Viral Pathogenesis PDF

12/9/2023 Viral Pathogenesis Pathogenesis: the entire process by which viruses cause disease. Studying pathogenesis is a major step required to treat or eliminate viral diseases. A viral disease can be considered an outcome of two...

12/9/2023 Viral Pathogenesis Pathogenesis: the entire process by which viruses cause disease. Studying pathogenesis is a major step required to treat or eliminate viral diseases. A viral disease can be considered an outcome of two components: 1- The effects of virus replication on the host. 2- The effect of the host’s immune response on the virus. Pathogenesis mechanisms are remarkably consistent for each virus and include: 2 (1) implantation of virus at the portal of entry (2) local replication. (3) spread to target organs (disease sites). (4) spread to sites of shedding of virus into the environment. Factors that affect pathogenic mechanisms are (1) accessibility of virus to tissue, (2) cell susceptibility to virus multiplication, and (3) virus susceptibility to host defenses. Natural selection favors the dominance of low-virulence virus strains. 3 1  12/9/2023 For the successful initiation of an infection, three requirements must be met: 1. An inoculum containing sufficient viable virus. 2. Virus must reach and interact with susceptible cells capable of supporting virus replication. 3. The host innate immunity and pre-existing adaptive immunity must be insufficient to immediately abort the infection. 4 Cellular Pathogenesis Direct cell damage and death from viral infection may result from: (1) diversion of the cell's energy (2) shutoff of cell macromolecular synthesis (3) competition of viral mRNA for cellular ribosomes (4) competition of viral promoters and transcriptional enhancers for cellular transcriptional factors such as RNA polymerases (5) inhibition of the interferon defense mechanisms. Indirect cell damage can result from: (1) integration of the viral genome (2) induction of mutations in the host genome (3) inflammation and the host immune response. 5 2  12/9/2023 Tissue Tropism Viral affinity for specific body tissues (tropism) is determined by: (1) cell receptors for virus (2) cell transcription factors that recognize viral promoters and enhancer sequences (3) ability of the cell to support virus replication (4) physical barriers (5) local temperature, pH, and oxygen tension enzymes and non- specific factors in body secretions (6) digestive enzymes and bile in the gastrointestinal tract that may inactivate some viruses. 6 Examples: Polioviruses selectively infect and destroy certain nerve cells, which have a higher concentration of surface receptors for polioviruses than do virus-resistant cells. Rhinoviruses multiply exclusively in the upper respiratory tract because they are adapted to multiply best at low temperature and pH and high oxygen tension. Enteroviruses can multiply in the intestine, partly because they resist inactivation by digestive enzymes, bile, and acid. 7 3  12/9/2023 Examples indicating the role of cell receptors in determining tropism: Rabies virus uses the acetylcholine receptor present on neurons as a receptor. hepatitis B virus binds to polymerized albumin receptors found on liver cells. Epstein-Barr virus uses complement CD21 receptors on B lymphocytes. human immunodeficiency virus uses the CD4 molecules present on T lymphocytes as specific receptors. 8 9 4  12/9/2023 Viral Entry (Implantation at Portal of Entry) To infect the host, a virus must first enter cells at common entry sites of body surface. → the mucosal linings of the respiratory →alimentary, and urogenital tracts → the outer surface of the eye (conjunctival membranes or cornea) Routes (sites) of virus entry →the skin 10 Virus Entry via the Respiratory Tract The most common route of viral entry. →Absorptive area of 140 m2 & Resting ventilation rate of 6 L/min → introduces large numbers of foreign particles and aerosolized droplets with every breath → Many of which contain viruses. Host defense mechanisms (barriers) that block infection: →the tract is lined with a mucociliary blanket consisting of ciliated cells, mucous-secreting goblet cells, and sub-epithelial mucous-secreting glands. → Foreign particles deposited in the nasal cavity or upper respiratory tract are trapped in mucus, carried to the back of the throat, and swallowed. 11 5  12/9/2023 →In the lower respiratory tract, particles trapped in mucus are brought up from the lungs to the throat by ciliary action. The lowest portions of the tract, the alveoli, lack cilia or mucus, but macrophages lining the alveoli ingest and destroy particles. Other cellular and humoral immune responses also intervene. →Upper respiratory tract: Nose – pharynx – larynx. →Lower respiratory tract: Trachea – branchial tree – lungs. 12 13 6  12/9/2023 Viruses may enter the respiratory tract with the droplets expelled by an infected individual by coughing or sneezing, or through contact with saliva from an infected individual. Larger virus- containing droplets are deposited in the nose, while smaller droplets find their way into the airways or the alveoli. To infect the respiratory tract successfully, viruses must not be swept away by mucus, neutralized by antibody, or destroyed by alveolar macrophages. 