • HPIV-4 cause only mild upper respiratory disease. • Parainfluenza proteins: • HN: Glycoprotein spike (single) on envelope surface with hemagglutinin and neuraminidase functions, binds cell surface • F: fusion protein that allows the virus membrane to fuse with the host cell membrane • M: the matrix protein that coats the inside of the viral membrane, assists with budding • P: Polymerase phosphoprotein is part of the transcription complex • L: Large protein associated with nucleoprotein and functions as polymerase • N: Nucleoprotein, protects the viral RNA Compare and contrast the upper respiratory syndromes caused by the Picornavirus family and the viruses of the Paramyxovirus family and know the cellular receptors and viral proteins important to viral Replication of a negative sense (-)RNA, helical nucleocapsid: RSV 1. Adsorption 2. Fusion 3. Penetrati 4. uncoating on - RNA + RNA 6b. Transcription -RNA Geno me 5. RNA Dependent Transcription 6a. Translation Viral RNA polymerase Nucleocapsid proteins Matrix protein 7. Assembly of RNA and Protein Compare and contrast the upper respiratory syndromes caused by the Picornavirus family and the viruses of the Paramyxovirus family and know the cellular receptors and viral proteins important to viral Parainfluenza causes Croup • The virus initially infects the upper respiratory tract, and usually produces congestion of the nasal passages and nasopharynx • The classic signs of croup—stridor, hoarseness, and cough— arise mostly from the inflammation of the larynx and trachea. • The impeded flow of air through this narrowed area produces the classic high-pitched vibratory sounds, or stridor. • The characteristic manifestation of viral croup is the “hourglass” or “steeple” sign -noted on an anteroposterior neck X-ray is a narrowed shadow of the trachea in the subglottic area. -The diagnosis of croup can almost always be made on the basis of the characteristic epidemiologic features and the clinical manifestations so the X-ray is usually not necessary. https://www.youtube.com/watch?v=C1q6ATkMtm0 Croup (laryngotracheobronchitis). A, Posteroanterior view of the upper airway shows the so-called steeple sign, the tapered narrowing of the immediate subglottic airway ( arrows ). http://www.easyauscultation.com/c ases?coursecaseorder=13&coursei d=202 Compare and contrast the upper respiratory syndromes caused by the Picornavirus family and the viruses of the Paramyxovirus family and know the cellular receptors and viral proteins important to viral Respiratory Syncytial virus RSV • Pneumoviridae was Paramyxoviridae family • SS (-) RNA virus, enveloped, not segmented • 10 genes and 11 Proteins: NS1, NS2, N, L, P, SH M2-1 and M2-2, matrix M, F, G (F and G are glycosylated surface proteins) • The G protein mediates attachment of the virus to respiratory epithelial cells. • RSV causes characteristic syncytia due to F protein • F facilitates entry in the host cell by fusion • F is a drug target Compare and contrast the upper respiratory syndromes caused by the Picornavirus family and the viruses of the Paramyxovirus family and know the cellular receptors and viral proteins important to viral RSV epidemiology • Worldwide distribution • 33.8 million new episodes of lower respiratory tract infections among children under 5, per year. • 66,000 to 199,00 deaths /year in resource poor countries • 1.5 million RSV lower respiratory trans infection episodes in adults > 65 years of age • Until recently, there was no vaccine and care is mainly supportive • Most children have had and RSV infection by age 4 and will have recurrent infections through out life. Most RSV related hospitalizations occur 2-3 months after birth but peak incidence is 6-12 months. Risk factors prematurity, congenital heart diseases, lung diseases and Down’s syndrome. • Older children and adults have mild cold symptoms but elderly are at increase risk of severe infection • The most frequent cause of bronchiolitis • Bronchiolitis is swelling and mucus buildup in the smallest air passages in the lungs (bronchioles), usually due to a viral infection • Out breaks are seasonal from late fall through spring (October to May) • Viral shedding for less than 1 to 3 weeks in immuno-competent but longer in compromised Compare and contrast the upper respiratory syndromes caused by the Picornavirus family and the viruses of the Paramyxovirus family and know the cellular receptors and viral proteins important to viral Perinatal RSV Prophylaxis • After discharge, infants with a history of prematurity congenital heart diseases, chronic lung disease or bronchopulmonary disease, and/or immunodeficiencies are at increased risk of developing severe RSV infections. • The American Academy of Pediatric (AAP) recommends immunoprophylaxis with Palivizumab for infants at risk of severe RSV. • Palivizumab is an RSV-specific prophylactic for use in high-risk infants but treatment requires monthly injections. • Palivizumab is a monoclonal antibody produced by recombinant DNA technology. It is directed against an epitope in the A antigenic site of the F protein of RSV. Y F • Most treatments undergoing clinical trials target the F protein. • For example. The nebulized therapeutic nanobody ALX-0171 • ALX-0771 reduced viral replication but did not improve clinical symptoms I Describe the action of the drug Palivizumab used for RSV Prophylaxis in premature babies. I Y F Breaking News!!! FY I FDA Approves First Respiratory Syncytial Virus (RSV) Vaccine Arexvy Approved for Individuals 60 Years of Age and Older • News release May 03, 2023 • The vaccine significantly reduced the risk of developing RSV-associated LRTD by 82.6% and reduced the risk of developing severe RSV-associated LRTD