Virus Pathogens (MPLec) PDF

Virus as pathogens (MPLec)  Viruses Are Everywhere comprise an enormous proportion of our Why We environment, in both number and total mass Study biomass of bacterial viruses alone exceeds Viruses that of all of Earth’s elephants by more than...

Virus as pathogens (MPLec)  Viruses Are Everywhere comprise an enormous proportion of our Why We environment, in both number and total mass Study biomass of bacterial viruses alone exceeds Viruses that of all of Earth’s elephants by more than 1,000-fold. average human body contains approximately 1013 cells, outnumbered 10-fold by bacteria and as much as 100-fold by virus particles. intestinal tracts are loaded with myriad plant and insect viruses, as well as hundreds of bacterial species that harbor their own constellations of viruses. Viruses Can Cause Human Disease most devastating human diseases have been or still are caused by viruses; include smallpox, yellow fever, poliomyelitis, influenza, measles, and AIDS. Viruses are responsible for approximately 20% of the human cancer burden Host Range and Requirements Specific for each invertebrates, vertebrates, plant, fungi, bacteria May cross species Requires specific attachment on the host cells. Cell wall, fimbriae, flagella are receptor sites. Cell membranes are attachments for animal virus. Viruses Can Be Beneficial virus particles most abundant biological entities Infected whales excrete more than 1013 calicivirus particles daily. comprise 94% of all nucleic acid-containing particles in the oceans …15 times more abundant than the Bacteria and Archaea. Viral infections in the ocean kill 20 to 40% of marine microbes daily…release essential nutrients that supply phytoplankton at the bottom of the ocean’s food chain, as well as carbon dioxide and other gases that affect the climate of the earth. mice latently infected with some murine herpesviruses are resistant to infection with the bacterial pathogens Listeria monocytogenes and Yersinia pestis. Viruses Can Cross Species Boundaries cross-species (zoonotic) infections of humans are occurring with increasing frequency highly fatal Ebola hemorrhagic fever and the severe acute respiratory syndrome (SARS) are recent examples of viral diseases to emerge from zoonotic infections.  Direct contact: Indirect contact: Vector-borne: Foodborne Waterborne: https://www.cdc.gov/onehealth/images/zoonotic-diseases- spread-between-animals-and-people.jpg  Every cell in our body contains viral DNA. Human endogenous retroviruses, … make up about 5 to 8% of our DNA. Viruses “R” from infections of germ cells that have Us occurred over millions of years during our evolution. conservation of some of the viral sequences in vertebrate genomes suggests that they may have been selected for beneficial properties over evolutionary time. https://www.npr.org/201 When researchers began to analyze the human 0/07/30/128875905/vert ebrate-genomes-hide- genome, they found that about 8 percent of the ancient-viruses genetic code that's there actually came from viruses.  studies that focus on viral reprogramming of cellular mechanisms have provided unique insights into cellular biology and functioning of host defenses. studies of viruses that infect bacteria, the bacteriophages, laid the foundations of modern molecular biology Viruses Are Unique Studies of animal viruses established many fundamental principles of cellular function, including the presence of intervening sequences in eukaryotic genes. Tools To study of cancer (transforming) viruses revealed the genetic basis of this Study disease. Biology viral genomes as vehicles for the delivery of genes to cells and organisms for both scientific and therapeutic purposes. Viral vectors are to introduce genes into various cells and organisms to study their function has become a standard method in biology. Figure 1. A general overview of therapeutic uses of viruses, including direct use as immunogens for vaccines, gene therapy vectors for delivery of therapeutic protein-coding sequences, tools for destroying cancer cells in oncolytic virotherapy and as sources for novel therapeutic proteins. https://doi.org/10.3390/jcm9040972   Acellular (lack Basic cellular structures)  Very small (20-1000 nm) – virion – a virus particle  Have few or no enzymes for metabolism – direct cell machinery for its own use.  Contain either DNA or RNA – as genetic material; single or double stranded; codes for, at most, four types of proteins.  