14 Virus Entry via the Alimentary Tract Alimentary tract provides a good opportunity for viruses to encounter a susceptible cell and to interact with cells. Extremely hostile environment for a virus. → Acidic stomach; alkaline intestine; presence of digestive enzymes and bile detergents, mucus; and the lumenal surfaces of intestines contain antibodies and phagocytic cells. Viruses that infect by the intestinal route must, at least, be resistant to extremes of pH, proteases, and bile detergents. Viruses that lack these features are destroyed when exposed to the alimentary tract, and must infect at other sites. 15 7  12/9/2023 This hostile environment may facilitates infection by some viruses. For example, reovirus particles are converted by host proteases in the intestinal lumen into infectious subviral particles, the forms that subsequently infect intestinal cells. Most enveloped viruses do not initiate infection in the alimentary tract, because viral envelopes are susceptible to dissociation by detergents such as bile salts. Enteric coronaviruses are notable exceptions, but it is not known why these enveloped viruses can withstand the harsh conditions in the alimentary tract. 16 Nearly the entire intestinal surface is covered with columnar epithelial cells with apical surfaces that are densely packed with microvilli. This, together with a surface coat of glycoproteins and glycolipids, and the overlying mucous layer, is permeable to electrolytes and nutrients, but presents a formidable barrier to microorganisms. Viruses such as enteric adenoviruses and Norwalk virus replicate extensively in intestinal epithelial cells. The mechanisms by which they bypass the physical barriers and enter susceptible cells are not well understood. 17 8  12/9/2023 Throughout the intestinal mucosa, there are lymphoid follicles that are covered on the lumenal side with a specialized follicle- associated epithelium consisting mainly of columnar absorptive cells and M cells (membranous epithelial cells). M-cell transcytosis is believed to provide the mechanism by which some enteric viruses gain entry to deeper tissues of the host from the intestinal lumen. 18 Virus Entry via the Skin Outer layer of dead, keratinized cells cannot support viral infection unless it is breached mechanically, either by direct trauma, by insect or animal bites, or various inoculation or transfusion procedures. Epidermis is devoid of blood or lymphatics; local replication Dermis and sub-dermal tissues are highly vascularized; infection may spread. 19 9  12/9/2023 Virus replication may then remain localized either in cells of the epidermis (papillomaviruses). Alternatively, virus progeny produced within the dermis may be carried by the bloodstream, lymphatics, or nerves to more distant sites. Virus may also be taken up by dendritic cells (Langerhans cells) in the skin and then be transported directly to local lymph nodes. 20 Virus Entry via Urogenital Tract Protected by mucus, low pH Minute abrasions may allow viruses to enter Some viruses produce local lesions (papillomaviruses) Some viruses spread from urogenital tract (HIV) Virus Entry via the Eyes The conjunctiva is constantly cleansed by the flow of tears and is regularly wiped by the eyelids. Infection is more likely to be introduced if abrasions to the conjunctiva or cornea are present, for example, in dusty environments. Infection usually occurs after injury: rubbing with fingers, ophthalmologic procedures, improperly sanitized swimming pools. Infection can be localized or systemic. 21 10  12/9/2023 Local Replication and Spread Entry may be followed by local replication and local spread of virus to adjacent cells extracellularly or intracellularly. → Extracellular spread occurs by release of virus into the extracellular fluid and subsequent infection of the adjacent cell. → Intracellular spread occurs by fusion of infected cells with adjacent uninfected cells or by cytoplasmic bridges between cells. Intracellular spread provides virus with a partially protected environment because the antibody defense does not penetrate cell membranes. 22 Factors that Restrict Virus Spread from an Epithelial Surface 1. Directional (polarized) budding. Some viruses bud preferentially from the apical surface toward the lumen, while others bud from the baso-lateral surface toward the underlying tissues. 2. Virus may be unable to cross the basement membrane unless it is damaged. 3. Cell types in more distant parts of the body may lack receptors, or not be permissive for other reasons. 4. There may be systemic presence of neutralizing antibody. 23 11  12/9/2023 5. The particular virus strain may be temperature-sensitive, i.e., it may grow successfully in the nasal passages at 33°C but not deeper in the body at 37°C. 6. A fusion protein on the virion may require proteolytic cleavage for its activation; proteases capable of performing this cleavage may be restricted to a particular site, e.g., gastrointestinal or respiratory tract. 