Patterns of Viral Infection Lecture 18 PDF

INFECTION AND IMMUNITY - PANM22041 LECTURE 18 Patterns of Viral Infection Professor Andrew Davidson E46 Biomedical Sciences Building [email protected] 6/11/24  Overview What determines a successf...

INFECTION AND IMMUNITY - PANM22041 LECTURE 18 Patterns of Viral Infection Professor Andrew Davidson E46 Biomedical Sciences Building [email protected] 6/11/24  Overview What determines a successful virus infection? – Viral and host immune determinants Acute viral infections – Definition – Host defence and viral pathogenesis – Importance of acute viral infections Persistent viral infections – Definitions – chronic, latent and slow persistent infections – Importance of persistent infections – Evasion of the host immune response – Latent infections – Slow infections  Intended learning outcomes Understand the overall role of the host immune system in preventing viral infection. Be able to describe the general patterns of viral infection. Be able to describe the pattern of a typical acute infection and understand the viral and host interactions leading to disease. Understand the importance of acute infections. Understand the different types of persistent infection; chronic, latent and slow. Be able to describe how viruses may evade the host immune response to establish persistent infections. Understand the characteristics of a latent infection and provide examples. Understand what a slow infection is and provide examples. ATTACHMENT PENETRATION HOST UNCOATING FUNCTIONS Transcription Translation REPLICATION VIRAL LIFE ASSEMBLY (MATURATION) CYCLE RELEASE Infection: a delicate balance Human Natural barriers to infection – Skin, mucus Virus Innate response Establishment of – Interferons infection – NK cells Regulation of gene – Macrophages expression - persistence – Apoptosis Antigenic variation Adaptive response Immune evasion – Dendritic cells Immune subversion – CD4+ T-cells – CD8+ T-cells – antibody  Initiating an infection Basic requirements – Sufficient virus must be present to initiate an infection. Virus stability in environment important. Many virus particles are not infectious or may not initiate an infection. – Cells at the site of infection must be susceptible and permissive for the virus. Tropism - affects pattern of infection, pathogenesis, long term viral survival. – Local host antiviral defence mechanisms must be absent or initially ineffective. Virus may overwhelm host defences eg 100 million rhinovirus particles in a single aerosol droplet. Cuts, abrasions, biting insects, needle stick injuries Organ transplantation Immune evasion Innate defence against viral infections – Type I and III Interferon responses – antiviral cytokines Interferon Producer cell Inducers IFN-α Most if not all viral infection, dsRNA nucleated cells IFN-β Most if not all viral infection, dsRNA nucleated cells IFN-λ Mainly epithelial cells viral infection, dsRNA and some immune cells Interferon signaling results in the transcription of interferon sensitive genes → antiviral effects – Lysis of infected cells by natural killer cells Early source of cytokines and chemokines Non-specific cytotoxic effector cells Adaptive defence against viral infections Antibody: Virus infection induces at least three ADCC: antibody-dependent classes of antibody: IgG, IgM, & IgA.. cell mediated cytotoxicity Neutralisation Complement Oposonization - phagocytosis ADCC Huber & Trkola (2007) J Int Medicine v262 p5 Prevents Binding/Entry  Adaptive defence against viral infections Cell-mediated immunity is probably more important than humoral immunity in the control of many virus infections: Congenital defects in cell-mediated immunity tend to result in predisposition to virus (and parasitic) infections, rather than to bacterial infections. The functional defect in acquired immune deficiency syndrome (AIDS) is a reduction in the ratio of T-helper (CD4+):T-suppressor (CD8+) cells. AIDS patients commonly suffer many opportunistic virus infections (e.g. various herpesviruses such as HSV, CMV and EBV), which may have been present before the onset of AIDS but were previously suppressed by the intact immune system. HSV = herpes simplex virus CMV = cytomegalovirus EBV = Epstein Barr virus Cell mediated defence against viral infections Effected through three main mechanisms Successful viral infections evade host defences Rapid evolution of antigenic targets – Exchange of genetic information by reassortment of genome fragments to replace entire surface proteins - influenza – High rate of mutation during genome replication - HIV Blocking of specific immune defences – Herpesviruses, HIV, adenoviruses Initiation of a non-cytopathic infection to delay or avoid a robust immune response – Papillomaviruses (warts) General patterns of viral infection. Virus shedding Acute SARS-CoV-2 Symptoms Poliovirus Influenza virus Persistent - chronic Hepatitis B Hepatitis C Persistent - latent (reactivating) Herpes simplex Varicella zoster Persistent - Slow HIV Measles SSPE Time Flint - Principles of Virology (2015) Vol 2 Fig 5.1 The course of a typical acute viral infection. Flint - Principles of Virology (2015) Vol 2 Fig 5.3  Defence against acute viral infections Innate immune response most important in limiting acute infections. – Interferon response. – Lysis of infected cells by natural killer cells. The adaptive immune response: – Does not influence viral growth for several days. – Important in final clearance of the virus and infected cells from the host. – Provides memory for protection against subsequent infections. In an immunocompromised host the infection may not remain localised to the primary site of infection.  Pathogenic effects Many disease symptoms may be the result of an active immune response: – fever, malaise, aches, nausea Virus may also cause direct cellular damage – direct result of cellular lysis – toxic viral proteins - eg HIV, rotaviruses – cell killing by the immune system – symptoms include diarrhea, poor lung or liver function, breakdown of capillary beds – provides opportunities for the establishment of secondary infections The course of a typical acute virus infection Flint - Principles of Virology (2015) Vol 2 Fig 5.3  Clinically inapparent acute viral infections Successful acute infections that produce no disease or symptoms. Sufficient virus is produced to maintain infection cycle but not to cause symptoms. Most acute infections are clinically inapparent. Infection rapidly controlled by the host immune system. – eg antiviral antibodies may be detected in the host Well adapted pathogens may follow this pattern – eg poliovirus  Multiple acute viral infections Initial acute infection may be followed by a second or third round of infection. Initial cell → blood (primary viraemia) → internal organs → blood (secondary viraemia) → target tissues/organs. May result in a second acute infection eg poliovirus or another pattern of disease. An acute infection: human poliomyelitis Small Intestine Bloodstream Day 2 Invasion Multiplication (Final excretion in feces through large intestine) CNS EFFECT PARALYSIS Day 10 Invasion Primary Viraemia Multiplication Day 6 Viral Multiplication Intraneural Spread PATHOGENESIS  Acute infections and public health Acute infections often associated with serious epidemics. – measles, influenza, polio, SARS-CoV-2, noroviruses, Difficult to treat as by the time of diagnosis the virus has spread to the next host. Preventative measures are often too late. General patterns of viral infection. Virus shedding Acute SARS-CoV-2 Symptoms Poliovirus Influenza virus Persistent - chronic Hepatitis B Hepatitis C Persistent - latent (reactivating) Herpes simplex Varicella zoster Persistent - Slow HIV Measles SSPE Time Flint - Principles of Virology (2015) Vol 2 Fig 5.1  Persistent viral infections Includes chronic, latent and slow infections Persistent infections are not cleared quickly or at all – Virus particles or products continue to be produced for long periods. – Infectious virus may be produced intermittently or after long periods of time. – Distinction between Chronic infection - persistent infection that may eventually be cleared (unless the infection proves fatal). Latent and slow infections - last the life of the host. Virus adjusts its replication and pathogenicity to avoid killing the host. Evasion of the host immune response is integral to establishment of a persistent infection.  