Has a protein coat surrounding the n.a. II. General  May have envelope of Phospholipids – derived from previous host. Characteristics Others:  Obligate intracellular parasites, to multiply, must be inside a host cell  Can't be grown on culture media  Often damages and kills cell  Viral genes can integrate to host genes - conversion to cancer cells Viral Size  units commonly used in descriptions of virus particles or their components are the nanometer (nm [10􏰈9 m]) and the angstrom (Å [10􏰈10 m]). (3) Contain either DNA or RNA (for SARS-CoV-2 ) (4) Viruses are obligate intracellular parasites. https://openstax.org/boo ks/biology/pages/21-2- virus-infections-and-hosts (5) Virus damages and Kill cells THE SEVEN CLASSIFICATION OF VIRUSES 18 2012 ICTV 7 Orders 96 Family 22 Subfamilies 420 Genera 2618 viruses  1. Viral genome‘s nucleic acid ( DNA or RNA ) 2. Strandedness (single-stranded or double-stranded) 3. Sense Key Points Positive sense with RNA virus consists - viral mRNA that can be directly translated into proteins; and negative sense RNA virus - viral RNA that is complementary to the viral mRNA. 4. Method of replication determine its class 5. Other classifications are determined by the disease caused by the virus or its morphology.  Class I-II: replicate DNA and make Viral mRNA in cytoplasm for some. Class III-V. Transcription in cytoplasm. Class VI. Reverse transcription inside the virus; DNA copy is transported to cell nucleus for integration. Madigan et al. 2012 Virion Virus particles are elegant assemblies of viral, and occasionally cellular, macromolecules. (50-90% protein). Virus particles come in many sizes and shapes and vary enormously in the number and nature of the molecules from which they are built. they fulfill common functions and are constructed according to general principles that apply to them all. Watson and Crick predicted that the only two ways in which asymmetric subunits could be assembled to form virus particles would generate structures with either cubic or helical symmetry.  Virion and function 1. Protection of the genome Assembly of a stable protective protein shell. Specific recognition and packaging of the nucleic acid genome. Interaction with host cell membranes to form the envelope. 2. Delivery of the genome Binding to external receptors of the host cell. Transmission of signals that induce uncoating of the genome Induction of fusion with host cell membranes. Interaction with internal components of the infected cell to direct transport of the genome to the appropriate site. 3. Other functions Interactions with cellular components for transport to intracellular sites of assembly. Interactions with cellular components to ensure an efficient infectious cycle. Nomenclature used in description of virus structure  III. Main Viral Structures and General Morphology Core nucleic acids types: Capsid: Envelope: Envelope glycoproteins dsDNA Capsomeres are subunits Lipids, proteins and Enzymes ssDNA Multiple copies of one carbohydrates Non-genomic viral dsRNA protein Derived from membrane nucleic acid Capsid + n.a. = of host cell Cellular macromolecules ssRNA nucleocapsid Spikes help virus attach to Code for viral proteins: cells prior during special enzyme, Helical or icosahedral infection inhibitory proteins, structural proteins Not all viruses have envelope. *1.7 kb – 2.8 Mbp *http://book.bionumbers.org/how-big-are-genomes/  viral capsid - protein coat surrounding and protecting the viral genome capsomere - collection or assembly of protein molecules making up a viral capsid viral envelope - structure that consists of lipid-containing layers Helical - type of symmetry of capsomere arrangement associated with spiral- shaped viruses icosahedron - roughly spherical geometric structure with 20 triangular faces and the most efficient arrangement of capsomeres in a viral capsid. https://www.coursehero.com/sg/microbiology/what-are- viruses/  Capsids with Icosahedral Symmetry made up of 20 triangular faces, five at the top, five at the bottom and 10 around the middle, with 12 vertices. Three axes of symmetry by two-, three-, and fivefold axes. Each of 20 faces of an icosahedron is an equilateral triangle, and five such triangles interact at each of the 12 vertices a trimer of a single viral protein (the subunit) corresponds to each triangular face of the icosahedron As an icosahedron has 20 faces, 60 identical subunits (3 per face 20 faces) is the minimal number needed to build a capsid with icosahedral symmetry. (a) Asymmetrical subunits located at vertices of each triangular facet.  