24 Subepithelial Invasion and Lymphatic Spread Viruses →transverse the epithelium and basement membrane → reach subepithelial tissue →become exposed to macrophages → can enter lymphatics beneath the skin. Viruses in lymphatics → move to local lymph nodes → again get exposed to macrophages → or replicate in monocytes, macrophages and lymphocytes which circulate through the body between blood and lymph nodes. Some viruses pass directly to the blood stream. 25 12  12/9/2023 Mechanisms of Virus Spread to Distant Target Organs Hematogenous Spread (spread by Bloodstream) After escaping from local defenses, a disseminated infection could be accomplished by entering the bloodstream. → through capillaries, by replicating in endothelial cells, or through inoculation by a vector bite. Once in the blood, viruses may access most tissues in the host. Hematogenous spread begins when newly replicated particles produced at the entry site are released into the extracellular fluids, which can be taken up by the local lymphatic vascular system. 26 In the lymphatic system, virions pass through lymph nodes, where they encounter migratory cells of the immune system. Viral pathogenesis resulting from the direct infection of immune system cells (HIV, measles virus) is initiated in this manner. Some viruses replicate in the infected lymphoid cells, and progeny are released into the blood plasma. The infected lymphoid cell may also migrate away from the local lymph node to distant parts of the circulatory system. 27 13  12/9/2023 Viremia the presence of infectious virus particles in the blood free in the blood associated with infected cells such as lymphocytes. active passive produced by virus replication results when virus particles are introduced into the blood without viral replication at the site of entry primary secondary virions released into the blood after initial virions released into the blood after viral replication at the site of entry. spreading and replication in target organs. Low concentration. High concentration. 28 The role of primary and secondary viremias in the spread of viruses throughout the body. + indicates major sites of virus replication. arrows indicate sites of shedding to the exterior. * indicates replication in vascular endothelium 29 14  12/9/2023 Important cells that affect Interactions between viruses and Kupffer virions circulating the plasma Cells: are macrophages and vascular (1) Viruses may pass through the sinusoid endothelial cells. without being phagocytosed. (2) Virions may be phagocytosed and destroyed. (3) Virions may be phagocytosed and then transferred passively to adjacent cells (i.e., hepatocytes in the liver). (4) Virions may be phagocytosed by Kupffer cells and then replicate in them, with or without spread to adjacent hepatocytes and excretion into bile ducts or release to the bloodstream. 30 Neural Spread Virus spread by entering local nerve ending. Viruses neurotropic neuroinvasive neurovirulent virus can infect neural virus can enter the central virus can cause disease of cells via neural or nervous system (spinal cord nervous tissue, manifested hematogenous and brain) after infection of a by neurological symptoms peripheral site and often death Following spread, invasion of skin, CNS, other organs and sometimes the fetus may occur. 31 15  12/9/2023 Virus shedding This is important to maintain infection in populations. It usually occurs from one of the body openings or surfaces involved in virus entry. Some viruses are shed from multiple sites. Examples include: Respiratory and mouth secretions. Feces Skin Other routes Urine Milk Blood Body secretions No shedding → “dead end” sites of virus replication. 32 Persistent Viral Infections Acute (self-limited) infections result more commonly in recovery with elimination of the virus from the body. Persistent infections are those in which the virus is not cleared from the host following primary infection, but remains associated with specific cells. Prerequisites for establishment and maintenance of a persistent infection include: 1. Avoidance of elimination by the immune system. 2. Limitation of expression of the genome (of cytocidal viruses). 33 16  12/9/2023 In true latent infections (the genome persists in the absence any viral replication), reactivation of the latent genome to initiate viral replication must occur at some time during the life of the host (a further requirement). 34 Categories of Persistent Infections They can be sub-divided into: Latent infections: characterized by the lack of demonstrable infectious virus between episodes of recurrent disease. Chronic infections: characterized by the continued presence of infectious virus following the primary infection and may include chronic or recurrent disease. Disease may be absent or chronic, or may develop late, often with an immunopathologic or neoplastic basis. Slow infections: characterized by a prolonged incubation period , leading to a slowly progressive lethal disease. 