by 94.1%. • AREXVY, contains recombinant respiratory syncytial virus glycoprotein F stabilized in the prefusion conformation (RSVPreF3). I Y F Breaking News!!! FY I • On November 1, 2022 Pfizer positive data from the Phase 3 clinical trial MATISSE (MATernal Immunization Study for Safety and Efficacy) • A bivalent RSV prefusion vaccine candidate, RSVpreF or PF-06928316, when administered to pregnant participants to help protect their infants from RSV disease after birth. • Vaccine efficacy of 81.8% was observed against severe medically attended lower respiratory tract illness due to RSV in infants from birth through the first 90 days of life • with high efficacy of 69.4% demonstrated through the first six months of life • RSVpreF vaccine administered during pregnancy was effective against medically attended severe RSV-associated lower respiratory tract illness in infants, and no safety concerns were identified. N Engl J Med 2023; 388:1451-1464 DOI: 10.1056/NEJMoa2216480 • A new antiviral medication, nirsevimab, against respiratory syncytial virus, or RSV, appears to be safe and lowered viral levels and symptoms significantly more than a placebo, according to the results of a study published in The New England Journal of Medicine last year. • Nirsevimab (MEDI8897) is an RSV F protein monoclonal antibody Human Metapneumovirus (HMPV) • A new Paramyxovirus, was first identified in 2001 • SS (-) RNA virus, enveloped, not segmented https://wwwnc.cdc.gov/ei • Occurs in children at a slightly older age than RSV but very similar to d/article/9/9/03-0304_art icle RSV • Usually causes upper respiratory symptoms: fever, cough, rhinorrhea but can also cause bronchiolitis, croup, pneumonia and exacerbates asthma • Airway epithelial cells are the predominant target of HMPV infection but also airway macrophages, Dendritic cells (interfering with CD4 T cell activation) • Proteins : G attachment, F protein for fusion, and SH a small hydrophobic protein • Receptors: Glycosaminoglycans (GAGs) Glycosaminoglycans (GAGs) are long, unbranched polysaccharides that consist of repeating disaccharide subunits, of which heparan sulfate (HS) and, to a lesser extent, chondroitin sulfate (CS) can act as attachment factors for a range of human viruses • Diagnosis by RT-PCR in multiplex assays for respiratory viruses Objective: Describe how there are other viruses that cause the common cold, which are frequently associated with lower respiratory symptoms including RSV, Influenza, Parainfluenza and Adenovirus and Less common viral causes of Pharyngitis Family Name Genome Morphology Cellular Receptor Disease with pharyngitis Transmission Herpesvirid ae Herpes simplex virus dsDNA Enveloped, icosahedra l HVEM, nectin-1 and 3-OS-HS Herpetic pharyngitis Intimate contact, exposure to body secretions Herpesvirid ae Epstein –Barr virus dsDNA Enveloped, CD21 (complement receptor 2) Mononucleosis Kissing, exposure to body secretion like saliva CD4 and coreceptors CCR4 and CCR5 Primary HIV infection prior to Stage 1-3 Sexual transmission and parenteral , exposure to blood products icosahedra l Retroviridae Human immunodefici ency virus (HIV) Ss (+) RNA Enveloped, cone shaped capsid Compare the transmission, genomic structure and virion structure of the less common viral causes of pharyngitis (herpes, Epstein-Barr virus, human immunodeficiency virus (HIV)) to the most common viral causes of sore throat. Herpesvirus Family (Herpesviridae) Linear ds DNA virus Capsid is icosadeltahedral (162 capsomers) Enveloped • The fact that it is enveloped makes it sensitive to acid, solvents, and detergents and drying. Sub-Families: Alphaherpesvirinae: HSV-1, HSV-2, Varicella zoster (HHV-3) Gammaherpesvirinae: Epstein Barr Virus (EBV or HHV-4), HHV8 Betaheperpesvirinae, CMV (HHV-5) , HHV6, HHV7, EBV Clinical Presentation of Mononucleosis o o o o Caused by Epstein-Barr Virus (EBV) a Herpesvirus A human pathogen, spread through saliva, genital secretions Long incubation 30-50 days Two peaks in incidence are found in developed countries: before 5 years of age (largely subclinical) and adolescence o Triad of symptoms (>80%): FEVER (resolves in 10-14 days) EXUDATIVE PHARYNGITIS (sore throat 3-5d) POSTERIOR CERVICAL LYMPHADENOPATHY o Can be mistaken for Strep throat. o Rash present in 5% of patients due to viral infection itself o Administration of Ampicillin or Amoxicillin produce a rash in 90% to 100% of patients o Chronic fatigue syndrome o Splenomegaly in 50% of cases is maximal at 2w and regresses over 10d. Herpetic pharyngitis due to HSV • An infection is commonly observed in children and young adults. • HSV may cause gingivitis or stomatitis. • A sore throat with associated gingivostomatitis is the typical presenting symptom. • Other associated symptoms include fever, pain when swallowing (odynophagia), myalgia and malaise. Pharyngitis and HIV primary infection • Primary exposure and transmission of HIV often occurs through sexual contact or exposure to body fluids and/or blood products • In primary HIV infection, 50-75% of patients present with an acute illness 3 to 6 weeks after exposure to HIV ( Pharyngitis, fever, rash) • HIV infection progresses from an asymptomatic nonspecific disease to profound immuno-suppression, referred to as “full-blown AIDS” Human Immunodeficiency Virus Structure • Viral glycoproteins ▫ Gp160 (Env) is cleaved into ▫ TM (Gp41) – promotes fusion ▫ SU (Gp120) –promotes tissue tropism • Other Viral Proteins: ▫ Gag is cleaved into ▫ CA (p24), MA (p17), NC (p7), p6 ▫ Pol is cleaved into ▫ Reverse Transcriptase, Protease, & Integrase ▫Viral Regulatory Proteins ▫ Tat-(transactivator) ▫ Rev-(regulates splicing) ▫ Nef, Vif, Vpu, Vpr Created with BioRender.com HIV life cycle