envelope formed by a viral protein-containing membrane that is derived from the host cell, but they vary considerably in size, morphology, and complexity. Viral differ in lipid composition, the number of Envelopes proteins they contain, and their location form the outermost layer of enveloped animal viruses, but in bacteriophages and archaeal viruses of the PRD1 family the membrane lies beneath an icosahedral capsid  Enzymes virus particles contain enzymes necessary for synthesis of viral nucleic acids catalyze reactions unique to virus-infected cells, such as synthesis of necessary because transcription of the viral double-stranded DNA genome takes place in the cytoplasm of infected cells vs cellular DNA- dependent RNA polymerases and the RNA-processing restricted to the nucleus. Other types of enzymes found in virus particles include integrase, cap- dependent endonuclease, and proteases Multiplication of Animal Viruses Replication of a DNA- Containing Animal Virus  genome must enter a cell for the viral reproduction cycle to occur. physical properties of the virion are obstacles to this – viruses too large to diffuse passively across the plasma membrane viral genome is encapsulated in a stable coat Viral first step is adherence of virus particles to the plasma membrane specific receptor molecule on the cell surface - plays an important role replication in uncoating (exposure of genome to the cytoplasm) Cytoplasm – site of replication of RNA-containing viruses. Nucleus – site of replication of DNA-containing viruses and RNA- containing retroviruses, Uses normal cellular processes, including endocytosis, membrane fusion, vesicular trafficking, and transport into the nucleus.  virus must first gain proximity to a cell within a susceptible organism Free- living bacterial cells encounter virus in the environment through random diffusion. For plants, viruses commonly delivered to a new host by a vector species. Virus encounter In animals, viruses may be delivered to the body surface by a vector or by direct contact with particles on surfaces, or else viruses can be internalized into the body from the environment via the respiratory, gastrointestinal or genital tracts where potential target cells may then be encountered.  Infection of cells by many, but not all, viruses requires binding to a receptor on the cell surface. receptor is a cell surface molecule that binds the virus particle (attachment proteins) and participates in entry. inherited characteristics of the host. Attachment: Receptors of host proteins, carbohydrates, and lipids Purpose: induce conformational changes in the virus particle that lead to membrane fusion or penetration, it may also transmit signals that cause uptake bring the bound particle into endocytic pathways. receptor in a particular cell type does not ensure that virus reproduction Figure 5.2 Some cell attachment factors and receptors for viruses. Schematic diagrams of cell molecules that function during virus entry. GlcNAc, N-acetylglucosamine; GalNAc, N-acetylgalactosamine; Ldlr, low-density lipopro- tein receptor; DC-SIGN, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; Car, coxsackievirus-adenovirus receptor. Receptors Fig. 6.1 Entry of animal virus genomes into cells. Entry by endocytosis is followed by a fusion of the vesicle with an endosome and a decrease in the pH of the endosome. This promotes conformational changes in viral proteins.  human species C adenoviruses that utilize Chimeric antigen Receptor (CAR) as their receptor Attachment facilitates a secondary interaction between the capsid protein at the base of the fiber, known as penton base, and cell surface integrins these interactions promote endocytosis via clathrin-coated pits  The lytic cycle of a T-even bacteriophage. T-even bacteriophages are large, complex, and non- enveloped, with a characteristic head- and-tail structure. phage has enough DNA for over 100 genes. five distinct stages: attachment, penetration, biosynthesis, maturation, and release. Bacteriophages can multiply by two alternative mechanisms: the lytic cycle or the lysogenic cycle. lytic cycle ends with the lysis and death of the host cell, whereas the host cell remains alive in the lysogenic cycle. Receptors iron-uptake protein Carbohydrates in lipopolysaccharid e (LPS) flagella and pili  Entry of bacteriophage genomes into bacterial cells T-even bacteriophage injects its DNA (nucleic acid) into the bacterium. bacteriophage’s tail releases an enzyme, phage lysozyme, which breaks down a portion of the bacterial cell wall. During the process of penetration, the tail sheath of the phage contracts, and the tail core is driven through the cell wall. shortening of the tail sheath pushes the non- contractile tail core through the outer layers of the bacterium with a twisting motion When the tip of the core reaches the plasma membrane, the DNA from The mechanism of entry of the phage T4 genome the bacteriophage’s head passes through the tail core, through the into the bacterial cell. plasma membrane, and enters the bacterial cell.  contraction of the head forces the injection of the phage DNA through the tail core into the cell capsid remains outside the bacterial cell. Therefore, the phage particle functions like a hypodermic syringe to inject its DNA into the bacterial cell.  