Lecture 24 Studyguide (Immunology)

Immunity to microbes: viruses Viruses: have either an RNA or DNA genome are obligatory intracellular microorganisms infect host cells via binding to specific cell surface proteins (receptors) are ingested by receptor-mediated endocytosis and escape to cytosol use host nucleic acid & protein syntheti...

Immunity to microbes: viruses Viruses: have either an RNA or DNA genome are obligatory intracellular microorganisms infect host cells via binding to specific cell surface proteins (receptors) are ingested by receptor-mediated endocytosis and escape to cytosol use host nucleic acid & protein synthetic machinery to produce more viral particles debilitate and ultimately kill the infected cell (often through lysis) may indirectly induce tissue damage by triggering host inflammatory response Certainly! Let's break down the transcript: 1.Overview of Viruses: Viruses are discussed as having either RNA or DNA genomes. They are described as obligate intracellular microorganisms, meaning they can only survive and replicate inside host cells. While some debate exists on whether viruses are technically organisms, they are commonly referred to as microorganisms or microbes. 2.Infection Mechanism: Viruses infect host cells by binding to specific proteins on the cell surface, known as receptors. It's noted that the host cells didn't evolve these receptors for virus entry; rather, viruses evolved to exploit these receptors for cellular entry. Once bound to the receptor, viruses enter the cell via a process called receptor-mediated endocytosis. 3.Replication Inside Host Cells: Once inside the host cell, viruses utilize the cell's machinery for nucleic acid and protein synthesis to produce more viral particles. This process involves hijacking the host cell's resources to replicate and assemble new virus particles. Infected cells may be debilitated or killed, often through inducing cell lysis, which ruptures the cell membrane and releases viral particles. 4.Inflammatory Response: While viruses can directly damage cells through lysis, the transcript highlights that the majority of damage results from the host immune system's response. This immune response triggers inflammation 1 as the body attempts to combat the virus. However, excessive inflammation can lead to tissue damage and contribute to the severity of the illness. Thus, there's a delicate balance between an effective immune response and one that causes excessive harm to the host tissues. In summary, the transcript provides an overview of how viruses infect host cells, replicate, and trigger immune responses, emphasizing the importance of immune regulation in controlling viral infections. 1 Coronavirus life cycle ACE2 ACE2 = angiotensin-converting enzyme 2 The transcript describes the life cycle of a coronavirus, focusing on the steps involved in viral replication within host cells. Here's a breakdown of the key points: 1.Coronavirus Structure: The coronavirus is depicted with spike proteins on its surface. These spike proteins interact with a specific receptor called ACE2 (Angiotensin Converting Enzyme 2) on the surface of host cells. ACE2 has no inherent relationship with the virus, but the virus has evolved to bind to it. 2.Viral Entry: The virus enters the host cell through receptor-mediated endocytosis. This process involves the host cell engulfing the virus after it binds to the ACE2 receptor. 3.Viral Genome Replication: Once inside the host cell, the viral genome, which is RNA, is released. The viral RNA undergoes translation, followed by RNA replication and transcription. This results in the production of a coding sequence that can be used by the host cell machinery to synthesize viral proteins. 4.Protein Synthesis: The viral RNA directs the host cell machinery to produce a small set of viral proteins. These include the spike protein, membrane protein, envelope protein, and nucleocapsid protein. These proteins play various roles in forming the structure of the virus and packaging its RNA. 5.Viral Particle Assembly: The newly synthesized viral proteins assemble with the replicated viral RNA to form new 2 virus particles inside the host cell. 6. Release of New Virus Particles: The assembled virus particles are then secreted from the host cell back into the extracellular environment. These newly formed virus particles can then infect other cells and continue the cycle of viral replication. The transcript emphasizes that this basic life cycle of coronaviruses is shared among many RNA viruses, with variations in specific details. Additionally, it underscores the importance of viral entry into host cells and subsequent replication to produce new virus particles. 2 Kinetics of innate and adaptive responses to virus infection The transcript outlines the kinetics of both innate and adaptive immune responses to viral infection, providing a timeline of events following the initial exposure to the virus. Here's a breakdown of the key points: 1.Early Innate Immune Response (Days 0-2): 1. Following viral infection, there is a rapid production of type 1 interferons, which are cytokines involved in antiviral defense. 2. Natural killer (NK) cells become activated and begin to increase their activity. 3. Virus particles in the extracellular fluid start to accumulate due to infected cells releasing more viruses. 