Persistent viral infections of humans Table 5.2 Flint - Principles of Virology (2015) Vol 2  Evasion of the host immune response Avoidance: Virus hides from the immune system but does not actively disturb the host immune response. Infection of immune privileged sites. – Tissues with surfaces exposed to the environment do not employ active immune surveillance - skin, bile ducts, kidney tubules eg papillomavirus infection – Eye, brain and CNS Isolated from routine immune surveillance. Immune defence by cell death is not desirable. Do not express high levels of MHC proteins Favoured sites for establishment of persistent viral infections - eg herpesviruses Down-regulation of viral gene expression – Control of antigen production Virus protein structure limits its antigenicity High frequency variation of antigenic epitopes recognised by the immune system – eg HIV, hepatitis C virus  Evasion of the host immune response Inhibition: Virus inhibits either the induction or the effector phase of the immune response. Direct subversion of the immune system: – Inhibition of MHC class I and class II restricted antigen presentation. – Inhibition of natural killer cell lysis. – Interference with apoptosis. – Inhibition of cytokine action especially interferon. Production of compounds which mimic normal immune system regulators. Direct infection of the immune system – Lymphocytes and monocytes Mobile - facilitates viral spread. Infection may reduce competence of the immune system eg HIV General patterns of viral infection. Virus shedding Acute SARS-CoV-2 Symptoms Poliovirus Influenza virus Persistent - chronic Hepatitis B Hepatitis C Persistent - latent (reactivating) Herpes simplex Varicella zoster Persistent - Slow HIV Measles SSPE Time Flint - Principles of Virology (2015) Vol 2 Fig 5.1  Latent virus infections Characterised by four general properties A non-replicating cell is infected or the viral and host DNA is replicated together ensuring the cell cycle is not disrupted. Immune detection of the infected cell is reduced or eliminated. Expression of viral genes involved in virus particle production is absent or inefficient. The viral genome persists and remains capable of initiating an acute virus infection at a later time.  DISEASE HERPES SIMPLEX - Type 1 PRIMARY INFECTION Usually cold sores; sore throat, fever TRIGEMINAL and, rarely, Encephalitis NERVE LATENT INFECTION Asymptomatic - No virus or virion proteins produced Viral DNA resides in sensory cells of Trigeminal nerve ganglion REACTIVATION Virus replicates and travels down sensory nerve fiber to infect epithelial cells around the nose and mouth General patterns of viral infection. Virus shedding Acute SARS-CoV-2 Symptoms Poliovirus Influenza virus Persistent - chronic Hepatitis B Hepatitis C Persistent - latent (reactivating) Herpes simplex Varicella zoster Persistent - Slow HIV Measles SSPE Time Flint - Principles of Virology (2015) Vol 2 Fig 5.1  Slow infections A number of fatal brain diseases are caused by an extreme variation of a persistent infection. Well known viruses generally associated with other diseases may result in slow diseases in some cases. Many years may pass between the initial contact with the infectious agent and fatal disease. Difficult to study because of the long duration of the disease. Unconventional agents also cause slow disease – Transmissable spongiform encephalopathies (TSEs) Humans - Kuru, Creuzfeldt-Jakob disease Animals - Scrapie, bovine spongiform encephalopathy (BSE)  Slow infections - measles Measles virus - normally an acute disease but may cause a persistent disease. Subacute sclerosing panencephalitis (SSPE) – Slow infection arising 7-10 years after initial infection – 1 in 106 people affected – Leads to progressive neurologic deterioration and death – Defective measles virus can be detected in the brain. An initial acute infection leads to virus dissemination and a pronounced immunosuppression. – May be required for the establishment of a persistent infection. – Virus can enter the brain via infected lymphocytes. – Antibodies produced against virus in an acute infection may drive virus into a persistent infection. – Cells in the CNS may contribute to the maintenance of the persistent infection.  Summary The outcome of viral infection is determined by a balance between the host defences and virus properties. There are a number of characteristic outcomes – Acute, persistent: chronic, latent and slow. – Some viruses may combine different outcomes. Different infection outcomes have different implications for pathogenicity, public health and treatment.  Further reading Books: Principles of Virology. Volume II Chapter 5. 5th Edn Eds. S.J. Flint et al. Published by ASM Press (2020) – available as eBook – UoB electronic resources Viruses – Biology, Applications and Control. Chapter 4. DR Harper, Garland Science. 2012. Principles of Molecular Virology. Chapter 6 (6th edition) Rybicki and Cann. Academic Press. 2023 – available as eBook – UoB electronic resources Viral Pathogenesis and Immunity. Chapter 10 2nd Edn Eds N. Nathanson. Academic Press 2007 – available as eBook – UoB electronic resources