Virus-host interaction Evolution of host Induction of symbiotic relationship Contents Infection and pathogenesis Damages caused by viruses Factors affecting Viral pathogenesis Virus-induced Neoplasma The 7 Viruses That Cause Human Cancers Human tumor viruses account for an estimated 12% to 20% of cancers worldwide. Epstein-Barr Virus: Burkitt’s Lymphoma, Hodgkin’s Disease, and Nasopharyngeal Carcinoma Human Papillomaviruses 16 and 18: Cervical Carcinoma, Anal Carcinoma, Oropharyngeal Carcinoma, Penile Carcinoma Kaposi’s Sarcoma-Associated Herpesvirus: Kaposi’s Sarcoma, Primary Effusion Lymphoma, Multicentric Castleman’s Disease Hepatitis B Virus and Hepatitis C Virus: Hepatocellular Carcinoma Human Adult T-cell Leukemia Virus Type 1 (HTLV-1): T-cell Leukemia Merkel Cell Polyomavirus: Merkel Cell Carcinoma https://asm.org/Articles/2019/January/The-Seven-Viruses- that-Cause-Human-Cancers Introduction “a major motivating factor for the study of virology is that viruses cause disease of varying levels of severity… not surprising that virus infections have historically been considered episodic interruptions of the well being of a normally healthy host (referring to the lytic cycle). However, another type of bacterial virus could ensue in the host population - a persistent infection …(Lysogenic cycle) stress to the lysogenic bacteria could release infectious virus long after the establishment of the initial infection. “persistent infections it is only upon the with low or no levels introduction of a of viral disease are virus into a novel universal in virus– population that host ecosystems that widespread disease have evolved and host morbidity together for occurs. extended periods”  dynamic effective physiological responses to infectious disease have evolved in the organism viruses respond by exploiting their naturally occurring genetic variation to accumulate and Virus-host select mutations to become wholly or partially resistant to these responses. interaction such resistance will lead to periodic or episodic reemergence of a previously controlled diseas – most obvious example is periodic appearance of human influenza viruses  interaction between viruses and hosts had a measurable impact on evolution of the host. Viruses provide environmental stresses to which organisms evolve responses. Virus-host Case in point: a. cellular-based antiviral interferon (IFN) response, and interaction: many of the inflammatory and other responses that multicellular organisms can mount to ward off infection is the result of successful genetic adaptation to infection. host B. There is good circumstantial evidence that the specific origin of placental mammals is the result of an ancestral evolution species being infected with an immunosuppressive proto- retrovirus. It is suggested that this immunosuppression permitted an immunological accommodation in the mother to the development of a genetically distinct individual in the placenta during a pro- longed period of gestation! Virus Infection and Pathogenesis infection of a cell with a single virus particle will result in the synthesis of more than one (often by a factor of several powers of 10) infectious virus - a productive infection. actual number of infectious viruses produced in an infected cell is called the burst size, and this number can range from less than 10 to over 10,000, depending on the type of cell infected, the nature of the virus, and many other factors. Infections with many viruses completely convert the cell into a factory for replication of new viruses. viruses must gain entry into their host’s body before they can exert their pathogenic effects; entry of virus into the host can occur through any of a variety of potential routes, depending on the properties of the individual virus  Table 3.1. Obligatory Steps in Viral Infection Step in Infection Process Requirement for Virus Survival and Progression of Infection Evade host’s natural protective and cleansing mechanisms; at Entry into host and primary virus the cellular level, the