Viral Pathogenesis I 2023 PDF

Viral Pathogenesis I Department of Microbiology College of Medicine, IAU Thursday, December 7, 2023 Learning objectives ✓Revisit the principles of viral pathogenesis ✓Describe mechanisms of viral pathogenesis and their clinical significance including – – – – Latency Transformation Chronic infec...

Viral Pathogenesis I Department of Microbiology College of Medicine, IAU Thursday, December 7, 2023 Learning objectives ✓Revisit the principles of viral pathogenesis ✓Describe mechanisms of viral pathogenesis and their clinical significance including – – – – Latency Transformation Chronic infection Evolution of viruses and evasion of immune system Thursday, December 7, 2023 Presentation title Viral pathogenesis ▪ Processes by which viral infections cause diseases ▪ Involve virus–host interactions at the cellular and systemic level that determine whether a virus will cause a disease, what form that disease takes, and how severe the disease will be. EEE ▪ Pathogenesis of each virus is unique, yet there are several common points in the virus life cycle that are shared between all pathogenic viruses Thursday, December 7, 2023 Presentation title Viral pathogenesis chicken Thursday, December 7, 2023 Presentation title salivaryglands At cellular level ▪ Tropism: susceptibility, permissiveness, and accessibility ▪ Viral replication leading to: – Release of EE4 new virion – Antigenic variation – Morphological changes morphological changes Thursday, December 7, 2023 4 Presentation title 1:29 PM Cellularsite of viral replication k r DNA viruses be cytogfication Replicate in the cytoplasm. need to translocate to nucleus for replication. Exception influenza virus and retroviruses. Exception poxvirus. Exception influenza virus Retroviruses DNA virus Thursday, December 7, 2023 RNA viruses need intrastate Presentation title Viral Pathogenesis I & II 6 I pause Viral pathogenesis What are the scenarios of virus infection? What happens to the cell after virus infection? Thursday, December 7, 2023 Presentation title Outcomes of Viral Infection I 1. Failed infection - abortive 2. Lytic: – cytolytic/cytocidal infection resulting in host cell death 3. Non-lytic productive infection 4. Persistent ✓ Chronic - carrier of virus ✓ Latent/Subclinical - presence of viral genome with no active replication, reactivation is possible ✓ Transforming (Oncogenesis) ✓h Slow infection i Thursday, December 7, 2023 Presentation title fhhispossible Rea 1 2 3 1:29 PM Tumor cell division, Transformation into tumor eg HPV Lytic infection. Cell destroyed as a result of virus infection, eg influenza Persistent/chronic infection no integration of genome, cell remains viable even though infected, eg. HCV Latency can be reactivated resulting in complete virus replication 4 Latent infection ± integration of genome, cell remains viable even though infected. Virus does not complete full cycle of replication, limited expression of some gene products (latency associated) eg HIV, herpesviruses Fig. 9.22: Brock, Biology of Microorganisms. Madigan et al. (eds.) 13th edition 2012. Fig. 5.16: Prescott’s Microbiology. 8th edition. 2011. Thursday, December 7, 2023 Presentation title 9 But in most cases virus infection is self-limiting Immune response develops against the invading virus and patient recovers with few exceptions……………. Thursday, December 7, 2023 Presentation title Pathogenesis of Some DNA and RNA Viruses • Herpes simplex viruses (HSV) • Human papilloma virus (HPV) DNA • Hepatitis C virus (HCV) • Human immunodeficiency virus (HIV) • Influenza virus Thursday, December 7, 2023 Presentation title Run 1:29 PM DNA viruses Thursday, December 7, 2023 Presentation title Viral Pathogenesis I & II 12 1:29 PM Families of DNA Viruses Papillomaviridae Thursday, December 7, 2023 Presentation title 13 HERPES SIMPLEX VIRUS (HSV) 0 HSV Thursday, December 7, 2023 1:29 PM Herpes Simplex Virus (HSV) I • Belong to the family Herpesviridae • Enveloped icosahedral virus with dsDNA virus • 2 types: HSV-1 and HSV-2 • Establish latent infection in its sensory ganglia HSVIT.ve Establish latent infection in Thursday, December 7, 2023 sensory Ganglia Presentation title 15 Herpes simplex viruses ▪ 2 types: HSV-1, HSV-2 HSV -1 upperpart Predominant Causative agent of herpetic gingivostomatitis, pharyngitis, tonsilitis Most common cause of sporadic encephalitis (except neonate) HSV-2 a Predominant causative agent of genital herpes More likely to cause encephalitis in neonate seroustnfa.atBrain More likely to reactivate ▪ Both HSV-1 and 2 can cause oropharyngeal and genital infection. Generally, HSV-1 causes infection above the waist and HSV-2 below the waist Thursday, December 7, 2023 Presentation title Epidemiology ▪ HSV-1 and HSV-2 are ubiquitous ▪ Transmission occurs via direct contact with vesicular lesion and infectious fluid ▪ HSV-1 global prevalence of 66.6% in 0–49-year-olds (More than 3.7 billion)*. ▪ 13.2% of the world’s population aged 15–49 years are HSV-2 seropositive* *James C, Harfouche M, Welton NJ, Turner KM, Abu-Raddad LJ, Gottlieb SL, Looker KJ. Herpes simplex virus: global infection prevalence and incidence estimates, 2016. Bull World Health Organ. 