Basic Medical Science 1 PDF

Heme/Onc/ID Basic Medical Science I Cathleen J. Ciesielski, Ph.D.  Objectives BMS 1.17 The student will characterize the difference between innate and acquired immunity. BMS 1.24 The student will define and differentiate the following bacterial based on n...

Heme/Onc/ID Basic Medical Science I Cathleen J. Ciesielski, Ph.D.  Objectives BMS 1.17 The student will characterize the difference between innate and acquired immunity. BMS 1.24 The student will define and differentiate the following bacterial based on normal physiology, etiology, and pathophysiology (changes to normal pathology). Gram positive bacteria Gram negative bacteria Spirochetes Atypical bacteria BMS 1.25 The student will define and differentiate the following mycobacterial based on normal physiology, etiology, and pathophysiology (changes to normal pathology). Tuberculosis Atypical mycobacterial disease BMS 1.26 The student will describe the taxonomy of pathogenic human viruses based on viral structure: Identify and characterize the stages of viral infection, viral gene expression, viral replication, and cytopathic effect at the cellular level Describe the biology of the human immunodeficiency [retro] virus (HIV) molecular structure and replicative cycle and the epidemiology, pathogenesis, and transmission  Objectives BMS 1.26 The student will define and differentiate the following fungi based on normal physiology, etiology, and pathophysiology (changes to normal pathology). Superficial mycoses Subcutaneous mycosis Systemic mycosis BMS 1.28 The student will define and differentiate the following parasite (and disease state) based on normal physiology, etiology, and pathophysiology (changes to normal pathology). Protozoa Helminthic Immunity  The Body’s Defenses ▪ Innate Defenses = non-specific defenses ability to resist damaging organisms and toxins barriers (skin/gastric acid) cells (neutrophils & macrophages) chemicals (lysozyme, complement) processes (fever, phagocytosis, inflammation) ▪ Acquired or Adaptive Defenses = specific immunity B cell: humoral or antibody-mediated immunity ----> comes from activated B cells T cell: cellular or cell-mediated immunity ----> comes from activated T cells BMS 1.17  B-Cells First made in liver during mid fetal life Red bone marrow takes over production late fetal life and after birth Activated B lymphocyte (plasma cell) produce antibodies best at fighting bacteria and/or toxin bacteria produce can help identify viral antigens extracellularly or when on the surface of an infected cell the antibodies combine with and destroy foreign antigens (microbes) BMS 1.17 T- Cells T Lymphocytes start in the red bone marrow but must move to the thymus to mature will become CD4+ or CD8+ T-lymphocyte before leaving the thymus cells divide rapidly extreme diversity; each lymphocyte will react to only one antigen thousands of antigens can potentially be recognized CD8+ T cells best at fighting intracellular microbes BMS 1.17  T- Cells Surface cell receptor proteins (T-cell markers): react with specific antigens Activation causes clonal proliferation (replication) some lymphocytes remain in the tissues T-lymphocyte will create a memory cells BMS 1.17 T-Cell activation ▪ T cells MUST interact with another cell in body (cell- mediated immunity) T cells only recognize a foreign antigen when that foreign is presented on surface of target cell ▪ An activated T cell can produce cytotoxic cytokines or use cytokines to signal other cell to the area  Lymphocytes: Review 20–30% of circulating WBCs Migrate in and out of blood Before activation, are small cells with a spherical nuclei taking up a majority of the cell Most are located in lymphatic organs & tissue Most are Specific Defenses (adaptive/acquired immunity) T Cells function in cell mediated immunity attack foreign cells directly endogenous antigen B Cells function in antibody medicated or humoral immunity differentiate into Plasma cells (activated B cells) & secrete antibodies Natural Killer Cells (most group into innate or non-specific immunity) secrete cytotoxic cytokines to destroy abnormal tissue BMS 1.17  B-Cells A mature B cell has the markers CD19 & CD20 B lymphocytes once activated (called Plasma cells) secrete antibodies (or immunoglobins) the antibodies combine with and destroy foreign antigens (microbes) An antibody is first a B-cell receptor (BCR) attached on the surface of a B cell once the antibody is needed, the BCR is cleaved from the surface of the