virus takes over necessary host-cell replication functions for its own replication processes Local or general spread in the host Evade immediate host defenses (innate immune and (defined by cell and tissue tropism), inflammatory responses) and natural barriers to spread with secondary virus replication Damage to the host may occur at this and later stages Exit host body at site and at concentration needed to ensure Shedding from host infection of the next host Adaptive immune responses mediate clearance, although Clearance from the host clearance is not always complete; viruses may persist and contribute to long-term shedding or chronic disease  Outcomes: A. state of coexistence between the cell and infecting virus, which can persist for as long as the life of the host Small amount of virus is produced or no evidence of viral gene expression (subclinical syn., asymptomatic, inapparent) B. Disease dynamic nature of the virus–cell relationship is defined in terms that describe the degree of damage to the infected cell and the production of viral progeny. Figure 3.1. The iceberg concept of viral infection and diseases.  Effects of Viruses On Cells  pathological effects of the diseases caused by viruses result from the interplay of several factors:  toxic effects of viral gene products on the metabolism of infected cells  reactions of the host to infected cells expressing viral genes, and  modifications of host gene expression by structural or functional interactions with the genetic material of the virus.  in most instances the symptoms and signs of acute virus diseases can be directly related to the destruction of cells by the infecting virus.  Damages Caused by virus thru… Cytopathic Infections- characterized by loss of cell functions that are essential to survival. Cell degeneration and necrosis or virus-induced apoptosis are final outcomes of cytopathic infections. Cytocidal (meaning “cell death”) or cytolytic (meaning “cell lysis” or “rupture”) Cell lysis - required for release of nonenveloped viral progeny progeny of enveloped viruses can be released by budding from viable cells. Clinical  Cytopathic effects produced by viruses Inclusions may reflect viral replication complexes in the nucleus or cytoplasm. Cell rounding - follow after cytoskeletal disruption. Syncytia formation may be seen following infection with enveloped viruses. Apoptosis is a programmed cell death resulting in morphologic changes that are distinct from necrosis or lysis (ie, forms of nonprogrammed cell death), and is a form of host defense. A single virus may cause combinations of these cytopathic effects. https://www.sciencedirect.com/science/article/pii/B97801280 09468000039 Direct Examination Light Microscopy A, Pap-stained smear showing multinucleated Cytopathic Effect giant cells typical of herpes simplex or varicella- zoster viruses. B, Hematoxylin and eosin (HE)–stained lung tissue containing intranuclear inclusion within enlarged cytomegalovirus (CMV)–infected cells. C, HE-stained lung tissue containing epithelial cells HSV or VZV CMV with. intranuclear inclusions characteristic of adenovirus D, HE-stained liver from stillborn fetus showing intranuclear inclusions in erythroblasts (extramedullary hematopoiesis) resulting from Adenovirus Parvovirus parvovirus infection Cyto…Inclusion bodies sites of viral transcription and genome replication in the cell that are readily apparent by light microscopy. Types: intranuclear inclusion. Displaced host cell DNA from the nuclear matrix result in chromatin margination along the nuclear membrane as aggregates of viral nucleic acid and protein accumulate i.e canine distemper Cytoplasmic inclusions. typical of viruses replicating to high levels in the cytoplasm, again reflecting aggregates of viral genomes engaged in transcription and replication. i.e typical of infections caused by poxviruses, paramyxoviruses, rhabdoviruses, and reoviruses  Genotoxic Effects: Following virus infection, breakage, Cytocidal fragmentation, Infection rearrangement and/or changes in the number of chromosomes may occur. Cyto…Inhibition of Host Cell Protein Production viral protein synthesis continues - a characteristic of many viral infections. shutdown occurs late in the course of infection and is more gradual, with noncytocidal viruses, there is no dramatic inhibition of host-cell protein synthesis, and no cell death. inhibition of both host-cell DNA replication and mRNA transcription is a consequence of DNA virus infection when cellular machinery is redirected to viral templates. this inhibition may also be the indirect consequence of viral effects on host-cell protein synthesis that decrease the availability of transcription factors required for DNA-dependent RNA polymerase activity. cumulative effect of inhibition of host-cell protein synthesis and depletion of nucleotide pools can be the loss of cellular homeostasis, resulting in a sequence of degeneration and necrosis.  