2020 May 1;98(5):315-329. doi: 10.2471/BLT.19.237149. Epub 2020 Mar 25. PMID: 32514197; PMCID: PMC7265941. Thursday, December 7, 2023 Presentation title Pathogenesis of HSV ▪ Once inoculated, virus replicate in mucosal epithelium -vesicles (primary infection) ▪ Vesicular lesions: 6 ballooning degeneration of intraepithelial cell with fluid accumulation ▪ Ulcerate-scab ▪ Heals with no scaring ▪ Virus gain access to sensory nerve ending……ganglion Thursday, December 7, 2023 Presentation title Pathogenesis of HSV • HSV-1 is maintained in the trigeminal ganglia while HSV-2 is latent in sacral or lumbar ganglia. (Latency) • During latency, the virus is dormant and cannot be transmitted. • Reactivation of viruses after primary infection occurs at or near the same site and occurs despite immunity developing Thursday, December 7, 2023 Presentation title 1:29 PM Clinical Presentation 3 stages: • 1ry infection: usually subclinical, gingivostomatitis, pharyngitis, tonsilitis, genital herpes • Lesions are watery blisters typically of the mouth, lips, genital area and heal with a scab. 10-14 days • Sometimes, HSV-1 can infect eyes, CNS • Latency: asymptomatic o • Reactivation IIETfng Usually subclinical gingivostomatitis Thursday, December 7, 2023 R.ee tintin Aymptomatil Presentation title 20 I tdI 1:29 PM nope Latency and Reactivation of HSV Latency • Is the retention of the viral genome in the nucleus of a cell for an extended period without production of infectious virions. Limited gene expression can occur during latency, but no infectious virus is produced. Genome can be maintained as a non-integrated episome (circular DNA) in the nucleus Reactivation • Is defined as the time at which virion formation occurs and new viruses are released. Switch in gene expression away from genes that may promote latency towards the expression of genes required for genome replication and structural protein expression. Thursday, December 7, 2023 Presentation title 21 Ganglia Thursday, December 7, 2023 Presentation title 1:29 PM During lytic replication of the virus after primary infection Gene expression occurs in a defined temporal pattern. 1.Immediate early IE 2.Early 3.Late • Lytic replication dependent on expression of IE genes • IE genes are responsive to a viral protein that surrounds the capsid called VP16 (tegument protein) • VP16 is transported to the nucleus and forms a complex with cellular proteins that begin transcription of IE genes • Following nuclear entry, the dsDNA genome circularizes. •The latency associated genes (LAT) are expressed and virus then goes into latency Thursday, December 7, 2023 Presentation title Viral Pathogenesis I & II 23 1:29 PM Latency Maintained by Latency Activated nucleus Transcripts (LAT) • Only genes expressed during latency are the LATs. All viral lytic genes are repressed • Expression of LATs inhibits programmed cell death (apoptosis) thus promoting survival of infected cells. Latent viral episomes binding to the cellular chromatin Thursday, December 7, 2023 Presentation title 24 1:29 PM How does the virus stay latent without being detected ? Immune Evasion of HSV: A Key to Pathogenesis. • For HSV, multiple strategies of immune evasion have evolved: 1. Virion host shut off protein (vhs) and infected cell protein 0 (ICP0): inhibit type I interferon-mediated responses in infected cells 2. glycoprotein C: binding and inactivation of C3b component of complement 3. glycoprotein E: Fc binding ability 4. HSV encoded protein ICP47 binds the MHC class I TAP transporter. • The combination of these strategies enables the virus to survive despite our immune systems Thursday, December 7, 2023 Presentation title 25 1:29 PM HSV Protein ICP47 Binds at High Affinity to the TAP Transporter Transporter associated with antigen processing (TAP): It delivers cytosolic peptides into the endoplasmic reticulum (ER), where they bind to nascent MHC class I molecules. ICP47 binds to TAP and inhibits transport of virus peptide and therefore inhibits its presentation to the immune system Thursday, December 7, 2023 Presentation title ICP47 26 1:29 PM Reactivation from Latency • Cellular factors and external stimuli ✓ UV light ✓ Stress, fever, tissue