35 17  12/9/2023 Pathogenesis of Persistent Infections Abrogation of the Cytocidal Capacity of the Virus Restricted Expression of Viral Genes Latency in nonpermissive, Resting, or Undifferentiated Cells Noncytocidal viruses Evasion of the Immune Response Evasion of Neutralization by Antibody Cell Fusion Blocking by Nonneutralizing Antibodies Antigen Decoy Immunosuppressive Epitopes Antigenic Drift Immunosuppression by infection of Effector Cells Abrogation of Lymphocyte Function Abrogation of Macrophage Function 38 Evasion of Cytokines Induction of Immunologic Tolerance 39 19  12/9/2023 Virus Persistence in Vitro Three types of persistent infection can be distinguished in cultured cells. 1- chronic focal infection (carrier culture) 2- chronic diffuse infections (steady-state infections) 3- true latent infection → the viral genome is replicated and segregated to the daughter cells either within the chromosomes or extrachromosomally. 46 47 23  12/9/2023 Mechanisms of Viral Oncogenesis Oncology: the study of tumors. Oncogenesis, tumorigenesis or carcinogenesis: The process of development of tumors. Benign tumor: a growth produced by abnormal cell proliferation that remains localized and does not invade adjacent tissue. Malignant tumor (cancers): a growth that is locally invasive and may be metastatic → spreads through lymphatic and blood vessels to other parts of the body. Malignant tumors of epithelial cell origin → carcinomas Malignant tumors arising from cells of mesenchymal origin → sarcomas 50 Malignant tumors from leukocytes → lymphomas (if solid tumors) → leukemia (when circulating cells are involved). Cell transformation: the changes associated with loss of normal homeostatic control which results in the development of neoplastic phenotype. →to reproduce the genetic changes (in cultured cells) that led to a phenotypic behavior resembling cancer. Transformation by DNA viruses is non-productive → the transformed cells do not yield infectious progeny virus, but may express virus- encoded antigens. 51 25  12/9/2023 Oncogenes and tumor suppressor genes (Two of the main types of genes that play a role in cancer) Oncogenes Proto-oncogenes are genes that normally help cells grow. When a proto-oncogene mutates (changes) or there are too many copies of it, it becomes a oncogene that can become permanently turned on or activated when it is not supposed to be. → the cell grows out of control leading to cancer. Therefore, Protooncogenes (c-onc genes) are the cellular counterparts of v-onc genes. Their functions are cellular growth and development. 52 The genes in the viral genome that change host cell proliferation control, lead to the synthesis of new proteins, and are responsible for transformation characteristics are called viral oncogenes (v-onc genes). Tumor suppressor genes (antioncogenes) Tumor suppressor genes are normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die (a process known as apoptosis or programmed cell death). When tumor suppressor genes don't work properly, cells can grow out of control, which can lead to cancer. 53 26  12/9/2023 An important difference between oncogenes and tumor suppressor genes is that oncogenes result from the activation (turning on) of proto-oncogenes, but tumor suppressor genes cause cancer when they are inactivated (turned off). 54 Classification of oncogenes Growth factors Growth factor receptors Signal Transducers Transcription Factors or hormone receptors. In normal cells, growth factor receptors bind particular growth factors, thereby sending a growth signal to the cell nucleus. 55 27  12/9/2023 Programmed Cell Death (apoptosis) Regulation Normal tissues exhibit a regulated balance between cell proliferation and programmed cell death. Studies of cancer cells have shown that both uncontrolled cell proliferation and failure to undergo programmed cell death can contribute to neoplasia and insensitivity to anticancer treatments. Many are transcription factors which positively regulate a number of target genes whose expression leads to cell division. 56 Activation of cellular oncogenes Abnormal c-onc transcription may occur in a variety of ways: 1- Insertional mutagenesis 2- Transposition 3- Gene amplification 4- Mutation 57 28  12/9/2023 60 Viral vaccines A biological preparation that improves immunity to a particular disease. Purpose: Utilization of immune response of the host to prevent viral diseases. → Immune memory To break the chain of infection. Types of immunization (vaccination) Passive Immunization natural maternal antibodies, antitoxins, and immunoglobulins. Protection transferred from another person or animal. Effects are temporary. The transfer of antibodies will not trigger the immune system. There is no presence of memory cells. 