Cyto… Interference with Cellular Membrane Function alter plasma membrane permeability, affect ion exchange and membrane potential, or induce the synthesis of new intracellular membranes or the rearrangement of previously existing ones viral proteins are inserted into the cell membrane in preparation for viral assembly (budding), but if they contact a neighboring uninfected cell, they can mediate attachment to and fusion with the membranes of that neighboring cell. result is a multinucleated syncytium. suggested as a means by which viruses spread in tissues: fusion bridges may allow subviral entities, such as viral nucleocapsids and nucleic acids, to spread while avoiding host defenses Figure 3.10. Formation of syncytia by enveloped viruses. https://www.sciencedirect.com/science/article/pii/B97801280 09468000039 Figure 3.11. Hemadsorption and hemagglutination. viral membrane glycoprotein serves as a receptor for ligands on the surface of erythrocytes. Viral envelope proteins may bind glycoproteins expressed on the surface of erythrocytes. Erythrocytes may bind to infected cells that express these viral envelope proteins on their surface (hemadsorption) or cell free viruses may cross-link erythrocytes to form aggregates (hemagglutination), indicating the presence of virus infection. Hemadsorption and hemagglutination are not known to play a part in the pathogenesis of viral diseases. https://www.sciencedirect.com/science/article/pii/B97801280 09468000039 Cyto… Disruption of the Cell Cytoskeleton causes changes in cell shape (eg, contributes to the drastic cytopathic rounding) that are characteristic of many changes that precede cell lysis in viral Infections. many infections Damage to specific filament systems: for elements of the cytoskeleton also example, canine distemper virus, employed by many viruses in the vesicular stomatitis viruses, vaccinia virus, and herpesviruses cause course of their replication: in virus a depolymerization of actin-containing entry, in the formation of replication microfilaments, and enteroviruses complexes and assembly sites, and in induce extensive damage to virion release. microtubules Cyto…Apoptosis programmed cell death, which is essentially a mechanism of cell suicide that the host activates as a last resort to eliminate viral factories before progeny virus production is complete. Activated either thru: Intrinsic (Mitochondrial) Pathway. The mitochondrial pathway is activated as a result of increased permeability of mitochondrial membranes subsequent to cell injury, such as that associated with a viral infection. Extrinsic (Death Receptor) Pathway. The extrinsic pathway is activated by engagement of specific cell- membrane receptors, which are members of the tissue necrosis factor (TNF) receptor family (TNF, Fas, and others). culminate in the activation of host-cell caspase enzymes that mediate death of the cell (the so-called executioner phase). Non-cytopathic effects in Virus infected cells Usually do not kill the cells in which replication occurs. cause persistent infection during which infected cells produce and release virions but cellular metabolism that is essential to maintaining homeostasis is either not affected or is minimally affected. cells even continue to grow and divide. slowly progressive changes that ultimately lead to cell death. cell replacement occurs so rapidly in most organs and tissues that the slow fallout of cells as a result of persistent infection may have no effect on overall function, terminally differentiated cells such as neurons, once destroyed, are not replaced, and persistently infected differentiated cells may lose their capacity to carry out specialized functions.  Factors affecting Viral pathogenesis Virus tropism - refers to the preference of the virus’s host of replication in distinct kinds of cells in an organ. determined through the capability of viral surface proteins to bind or fuse to the surface receptors of targeted cells to initiate an infection HIV-1 requires target cells to express co-receptors CCR5 or CXCR4 in addition to the CD4 receptor for the purpose of facilitating attachment of the virus. other intracellular factors for instance, the transcription factors that are specific to tissues. John Cunningham virus gene expression is dependent on host transcription factors which are expressed only within the glial cell.  