damage, immune suppression • Infectious virus is transported anterograde back to the periphery and infects epithelial cells • Reactivation can occur in the absence of clinical symptoms- asymptomatic reactivation • In HSV-2, asymptomatic reactivation and virus shedding occurs on 25% of days. very important means of transmission E Thursday, December 7, 2023 Presentation title 27 Human Papilloma Virus Thursday, December 7, 2023 1:29 PM Human Papilloma Virus • Belong to Papillomaviridae • Virions are non-enveloped 55nm in diameter Icosahedral capsid • ds DNA, circular, between 6.8kb8.4kb • Causative agent of benign to potentially malignant proliferative lesions Thursday, December 7, 2023 Presentation title 29 1:29 PM Epidemiology ▪ Ubiquitous virus- estimated that up to 80% of people so are exposed to HPV F ▪ Classified in to >200 types, mucosal and cutaneous lesions ▪ One of most common Sexually transmitted diseases ▪ Causes cervical cancer ,the fourth most common cancer among women globally (WHO) Thursday, December 7, 2023 Presentation title 30 Thursday, December 7, 2023 Presentation title Thursday, December 7, 2023 Presentation title ▪ Based on associated with cervical cancer Eicalvirus – High-risk – This includes HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 – Low-risk – 6, 11, 40, 42, 43, 44, 53, 54, 61, 72, 73, and 81 Thursday, December 7, 2023 Presentation title Transmission – Direct contact – Sexual contact – During birth from infected birth canal II.eu tTuving interleaved Thursday, December 7, 2023 Presentation title Clinical Manifestations – Many are subclinical – Skin warts: plantar, common and flat warts, epidermodysplasia verruciformis – Benign head and neck tumors: laryngeal, oral and conjunctival papilloma – Anogenital warts, condyloma acuminatum and cervical intraepithelial neoplasia – cervical cancer Flart Thursday, December 7, 2023 Presentation title 1:29 PM Human Papillomavirus (H PV) :Formation of a Wart by Cell Proliferation Skin epithelium Stratum corneum Differentiating cells become permissive for vegetative viral DNA replication Viral DNA (episome) Papilloma virus infection • Basement epithelium (nonpermissive) Benign transformation Thursday, December 7, 2023 Presentation title 36 1:29 PM Human Papillomavirus (H PV): Formation of a Wart by Cell Proliferation Cells proliferate locally, differentiate and cause wart or papilloma Early viral gene expression Some HPV types can progress to malignancy via genome integration and continued cell replication along with accumulating mutations Thursday, December 7, 2023 Presentation title 37 Thursday, December 7, 2023 Presentation title 1:29 PM HPV -16 and HPV -18 are Associated With Cervical Squamous Neoplasia Growth enhancement due to E6 and E7 gene products -inactivate normal functions of the p53 and Rb proteins (tumor suppressor proteins) -HPV E6 protein binds to cellular p53 protein to form a complex which neutralizes the normal response of cervical epithelia to DNA damage (apoptosis mediated by p53) -HPV type 16 and 18-specific E7 protein bind retinoblastoma gene product, affecting its tumor suppressor role Oncogenic transformation is coincident with integration of papillomavirus DNA into cellular DNA, - expression of E6, E7 without virus production, possible progression to neoplasia, - as these transformed cells continue to divide, they accumulate mutations that eventually allow them to spread to and invade other tissues, and form disseminated tumors (metastasis). In the case of benign warts in the skin and elsewhere, either inactivation of the p53 and Rb proteins is not so profound, or the stimulated cells are so close to death in their terminally differentiated state that they cannot become cancerous. Thursday, December 7, 2023 Presentation title 39 1:29 PM Pathogenesis of HPV ▪ Infects epithelial cells of skin and mucus membrane ▪ Replication depend on the stage of epithelial cell differentiation ▪ Cause benign overgrowth of cells into warts ▪ Some types are associated with dysplasia that may become cancerous Thursday, December 7, 2023 Presentation title 40 Progression to cervical cancer? Thursday, December 7, 2023 Presentation title Summary ▪ Viruses have different effect on infected cells (lysis, persistence, latency, transformation) virus which establishlatency in sensoryganglion ▪ HSV is a virus which establish latency in sensory ganglion utilizing multiple immune evasion mechanisms and can reactivate ▪ HPV, the causative agent of cervical cancer, causes a wide variety of clinical manifestations (benign to malignant) 16 18 ▪ Persistence of high-risk HPV can lead to development of anogenital cancers Thursday, December 7, 2023 Presentation title