B- cell and now it is an antibody the now active Plasma cell will produce more of this same antibody BCR can directly interact with microbe, toxins from a microbe or can receive help for CD4 cells BMS 1.17 Plasma Cells Activated B lymphocytes enlarge 1. Plasmablasts – Form plasma cells – Proliferate – 500+ cells per precursor produced during an infection – Gamma globulin antibodies are made at 2000/sec 2. Lymphoblasts – Form new B lymphocytes – Produce a memory cells – first exposure takes more time – weeks or months between immunizations Dormant until needed (repeat of same infection) Cell response rapidly once activated & more potent response on re-exposure BMS 1.17  Overview of Antibody Production Antigen presented to T cell and processed. Presented to B cell B cell produces specific antibody (immunoglobulins [Ig], gamma globulin) IgM, IgG, IgA, IgE, IgD Antibody attaches to specific antigen BMS 1.17  Basic Structure of Immunoglobulins An antibody contains both a heavy chain & light chain organized into: Fab (variable region) the “Y” end of the Fab contains antigen binding site Fc (constant region) is the region that determine biological properties of the immunoglobulin (Ig). BMS 1.17 Direct Action of Antibodies (how antibodies eliminate the foreign antigen) ▪ Neutralization – antibodies cover toxic site of antigenic agent (bind & inactivate) ▪ Agglutination – multiple particles with antigens are bound together into a clump ▪ Precipitation – soluble antigen and antibody form a large complex that is insoluble – tetanus toxin ▪ Complement – antibodies bind to membranes of invading agents to cause cell rupture ▪ Opsonization – facilitate phagocytosis of foreign substances BMS 1.17  The Complement System The complement system or complement cascade (C1-C9) activated by microbes and works to enhance parts of the immune system. Most complement proteins are produced in the liver and present in the plasma. Three primary functions: Lysis of antibody coated cells, such as bacteria and RBCs through a series of proteins which creates pores in the cell membrane Mediation of opsonization, preparation of foreign cells for phagocytosis. Generation of peptide fragments that regulate features of the inflammatory response. BMS 1.17  The Complement System promote inflammation promote inflammation MAC complex = activation unit MAC complex = attack phase BMS 1.17 Complement Pathway ▪ Membrane lesions = MAC complex MAC complex ▪ Opsonization (tag for phagocytosis) BMS 1.17  Antibodies IgM ▪ First antibody produced the first time a B cell is activated (important in primary immune response) ▪ 5-15% total of antibodies produced ▪ Does bind complement BMS 1.17  Antibodies IgG ▪ 75% total of antibodies produced ▪ Can cross the placenta (major line of defense for the first few weeks of baby’s life) ▪ Responds to bacteria, viruses & RBC ▪ Predominant in the secondary immune response IgM is converted to IgG to become a better antibody ▪ Does bind complement ▪ Four subclasses (IgG1, IgG2, IgG3 and IgG4) BMS 1.17 Antibodies IgA ▪ Found in body exocrine fluid (tears, saliva, colostrum breast milk, nasal, bronchial & intestinal secretions) ▪ Important role in protection of respiratory, urinary tract & bowel infection ▪ Does not bind complement BMS 1.17 Antibodies IgE ▪ Trace levels (o.oo4%); except with invading parasite ▪ Does not fix complement ▪ Allergic reactions, histamine release Fc region binds strongly to a receptor on mast cells & basophils = release of histamine IgD ▪ Less than 1% ▪ Does not fix complement ▪ Primarily a cell bound immunoglobulin found on the surface of B cells ▪ Little is known, may help CD4 Th BMS 1.17 **Immune Response** IgM IgG BMS 1.17  MHC on the Surface of All Cells Major Histocompatibility complex (MHC) tissue antigen ▪ Several genes produce MHC proteins ▪ MHC proteins are found on the surface of cells, variation of MHC is determined by your genetic ▪ The function of MHC: bind fragments of pathogens and display these fragments on the surface of cells T cells will not activate without MHC: T cell receptors and MHC on a different cell must interact important so our T cells tolerate “self” ▪ Human leukocyte antigen (HLA) is the MHC in humans ▪ MHC class I is present on all nucleated cells ▪ MHC class II is present on antigen presenting cells (APCs) such as dendritic cells, macrophages & some B cells BMS 1.17  T-Cell & MHC ▪ MHC class I: presents foreign peptides to cytotoxic T cells ▪ MHC class II: presents foreign peptides to