61 30  12/9/2023 Active Immunization natural infection, vaccines (many types), and toxoids. Relatively permanent stimulate the proliferation of T and B cells, resulting in the formation of effector and memory cells How Do Vaccines Work? Stimulates “protective” adaptive immune response Vaccines prevent or modify disease. Most do NOT prevent infection. Herd immunity reduces spread of disease. ▪ Disease agents require a certain level of transmission to be maintained. 62 Effectiveness of vaccination Small percentage of recipients will respond poorly (due to genetic determinants) Herd Immunity: → Immunize ‘enough people’ to block virus spread.→ Not everyone has to be immune to protect the population. Virus spread stops when the probability of infection drops below a critical threshold which is virus and population specific: Smallpox: 80 : 85% Measles: 93 : 95% 63 31  12/9/2023 Requirements of an effective Vaccine Activation of an appropriate immune response (Antigen- Presenting Cells to initiate antigen processing, cytokine production, activation of T and B cells to give a good yield of memory cells. Effective against virulent strains of the pathogen. Safe. Effective at the community level (Herd immunity) Long-lasting immunity. Cost effective. How it is applied. Storage conditions. 64 ‫ﻣﻬﻤﺔ‬ 65 32  12/9/2023 Types of viral Vaccines Live whole virus vaccines Killed whole virus vaccines Subunit vaccines;- purified or recombinant viral antigen Recombinant virus vaccines DNA vaccines 66 LIVE ATTENUATED VACCINES Virus replicative and fully immunogenic but not virulent. Utilizes virus mutants restricted in some steps in pathogenesis of disease. The virulence of the virus is reduced by: -Genetic engineering to get rid of pathogenicity factors. -Administration of pathogenic or partially attenuated virus by an unnatural route -Passage of the virus in unnatural host or host cell. Example → Polioviruses were passed in monkey kidney cells → Measles in chick embryo fibroblasts. 67 33  12/9/2023 68 Inactivated whole virus vaccines Easiest preparations to use Simply inactivated The outer virion coat should be left intact but the replicative function should be destroyed. must contain much more antigen than live vaccines Extreme care –no residual live virulent virus in vaccine 69 34  12/9/2023 Inactivation by heat or chemicals (formaldehyde or beta- propiolactone). Excessive treatment can destroy immunogenicity. Insufficient treatment can leave infectious virus capable of causing disease. Requires addition of adjuvants. Most widely used are aluminum salts (mainly hydroxide or phosphate) Enhance the immune response and inflammation. 70 71 35  12/9/2023 Break virus into components, immunize with purified components. Clone appropriate viral gene, express in bacteria, yeast, insect cells, cell culture, then vaccinate with purified protein. Antigen is usually a capsid or membrane protein. 72 73 36  12/9/2023 Viral vector-based vaccines They don’t contain antigens, but use the body’s own cells to produce them. This is achieved by using a modified virus (the vector) to deliver genetic code for an antigen into human cells. By infecting cells and instructing them to make large amounts of antigen, which then trigger an immune response, the vaccine mimics what happens during natural infection with certain pathogens. This has the advantage of triggering a strong cellular immune response by T cells as well the production of antibodies by B cells. 74 75 37  1/3/2025 Medically important viral groups DNA VIRUSES Enveloped Non-enveloped dsDNA dsDNA ssDNA Herpesviridae Adenoviridae Parvoviridae Hepdnaviridae Papovaviridae Poxviridae Linear X Papovaviridae Icosahedral X Poxviridae Replicate in nucleus X Poxviridae 67 Herpesviridae Human herpesviruses (HHV-8 members) Viral sub-family Alpha Beta Gamma Short infection cycle Long infection cycle Oncogenic Latent in sensory neurons Latent in WBCs Latent in lymphocytes Herpes simplex virus 1 (HSV-1) Human Cytomegalovirus (CMV) Epstein-Barr virus (EBV) Herpes simplex virus 2 (HSV-2) Human herpes virus 6 (HHV-6) Human herpes virus (HHV-8) Varicella-Zoster virus (VZV) Human herpes virus 7 (HHV-7) 68 1  1/3/2025 Infection Reactivation Lytic Latent Primary infection Reactivation Recurrent infection HSV-1 & HSV-2 Oral herps Genital herps Orofacial Urogenetal Attacks mucocutaneous junctions Mucus membrane of genital tract of mouth, lips, nose and eyes 69 ‫ﻣﻬﻢ‬ Pathogenesis Neurotropic viruses HSV-1 HSV-2 Transmission: by direct contact Transmission: sexual & vertical (skin, saliva or contaminated objects) Entry (skin or Replication mucous membranes) Lesion production Latency in trigeminal Reactivation and ulceration ganglia or sacral ganglia (vesicles) Primary infection Virions move back Vesicle formation to the epithelium Recurrent infection 70 2  1/3/2025 Diseases Herpes Labialis - Cold sore Herpetic Keratitis – Herpetic retinitis Herpetic Whitlow Encephalitis and Meningitis Herpes Genitalis Herpetic Keratitis Herpetic Whitlow TORCH Syndrome 71 Skin rash caused by hepesviruses Common types of skin rash includes: Macules: small and flat Papules: small, solid and raised Vesicles: small, elevated with clear fluid inside Pustules: small elevated with pus Nodules: large solid raised 72 3