2.Innate Immune Response Continues (Days 2-5): 1. The action of type 1 interferons and NK cells helps to slow down viral replication. 2. Virus-specific cytotoxic T lymphocytes (CTLs) become activated, indicating the transition to the adaptive immune response. 3.Adaptive Immune Response (Days 5 and Beyond): 1. Virus-specific CTLs continue to increase in activity and reach a plateau, correlating with a decline in virus titers as infected cells are targeted and destroyed. 3 2. 3. 4. 5. Around day 5, production of virus-specific antibodies begins. Antibody levels increase, peaking after a certain time. As the virus is cleared from the system, both CTL activity and antibody levels decrease. Antibodies may persist for some time after the virus has been eliminated, providing a degree of long-term immunity. In summary, the transcript illustrates the sequential activation and interaction of innate and adaptive immune responses to viral infection, highlighting the role of various immune cells and molecules in combating the virus and eventually clearing it from the body. 3 Innate and adaptive protection against viral infection “Interferon” derived from ability to interfere with viral infection Expression of Type I IFNs is induced in many cell types via pattern recognition receptor activation Abs: block binding of virus to its receptor may also opsonize particles => phagocytosis effective only against extracellular particles prevent cell-to-cell spread and re-infection Certainly! The transcript provides an explanation of how both the innate and adaptive immune systems work to protect the body against viral infections. Innate Immunity: The innate immune response is the body's first line of defense against pathogens, including viruses. It involves nonspecific mechanisms that provide immediate protection upon encountering a pathogen. In the context of viral infections, the transcript highlights the role of type 1 interferons. These molecules are produced by infected cells and act as signaling molecules to neighboring cells. Type 1 interferons induce an "antiviral state" in cells, making them more resistant to viral infection. This mechanism interferes with viral replication and helps limit the spread of the virus within the body. Essentially, type 1 interferons help to slow down the virus's ability to infect and replicate within host cells, providing an early defense against viral invasion. Adaptive Immunity: The adaptive immune response kicks in after the innate immune response and provides more targeted and specific defense against pathogens. In the context of viral infections, antibodies play a crucial role in 4 adaptive immunity. Antibodies are proteins produced by specialized immune cells called B cells in response to specific antigens present on the surface of viruses. These antibodies recognize and bind to viral antigens, a process known as neutralization. By binding to viral particles, antibodies can prevent them from attaching to and entering host cells, effectively neutralizing the virus and preventing infection. Additionally, antibodies can tag viral particles for destruction by immune cells such as macrophages or neutrophils through a process called phagocytosis. However, it's important to note that antibodies are only effective against extracellular viruses and cannot target viruses once they have entered host cells. Therefore, their main role is to prevent the spread of viruses within the body by neutralizing them before they can infect new cells. In summary, the transcript explains how both innate and adaptive immune responses work together to provide protection against viral infections. The innate immune response acts quickly to slow down viral replication and spread, while the adaptive immune response provides targeted defense by producing antibodies that neutralize viral particles and prevent further infection. 4 The cytokine-induced antiviral state IFNs also: Favor lymphocyte retention in nodes Enhance NK and CTL activity Upregulate class I MHC proteins Can also occur in infected cells Certainly! Let's break down the process of the cytokine-induced antiviral state in detail: 1.Virus-Infected Cell Signaling: 1. When a cell becomes infected by a virus, it recognizes the presence of viral components through specialized receptors known as pattern recognition receptors (PRRs). These receptors detect unique patterns or structures associated with viruses, such as viral nucleic acids or proteins. 2. Activation of PRRs triggers intracellular signaling pathways that lead to the production of type 1 interferons (IFNs) within the infected cell. Type 1 interferons are a group of cytokines that play a crucial role in antiviral defense. 2.Role of Type 1 Interferons: 1. Type 1 interferons, such as interferon-alpha and interferon-beta, act as signaling molecules that communicate the presence of a viral infection to neighboring cells. 2. These interferons can diffuse away from the infected cell and bind to specific receptors on the surface of adjacent uninfected cells. These receptors are known as interferon receptors. 3.Response of Uninfected Cells: 5 1. When uninfected cells detect the presence of type 1 interferons binding to their interferon receptors, they initiate a series of intracellular signaling cascades. 2. These signaling pathways lead to the activation of various genes involved in antiviral defense mechanisms. One key response is the induction of enzymes that inhibit viral replication. 