helper T cells ▪ Cytotoxic T Cells (CD8): kill infected cells by secreting toxic cytokines ▪ Helper Cells (CD4): ▪ secrete cytokines that can activate macrophages, CD8 cells & B-cells ▪ Suppressor T Cells: regulate activity BMS 1.17 T Lymphocyte Activation ▪ Antigen Presenting cells (macrophages, dendritic cells) in lymphoid organs ingest antigen and present antigenic peptides to helper T cells secrete IL-1, other cytokines that promote lymphocyte growth and differentiation ▪ Helper T cells produce additional cytokines that stimulate B and T cell proliferation and differentiation ▪ Both B and T cells require antigenic stimulation to proliferate BMS 1.17 T Helper Cells (CD4+) ▪ ∼70% of T cells ▪ Destroyed by AIDS virus ▪ Lymphokines of helper T cells IL2 o proliferation of cytotoxic and suppressor T cells o positive feedback to activate helper T cells IL3 IL4, IL5, IL6 – B-cell growth factors GM-CSF Interferon-γ BMS 1.17  Cytotoxic T Cells (CD8+) Killer cells – direct attack on micro- organisms Figure 1. Secretion of perforins – cell membrane 2. Fluid flows into the cell 3. Cytotoxic substances injected into the cell 4. Killer cell pulls away from its victim Kill tissue cells invaded by viruses Kill cancer cells Heart transplant cells BMS 1.17  Suppressor T Cells ▪ CD25+ ▪ Prevent over-reaction of the system ▪ Help protect against autoimmune response ▪ Inhibit B-lymphocyte production ▪ Mediation of dominant immunologic tolerance ▪ T cell–mediated suppression might be responsible for the low level of chronic infection seen with many pathogens BMS 1.17 Chasing down antigens  Monocyte-Macrophage Cell System ▪ Macrophages participate in phagocytosis, inflammation, and cellular immunity. ▪ Macrophages are mainly involved in nonspecific immunity and include the phagocytic cells: mononuclear phagocytes polymorphonuclear phagocytes (neutrophils) and eosinophils, basophils & mast cells BMS 1.17  Monocyte-Macrophage Cell System Derived from stem cell in the bone marrow. Monocytes circulate to sites of inflammation or migrate to various tissues. Macrophages have cell surface receptors, one of them being a receptor for the Fc portion of the immunoglobulin molecule. Tissue macrophages possess a receptor for the complement component C3b (& C5b) = opsonization  Reticuloendothelial System Monocyte-macrophage system Cells of the immune system are found within the blood, body tissues, thymus, spleen, liver, lymph nodes and body areas exposed to the external environment. These organs comprise the reticuloendothelial system (RES) Components monocytes, fixed tissue macrophages or mobile macrophages specialized endothelial cells  Types of Inflammation ▪ Acute inflammation: Short duration Edema ▪ Chronic inflammation: Mainly neutrophils Longer duration Lymphocytes & ▪ Granulomatous inflammation: macrophages Distinctive pattern of chronic predominate inflammation Fibrosis Activated macrophages New blood vessels predominate (angiogenesis) +/- Multinucleated giant cells BMS 1.17  Inflammation: Constitutive Defense of the Body ▪ Non-specific response to crossing the 1 st line of defense ▪ Signs: heat (calor), erythema (rubor), pain (dolor) & swelling (tumor) ▪ Typical localized response ▪ Activates: Complement system Chemical mediators: histamine, bradykinin Pro-inflammatory cytokines: TNF, IL-1, IL-6, IL-8 BMS 1.17  Inflammation: Constitutive Defense of the Body BMS 1.17  Inflammation: Constitutive Defense of the Body 1. Vasodilation 2. Increased capillary permeability 3. Clotting of interstitial fluid 4. Monocyte and granulocyte migration into the tissue 5. Swelling of tissue cells ▪ Substances involved: bradykinin, histamine, serotonin, prostaglandins complement, coagulation factors, lymphokines ▪ “Walling off” effect of inflammation fibrinogen clots – block lymphatic system bacterial toxins increase the intensity of the response BMS 1.17  Inflammation: Constitutive Defense of the Body  Inflammatory Response 1. Macrophages mobile macrophages not a large number of cells – already in the tissues 2. Neutrophils Margination – diapedesis – chemotaxis – within the first hour Neutrophilia → 4000 to 5000 cells become 15,000+ cells → released from bone marrow in 4 to 5 hours 3. Monocyte invasion → macrophages → develop lysosomes 8 hours or more 4. Bone marrow produces granulocytes and monocytes within 3 to 4 days BMS 1.17  Basophils: Medical Application (Review) Immediate Hypersensitivity (Type I) Mast cell degranulation through allergen-specific IgE Reactions