Virus factors - viral genetics that encode viral factors can determine the degree of pathogenesis triggered by viral infections for a virus to spread and cause disease to the body, it must encode specific genes within its genome, which allow it to beat the preventive physical barriers and to modulate the immune system’s ability to block replication of the virus.  Host factors - viral infections have demonstrated various manifestations that range from asymptomatic to asymptomatic, or even critical illness, because on the host’s factors. genetic factors such as age, immunocompetence and genetics are crucial in determining whether the virus is able to be controlled through the body of the patient. Mumps, polio and Epstein-Barr virus are more serious diseases in adults, while others , like rotavirus, cause more serious infections in infants. T Virus-induced Neoplasia Neoplasms - consequence of the dysregulated growth of cells derived from a few or a single, genetically altered progenitor cell(s). neoplasms - considered to originate from an oligoclonal or monoclonal outgrowth of a single cell regardless of the composition of several cell types. genetic changes responsible for neoplasia may be caused by naturally occurring mutations, chemical or physical agents or infectious agents including viruses, but all involve certain common cellular pathways. Definitions Neoplasm is a new growth (syn. tumor) which can be benign or malignant; neoplasia is the process that leads to the formation of neoplasms (syn. carcinogenesis); oncology is the study of neoplasia and neoplasms; benign neoplasm is a growth produced by abnormal cell proliferation that remains localized and does not invade adjacent tissue; malignant neoplasm (syn. cancer) is locally invasive and may also be spread to other parts of the body (metastasis). Carcinomas are cancers of epithelial cell origin, Sarcomas are cancers that arise from cells of mesenchymal origin. Solid neoplasms of lymphocytes are designated lymphosarcoma, malignant lymphoma, or lymphoma, leukemias are cancers of hemopoietic origin characterized by circulation of cancerous cells. Cellular Basis of Neoplasm result of nonlethal genetic injury, as may be acquired by chemical or physical damage, or from viral infections. results from the clonal expansion of cells that have suffered genetic damage, typically in one of four types of normal regulatory genes: tumor suppressor genes DNA repair (1) proto-oncogenes, which are cellular genes that regulate growth and differentiation; (2) tumor suppressor genes that inhibit growth, typically by regulating the cell cycle; (3) genes that regulate apoptosis (programmed cell death); (4) genes that mediate DNA repair. Carcinogenesis involves a multistep progression resulting from the cumulative effects of multiple mutations. Proto-oncogenes normal cellular genes that encode proteins that function in normal cellular growth and differentiation Include: 1) growth factors; (2) growth factor receptors; (3) intracellular signal transducers; (4) nuclear transcription factors; (5) cell cycle control proteins. Oncogenes - derived by mutation of normal cellular proto-oncogene counterparts expression of oncogenes results in production of oncoproteins that mediate autonomous (unregulated) growth of neoplastic cells. Viruses are classified as tumor viruses if part of the viral genome is present in tumors, with expression within the tumor of some viral genes  Characteristics of Neoplasm: (1) self-sufficient, proliferate without external stimuli; e.g. result of unregulated oncogene oncogene activation; (2) insensitive to normal regulatory signals that would limit their growth, such as transforming growth factor transforming growth transforming factor growth factor and the cyclin-dependent kinases that normally regulate orderly progression of cells through the various phases of the cell cycle; (3) resistant to apoptosis because of either the activation of antiapoptotic molecules or the inhibition of mediators of apoptosis such as p53; (4) limitless potential for replication. Cancers also may have the ability to invade and spread to distant tissues (metastasis), and neoplasms typically promote the proliferation of new blood vessels that support their growth. References: Wagner EK, Hewlett MJ, Bloom, DC, Camerini D. 2008. Basic Virology 3rd ed. USA (MA): Blackwell Publishing https://www.wiley.com/en- us/Basic+Virology%2C+3rd+Editio n-p-9781405147156 (available in pdf file)