3. These antiviral enzymes act at different stages of the viral replication cycle to impede the ability of the virus to replicate and spread within the cell. 4. For example, some of these enzymes may inhibit viral protein synthesis, degrade viral RNA, or interfere with viral gene expression. Others may disrupt the assembly of new virus particles. 1.Establishment of Antiviral State: 1. The combined actions of these antiviral enzymes within the uninfected cells create what is known as an "antiviral state." 2. In this state, even if a virus manages to enter an uninfected cell, the presence of antiviral enzymes makes it difficult for the virus to replicate and establish a productive infection. 3. Essentially, the cell is primed to resist viral infection and limit the spread of the virus within the body. 2.Additional Effects of Type 1 Interferons: 1. In addition to inducing the antiviral state in neighboring cells, type 1 interferons have other effects that contribute to antiviral defense. 2. They promote the retention of lymphocytes, such as T cells and B cells, within lymph nodes near the site of infection, enhancing the immune response. 3. Type 1 interferons also enhance the activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), which are immune cells that can kill virus-infected cells. 4. Furthermore, they upregulate the expression of major histocompatibility complex (MHC) class I proteins on the surface of cells, which allows infected cells to present viral antigens to the immune system for recognition. In summary, the cytokine-induced antiviral state mediated by type 1 interferons is a critical component of the innate immune response to viral infections. It involves the production of antiviral enzymes in uninfected cells, which helps to limit viral replication and spread, while also enhancing overall immune defenses against the virus. 5 Certainly! Let's delve into the details of the two scientific papers mentioned: 1.Title: Regulated Interferon Response Underlying Severe COVID-19 1. This paper likely explores the role of the interferon response in severe cases of COVID-19, particularly focusing on how dysregulated or impaired interferon signaling may contribute to the severity of the disease. 2. It likely discusses how the immune system, specifically the interferon response, reacts to the SARS-CoV2 virus, the causative agent of COVID-19. 3. The paper may investigate factors that regulate the production of interferons and their downstream effects on antiviral immunity. 4. It may explore how variations in the interferon response among individuals could influence susceptibility to severe COVID-19 outcomes. 5. This research could provide insights into potential therapeutic strategies aimed at modulating the interferon response to mitigate severe COVID-19 symptoms. 2.Title: Type 1 Interferon Response in COVID-19 Patients for Treatment 6 1. This paper likely examines the potential use of type 1 interferons as a therapeutic intervention for COVID-19 patients. 2. It may discuss the rationale behind using interferons to boost antiviral immunity in COVID-19 patients and their effectiveness in controlling viral replication. 3. The paper may present clinical data or experimental evidence supporting the efficacy of interferon-based treatments in COVID-19 patients. 4. It could explore the timing, dosage, and delivery methods of interferon treatments and their impact on clinical outcomes in COVID-19 patients. 5. This research may have implications for the development of novel therapies or the repurposing of existing interferon-based drugs for the treatment of COVID-19. Overall, both papers likely contribute to our understanding of the role of type 1 interferons in COVID-19 pathogenesis and treatment. They may shed light on the underlying mechanisms of severe COVID-19 and provide insights into potential therapeutic strategies aimed at modulating the interferon response to improve patient outcomes. 6 Innate and adaptive eradication of established infection Via killing of virus-infected cells NKs and CTLs use same mechanisms Activated in inflammatory response Massive proliferation during infection Use pattern recognition receptors Most are specific for just a few viral peptides Certainly! Let's break down the detailed explanation of innate and adaptive eradication of established infection, particularly focusing on the role of antibodies, natural killer cells, and cytotoxic T lymphocytes (CTLs): 1. Antibodies and Eradication: Antibodies play a crucial role in limiting the spread of viruses by neutralizing them in the extracellular environment. They do this by binding to viral antigens, preventing them from attaching to and entering host cells. Additionally, antibodies can mark virus-infected cells for destruction by immune cells through a process called antibody-dependent cell-mediated cytotoxicity (ADCC). However, antibodies are only effective against extracellular viruses and cannot neutralize viruses once they have entered host cells. Therefore, their main role is to prevent the spread of viruses between cells rather than eradicating established infections within cells. 