Lecture 5: Virus-Host Interaction Patterns of Infection

Lecture 5: Virus-Host Interaction: Patterns of Infection Slides compiled by: Pablo Serrano Some slides are designed and created by: Lisa D’Ambrosio Overview of the infectious cycle Viral infectious cycle 1. Attachment and entry 2. Production of viral mRNA and viral protein synthesis 3. Genome replic...

Lecture 5: Virus-Host Interaction: Patterns of Infection Slides compiled by: Pablo Serrano Some slides are designed and created by: Lisa D’Ambrosio Overview of the infectious cycle Viral infectious cycle 1. Attachment and entry 2. Production of viral mRNA and viral protein synthesis 3. Genome replication 4. Assembly and release of viral particles 5. Maturation Principles of Virology, 4th Edition, 2015 Viral Pathogenesis 1. Entry and primary replication 2. Viral spread 3. Cellular injury Productive infection requires a susceptible and permissive host cell 4. Host immune response 5. Viral clearance or establishment of persistent infection 6. Viral shedding Overview of the infectious cycle Susceptibility Permissiveness Refers to the capacity of a cell to become infected by a virus. Susceptibility is determined by the presence of a virus receptor expressed by the host cell. Refers to the ability of a cell to support virus replication when viral nucleic acid is introduced into the cell. Permissiveness therefore depends on the intracellular components of the cell to facilitate viral replication. ENTRY STEP REPLICATION STEP Cells must be susceptible AND permissive for successful viral infection to occur For example, cells can be susceptible but not permissive (i.e. virus can enter a cell, but the cell cannot support viral replication) or you can have cells that are not susceptible but are permissive (i.e. cell lacks the appropriate receptor but if viral components are delivered to cell, it would be able to support viral replication. Overview of the infectious cycle Lytic Cycle After replication, gene expression and assembly, virions are released through lysis of the host cell. (usually nonenvelope d, more virulent, cytopathic). Cytopathic to the cell Lysogenic Cycle https://en.wikipedia.org/wiki/Lytic_cycle Latent or Temperate. The virus genome and protein are replicated and translated. Non-cytopathic to the cells. A virus can be lysogenic for a long period of time, and then enter a lytic phase 1 2 3 VIRAL PATHOGENESIS Adverse physiological consequences that occur as a result of viral infection of the host organism. ACUTE INFECTION Pattern of infection whereby virus particles are produced rapidly & infection is resolved quickly by the immune system (short-term infection). PERSISTENT INFECTION Pattern of infection whereby the viral infection is not cleared by the immune system (long-term infection). Several mechanisms can establish a persistent viral infection – can involve interference with immune cell function. Slide design: L. D’Ambrosio 2 Recall: Viral pathogenesis Refers to the adverse physiological consequences that occur as a result of viral infection of the host organism The pathogenesis that may follow a viral infection relies on several parameters in addition to its impact on infected cells Slide design: L. D’Ambrosio 2 General patterns of viral infection Relative virus particle production plotted as a function of time after initial infection (blue line) Times when symptoms are present (bars) Acute: Virus particles produced, symptoms appear, infection is cleared (7-10 days) Persistent - Latent: Periodic episodes of acute infections followed by quiescent phase (little/no detection of viral particles); reactivation stimulated throughout host life (may result in virus particle production). Persistent – asymptomatic: Virus production continues for the life of the host or in tissues where immune cells do not often patrol (symptoms may or may not be apparent) Persistent – pathogenic: Period of years separates primary infection and fatal appearance of symptoms; production of virus particles may be continuous or not detectable throughout life Principles of virology, 4th edition 1 Principles of virology, 4th edition Incubation period The period of time before symptoms of disease appear following initial infection. During this period, viral genomes may be replicated & intrinsic/innate immune responses initiates production of cytokines (i.e. type I interferons). 1 1 2 3 VIRAL PATHOGENESIS Adverse physiological consequences that occur as a result of viral infection of the host organism. ACUTE INFECTION Pattern of infection whereby virus particles produce rapidly & infection is resolved quickly by the immune system (short-term infection). Survivors are usually immune to subsequent infections. PERSISTENT INFECTION Pattern of infection whereby the viral infection is not cleared by the immune system (long-term infection). Can be divided into multiple types (i.e. latent, asymptomatic, pathogenic). Viral genomes may remain. No single mechanism! Slide design: L. D’Ambrosio 2 The course of a typical Acute (short-term) viral infection Antibodies & memory lymphocytes produced during the adaptive response provide lasting protection to subsequent infections Adaptive immune responses are initiated if infection reaches a certain threshold (specific to virus & host) Principles of virology, 4th edition 2 ….More acute infection facts Although acute infections may be resolved within a few days, some viral progeny may be shed and transmitted to other hosts before the infection can be contained… Acute infections may also be inapparent (asymptomatic) whereby limited or no clinical symptoms may be detected. In these cases, virus replication occurs to levels that facilitate transmission, but may not damage host…well-adapted pathogens (i.e. poliovirus!) Search the rate of asymptomatic/ symptomatic (paralytic vs non-paralytic) cases of polio - CDC L. D’Ambrosio (2019) 2 Antigenic variation may facilitate repeated acute infections Antigenic Drift: Accumulated Mutation in viral genome that results in substantial change in genetic makeup. Can result in a new strain or evasion of the adaptive immune response. - Know the difference between antigenic drift and shift All HA amino acid substitutions isolated between 1968-1995 HA amino acid substitutions retained in subsequent years - This is why there’s typically a yearly ‘new’ vaccines for influenza Distribution of amino acid residue changes in hemagglutinin (HA) of influenza viruses (Hong Kong pandemic, 1968-1995) Virus-receptor binding site (yellow), substituted amino acids (green) 2 1 2 3 VIRAL PATHOGENESIS Adverse physiological consequences that occur as a result of viral infection of the host organism. ACUTE INFECTION Pattern of infection whereby virus particles produce rapidly & infection is resolved quickly by the immune system (short-term infection). Survivors are usually immune to subsequent infections. PERSISTENT INFECTION Pattern of infection whereby the viral infection is not cleared by the immune system (long-term infection). Can be divided into multiple types (i.e. latent, asymptomatic, pathogenic). Viral genomes may remain. No single mechanism! Slide design: L. D’Ambrosio 2 ….More persistent infection facts While there is no single mechanism responsible for establishing a persistent infection, when viral cytopathic effects are minimized & host defenses are suppressed, a persistent infection may be likely. As you may therefore expect, a feature of establishing persistent infection is the reduction of host defenses. In fact, modulation of the adaptive immune response may perpetuate a persistent infection… How? See next slides… L. D’Ambrosio (2019) 3 Persistent infections: Viral proteins may block Adaptive Immune Response Viral gene products may block presentation of viral peptides within MHC I complexes at several steps within the pathway (i.e. lowering expression of MHC I genes, blocking production of proteasome-derived viral peptides, interfering with MHC I biogenesis & transport to cell surface) This type of immune modulation may prevent or delay elimination of virus by cytotoxic T cells 3 General patterns of viral infection Principles of virology, 4th edition 3 …Latent infections may be characterized by 3 properties Viral gene products that promote virus reproduction are not synthesized (or synthesized in small quantities) Cells that contain the viral genome are poorly recognized by the immune system The viral genome persists intact within the infected cell to ensure productive infection may be initiated at a later time. Ensures that virus progeny may be transmitted to new hosts. Persistent - Latent L. D’Ambrosio 3 Herpesviruses Enveloped viruses | Group I: dsDNA genome Macrophage, VZV – virology and pathogenesis https://www.youtube.com/watch?v=eOHwaEzIHD0 Transmission: HHV-1: Saliva; HHV-2: sexual contact, maternal-neonatal| Infection: Primary site of infection – epithelial mucosal cells; Latency established in sensory ganglia| Associated diseases: Skin vesicles or mucosal ulcers Persistent - Latent Slide design: L. D’Ambrosio 3 Persistence & reactivation of herpes simplex virus (HSV-1) infection 3. Factors such as bacterial infection, hormonal changes, environmental stress can reactivate the virus 1. HSV-1 infects epithelial cells & spreads to sensory neurons 2. After immune response controls the epithelial infection, the virus persists in a latent state in the sensory neurons Persistent - Latent 4. Virus can then travel down the axons of the sensory neurons and re-infects the epithelial tissues 5. Immune responses are re-activated and controls local infection by killing epithelial cells, producing a new sore Slide design: L. D’Ambrosio 3 Herpes simplex virus primary infection of sensory neurons & reactivation Knipe et al. 2008 Establishment of latency Infection in epithelial cells at mucosal surfaces| Virus enters sensory neurons; nucleocapsids transported to the neuronal cell body via microtubule-based systems (retrograde) | Viral DNA is released into the neuronal nucleus & circularizes | Circular viral DNA persists in the neuronal cell nucleus | Latency-associated transcript (LAT) expressed Persistent - Latent Reactivation Viral lytic gene expression is initiated, and newly formed capsids are transported to the axonal termini | Infectious virus is released from the axon and infects epithelial cells, resulting in recurrent infection and virus shedding. What is LAT? What processes does it suppress? Slide design: L. D’Ambrosio 3 Latency-associated transcripts (LATs) of HSV-1 Origins of replication dsDNA genome mRNA transcripts During latent infection, transcription of lytic genes is blocked. Only a single transcription unit is expressed - LAT Persistent - Latent 3 Persistent Asymptomatic Infection of Lymphocytic Choriomeningitis Virus Non-cytopathic nature creates carriers If introduced congenitally or or immediately after birth, viral peptides cannot be recognized as foreign. If introduced later in life, mice dies of encephalitis and edema Though non-cytopathic, behavioural and learning assessment revealed that persistently infected mice are not as “smart” as their uninfected peers. In persistent infection, virtually all tissues would express the virus Persistent – Asymptomatic 3 Persistent Pathogenic Infection of HIV Virus Typical course of HIV infection Acute phase: Lasts for several weeks, high levels of virus in blood (viremia) & decline of CD4+ T cells. Adaptive immune response develops (CTLs & antibodies against HIV), HIV antibodies become detectable in blood (seroconversion), this response partially controls the infection resulting in a rebound of CD4+ T cells and decrease in viral titres in the blood. Asymptomatic phase: Lasts 5-10 years (without treatment), low viremia and slowly declining CD4+ T cell numbers, typically over several years. Low level of virus production. Opportunistic infections may occur. AIDS: Crash in CD4+ T cells, high viral titres, destruction of lymphoid tissue Persistent - Pathogenic Slide design: L. D’Ambrosio 3 Clinical signs of viral disease (fever, aches, tissue damage, nausea) largely stem from the host’s immune response to infection This damage is referred to as ‘immunopathology’ (may be the price to pay by the host to eliminate infection!) 3 nt e nd ion e ep fect d dy e in o ti b engu n a he t of d t rch men a e se Re h a n c en Agonizing limb pain (‘break bone”), fever, bleeding gums, rash, vomiting *4 serotypes of dengue virus – antibodies to any 1 serotype do not efficiently protect against infection by another* Immunopathology https://visual.ly/community/Infographics/health/what-dengue-fever-facts-about-dengue-fever Slide design: L. D’Ambrosio 3