2. Natural Killer Cells (NK Cells) in Eradication: NK cells are a type of innate immune cell that can directly kill virus-infected cells. NK cells recognize infected cells by detecting changes in the surface proteins, often induced by viral infection. They 7 do this through a process known as "missing self-recognition" or by recognizing stress-induced ligands. Once activated, NK cells release cytotoxic granules containing perforin and granzymes, which induce apoptosis (cell death) in the infected cells. NK cells play a crucial role in the early response to viral infections, as they can quickly eliminate infected cells before the virus has a chance to replicate and spread further. 3. Cytotoxic T Lymphocytes (CTLs) in Eradication: CTLs are a type of adaptive immune cell that specifically targets virus-infected cells. CTLs recognize infected cells by detecting viral peptides presented on the surface of cells in complex with major histocompatibility complex class I (MHC-I) molecules. Upon recognition of infected cells, CTLs release cytotoxic molecules, such as perforin and granzymes, which induce apoptosis in the infected cells. CTLs undergo rapid proliferation and expansion following activation, allowing for a robust immune response against viral infections. The specificity of CTLs for viral peptides is determined by the T cell receptor (TCR), which recognizes specific antigenic peptides presented by MHC-I molecules. 4. Relationship Between NK Cells and CTLs: NK cells and CTLs use similar mechanisms to kill infected cells, such as releasing perforin and granzymes. While NK cells are part of the innate immune system and can respond rapidly to infections, CTLs are part of the adaptive immune system and provide a more specific and targeted response. Both NK cells and CTLs play important roles in the eradication of established viral infections, with NK cells providing early, innate immunity, and CTLs providing a specific, adaptive immune response. In summary, antibodies, natural killer cells, and cytotoxic T lymphocytes all contribute to the eradication of established viral infections through various mechanisms of recognition and killing of infected cells. Each component of the immune system plays a unique role in limiting the spread of viruses and controlling infections within the body. 7 Viral mechanisms for evading host immunity 1. Alter surface antigens recognized by antibodies or TCRs by one or both of: Antigenic drift Antigenic shift => resulting variation creates strains no longer recognized by immune system Certainly! Let's integrate information from the transcript into the explanation: 1. Antigenic Drift: Involves gradual changes in surface antigens of viruses, making them less recognizable by antibodies or T cell receptors. These changes occur due to mutations in the viral genome. For example, influenza viruses undergo antigenic drift in their surface proteins, such as hemagglutinin (HA) and neuraminidase (NA). Mutations in these proteins can result in new viral strains that are no longer effectively recognized by the immune system. As a result, individuals previously exposed to the virus may still be susceptible to infection by the drifted strains. 2. Antigenic Shift: Involves sudden and significant changes in surface antigens due to genetic reassortment between different viral strains. This process typically occurs in viruses with segmented genomes, such as influenza viruses. 8 For example, two different influenza strains may infect the same host cell, leading to the mixing and matching of genetic material (RNA segments). The resulting viral strains may have novel combinations of surface antigens, making them unrecognizable by pre-existing immunity. Antigenic shift can lead to the emergence of pandemic strains and widespread outbreaks. Impact on Immunity: Antigenic drift and shift allow viruses to evade host immunity, leading to increased viral transmission and disease severity. These mechanisms result in the emergence of new viral strains that may not be effectively targeted by pre-existing immunity. As a result, individuals may remain susceptible to infection by drifted or shifted strains, even if they have been previously exposed to related viruses. Surveillance and vaccine development efforts are crucial for monitoring and addressing antigenic changes in viruses to maintain effective control of infectious diseases. In summary, antigenic drift and shift are mechanisms used by viruses to evade host immunity, leading to the emergence of new strains that may not be effectively targeted by pre-existing immunity. These mechanisms result in increased viral transmission and disease severity, highlighting the importance of surveillance and vaccine development to address antigenic changes in viruses. 8 Antigenic drift Results from point mutations that either: accumulate throughout the antigen over time (minor changes add up) occur in key antigenic site (major change) Influenza virus is reasonably well understood example “antigenic drift is the main reason why people can get the flu more than one time, and it’s also a primary reason why the flu vaccine composition must be reviewed and updated each year (as needed) to keep up with evolving influenza viruses.” https://www.cdc.gov/flu/about/viruses/change.htm Also common in rhinoviruses and HIV The transcript provides information about antigenic drift, which is a process where viruses undergo gradual changes in their surface antigens, primarily due to point mutations. Here's a breakdown of the explanation provided: 1.Mechanism of Antigenic Drift: 1. Antigenic drift typically results from point mutations, which are single nucleotide changes leading to single amino acid changes in viral proteins. 2. There are two main ways in which antigenic drift can occur: 1. Accumulation of point mutations over time: Minor changes accumulate throughout the genome, gradually altering the antigenic properties of the virus. 2. Mutation in key antigenic sites: Mutations occur in regions of viral proteins that are recognized by the immune system, known as epitopes. Even small changes in these epitopes can affect antibody binding affinity. 3. These mechanisms contribute to the gradual evolution of the virus, leading to changes in antigenicity 9 over time. 2. Examples of Antigenic Drift: 1. Influenza viruses are a well-known example of antigenic drift. The CDC acknowledges drift as the primary reason why people can get the flu multiple times and why flu vaccine compositions need to change annually. 2. Other viruses, such as rhinoviruses (common cold viruses) and HIV, also undergo antigenic drift, contributing to the challenges in developing effective vaccines and treatments. 3.Significance of Antigenic Drift: 1. Antigenic drift poses a constant challenge for the immune system and vaccine development efforts. Viruses continuously evolve, necessitating ongoing surveillance and adaptation of vaccines to keep up with viral antigenic changes. 2. Understanding antigenic drift is crucial for public health efforts to control viral infections and develop effective preventive measures. In summary, the transcript highlights the mechanism and significance of antigenic drift, focusing on how viruses undergo gradual changes in surface antigens through point mutations, leading to challenges in immune recognition and vaccine development. Examples provided, such as influenza viruses, emphasize the practical implications of antigenic drift for public health and disease control efforts. 9 Antigenic shift Genetic recombination of two viral strains Less frequent than antigenic drift => but more sudden and significant change Strains typically found in different hosts Simultaneous infection by two strains allows for reassortment of RNA strands => Can create new, antigenically distinct virus H1N1 influenza virus responsible for 2009 pandemic generated by reassortment of swine, avian and human viruses in pigs, then passed back to humans The transcript discusses antigenic shift, a less frequent but more drastic mechanism of viral evolution compared to antigenic drift. Here's a detailed explanation: 1. Antigenic Shift Overview: Antigenic shift refers to a sudden and significant change in the surface antigens of viruses, resulting in a rapid and drastic alteration in the virus's antigenicity. It is less common than antigenic drift but can lead to more severe consequences, including pandemics. Antigenic shift occurs through the recombination of genetic material between two different viral strains found in different hosts. 2. Mechanism of Antigenic Shift: The transcript describes a scenario where two viral strains, such as human and avian influenza viruses, infect the same host simultaneously. Each viral strain has its RNA genome segmented into eight segments and expresses surface proteins, such as hemagglutinin (H) and neuraminidase (N), which are key antigens recognized by the immune system. 10 During simultaneous infection, genetic material from both strains mixes and matches, leading to the emergence of a new viral strain with a combination of RNA segments from both parent strains. The resulting virus is antigenically distinct, expressing new surface antigens that may not be effectively recognized by preexisting immunity. 3. Example of Antigenic Shift: The transcript provides an example of the H1N1 influenza virus, which caused the 2009 pandemic. The H1N1 virus emerged through the reassortment of swine, avian, and human influenza viruses in pigs. This reassortment resulted in a new viral strain with a combination of surface antigens from different parent strains. The new H1N1 strain had novel surface proteins, including hemagglutinin subtype 1 (H1) and neuraminidase subtype 1 (N1), making it antigenically distinct from previously circulating strains. The ability of the H1N1 virus to evade pre-existing immunity in humans led to a widespread pandemic with severe health consequences. 4. Significance of Antigenic Shift: Antigenic shift poses a significant threat to public health due to its potential to cause pandemics. The emergence of new viral strains with novel surface antigens can evade pre-existing immunity in the population, leading to increased transmission and disease severity. Surveillance and monitoring of viral evolution, particularly in zoonotic hosts where different viral strains may coexist, are crucial for early detection and response to potential pandemic threats. In summary, the transcript explains antigenic shift as a mechanism of viral evolution involving the recombination of genetic material between different viral strains, leading to the emergence of new viral strains with novel surface antigens. The example of the H1N1 influenza pandemic highlights the significance of antigenic shift in driving pandemics and underscores the importance of surveillance and response efforts to mitigate the impact of emerging viral threats. 10