take place in minutes sneezing, runny nose, itching eyes, itching throat Anaphylaxis or Anaphylactic shock (Systemic Type I): Life Threatening BMS 1.17  Hypersensitivity Reaction “ACID” Allergic -anaphylaxis -urticaria Cytotoxic Delayed Immune complex --urticaria Delayed -dermatitis -Types I, II & III can be classified as ‘immediate’ reactions, meaning they can take place within 24hrs BMS 1.17  Hypersensitivity Reaction ▪ Type I (IgE-mediated) hypersensitivity mediated by IgE antibodies binding to mast cell/basophils minutes to 30 minutes to activation (under 24hrs) systemic hypersensitivity may only take minutes ▪ *Type II (cytotoxic, antibody-mediated) hypersensitivity mediated by IgG or IgM complement & cell lysis o other immune cells can become involved minutes to hours to activation, typically 2-24hrs to develop thrombocytopenia, neutropenia, autoimmune hemolytic anemia, ITP transfusion mismatch reaction, penicillin ▪ Type III (immune complex mediated) hypersensitivity antigen-antibody complex, activation of complement especially for recruiting inflammatory cells 3-6hrs to activation upon re-exposure (under 24hrs); takes 4-10 days to create the antibodies initially ▪ Type IV (delayed, cell-mediated) hypersensitivity T cell orchestrated (not-antibody mediated) could take up to a week (more common 48-72hrs but more than 12hrs after exposures)  Immunization Active immunity via different vaccine platforms ▪ Inactivated/dead organisms destroys pathogens ability to replicate) polio, hepatitis A, rabies ▪ Toxoids denatured/inactivated toxin) tetanus, diphtheria ▪ Subunit/conjugate or recombinant only a segment of the pathogen hepatitis B, influenza (injection), pertussis, pneumococcal, human papilloma virus (HPV), zoster ▪ mRNA technology around for decades mRNA makes a protein/antigen & the immune system responds to that protein/antigen mRNA cannot enter the nucleus thus cannot alter DNA for COVID-19: preferred during pandemic because of short manufacturing times and low cost *all platforms were/are being attempted ▪ Live attenuated unable to replicate enough to cause illness MMR, varicella, influenza (nasal spray), yellow fever Infections  INFECTION & INFECTIOUS PROCESS Infection is the lodgment & multiplication of organism in the tissue of host 1. Characteristics 2. Pathogenicity 3. Virulence  CHARACTERISTICS OF INFECTION ▪ Pathogen should be able to enter the body. ▪ Pathogen should be able to multiply in the tissue. ▪ Pathogen should be able to damage the tissue. ▪ Pathogen must be capable to resist the host defense.  PATHOGENICITY & VIRULENCE ▪ Pathogenicity is referred to the ability of microbial species to produce disease. ▪ Virulence is referred to the ability of microbial strains to produce disease.  FACTORS OF VIRULENCE The molecules produced by the pathogen that add to their effectiveness and enable them to evade, colonize & attach to the host ▪ Adhesion ▪ Invasiveness ▪ Toxigenicity: exotoxins & endotoxins ▪ Communicability: ability to spread from one host to another ▪ Coagulase: develop fibrin barrier to prevent phagocytosis ▪ Fibrinolysin: break through tissue barriers to promote spread of infection  INFECTIOUS DISEASES: CATEGORIZATION ▪ Bacterial Diseases – includes disease due to gram positive, gram negative, spirochetal, atypical and mycobacterial organisms ▪ Viral Diseases – includes infections due to DNA, RNA and retroviral agents ▪ Fungal Diseases – includes superficial and systemic mycoses and candida ▪ Parasitic Diseases – includes protozoal and helminthic infections BMS 1.24 Infectious Diseases: Five Kingdoms Animals Fungi Plants Protista BMS 1.24  Microbes Resident Flora Pathogens ▪ Microbes that live in or on ▪ Disease producing the body in non-sterile areas without causing microbes infection. Must be able to bind skin, mucous to specific receptors membrane, bowel, on human host cell(s) rectum, vagina ▪ Many are protective Direct destruction ▪ Delicate balance Interfere with metabolic function Toxins BMS 1.24  Microbes Bacteria ▪ Single-celled microorganism ▪ Aerobic, anaerobic, or both ▪ Highly adaptable ▪ Cocci, bacilli, or spirochetes BMS 1.24  Bacteria structure Structure ▪ Indiscreet nucleus ▪ Cytoplasm-Cytosol ▪ Cell Envelope/Cell Wall Barrier Protein and DNA synthesis Cell Division BMS 1.24 Bacteria shapes BMS 1.24  Aerobic Bacteria Aerobic – grow where oxygen is present ▪ Obligates – REQUIRE oxygen to thrive ▪ Same examples (know specific examples when also covered in Med Practice) Gram positive = Nocardia, Bacillus Gram negative = Pseudomonas aeruginosa Acid fast = Mycobacterium tuberculosis ▪ Facultative/Microaerophile ▪ Same examples (know specific examples when also covered in Med Practice) Gram positive = Staphyliococci, Corynebacterium, Listeria Gram negative = E. Coli Also yeasts BMS 1.24  Anaerobic Bacteria Anaerobic – grow where oxygen is not present ▪ Bacteria found in GI tract ▪ Infections include intra-abdominal, soft tissue and abscesses, wound, aspiration pneumonia ▪ Same examples (know specific examples when also covered in Med Practice) example of gram negative - Bacteroides, Fusobacterium example of gram positive – Clostridia BMS 1.24  Functions of the Bacteria Cell Wall ▪ Maintaining the cell's characteristic shape- the Functions of rigid wall compensates for the flexibility of the the cytoplasmic membrane phospholipid membrane and keeps the cell from assuming a spherical shape ▪ Countering the effects of osmotic pressure ▪ Providing attachment sites for bacteriophages ▪ Providing a rigid platform for surface appendages- flagella, fimbriae, and pili all emanate from the wall and extend beyond it ▪ Play an essential role in cell division ▪ Be the sites of major antigenic determinants of the cell surface ▪ Resistance of Antibiotics BMS 1.24  Bacteria CELL WALL Gram positive cell wall Gram negative cell wall ▪ Consists of ▪ Consists of a thick, homogenous an outer membrane sheath of peptidoglycan 20- containing 80 nm thick lipopolysaccharide (LPS) tightly bound acidic thin shell of peptidoglycan polysaccharides, including periplasmic space teichoic acid and lipoteichoic acid inner membrane cell membrane ▪ Retain crystal violet and stain ▪ Lose crystal violet and stain purple pink from safranin counterstain BMS 1.24 GRAM REACTION: CELL WALL TYPE -thicker -thinner -more permeable -less permeable In addition to peptidoglycan, gram-negative Bacteria contain an outer membrane consisting of lipopolysaccharide (LPS), protein and lipoprotein. BMS 1.24  Gram-Positive Cell Wall ▪ Thick, homogeneous sheath of peptidoglycan Number of layers: one Thickness: 20-80nm (thicker) Outer Membrane: No Periplasmic space (space between the cell membrane & wall): narrow Permeability to Molecules: more permeable Includes teichoic acid and lipoteichoic acid: function in cell wall maintenance and enlargement during cell division; move cations across the cell envelope; stimulate a specific immune response Some cells have a periplasmic space, between the cell membrane and cell wall BMS 1.24  Gram-Negative Cell Wall ▪ Number of layers: two ▪ Thickness: 8-11nm (thinner) ▪ Outer Membrane: Yes ▪ Periplasmic space (space between the cell membrane & wall): extensive ▪ Permeability to Molecules: less permeable ▪ Composed of an outer membrane and a thin peptidoglycan layer ▪ Outer membrane is similar to cell membrane bilayer structure Outermost layer contains lipopolysaccharides and lipoproteins (LPS) Lipid portion (endotoxin) may become toxic when released during infections May function as receptors and blocking immune response Contain porin proteins in upper layer – regulate molecules entering and leaving cell ▪ Bottom layer is a thin sheet of peptidoglycan Periplasmic space above and below peptidoglycan Resistance of Antibiotics: Site for enzymes- β-lactamases, that degrade penicillins & other β-lactam drugs. BMS 1.24  LPS Lipid A of lipopolysaccharide (LPS) is responsible for endotoxin activity Pathogenesis of sepsis (septicemia) BMS 1.24  The Gram Stain ▪ Differential stain that distinguishes cells with a gram-positive cell wall from those with a gram-negative cell wall Gram-positive - retain crystal violet and stain purple Gram-negative - lose crystal violet and stain red from safranin counterstain ▪ Important basis of bacterial classification and identification ▪ Practical aid in diagnosing infection and guiding drug treatment BMS 1.24 GRAM REACTION: CELL WALL TYPE Take up crystal violet stain = blue/violet colour Do NOT take up crystal violet stain = red/pink colour BMS 1.24 Gram Positive Bacteria BMS 1.24 CLOSTRIDIAL DISEASES BMS 1.24  CLOSTRIDIAL DISEASES Botulism ▪ Clostridium botulinum ▪ obligate anaerobic, rod-shaped, gram positive ▪ produces a neurotoxic protein requires zinc ▪ Pathophysiology: blocks the release of the neurotransmitter ACh from the motor neuron skeletal muscle cannot contract without the release of ACh BMS 1.24  CLOSTRIDIAL DISEASES Tetanus Clostridium tetani obligate anaerobic, gram positive Entry: wound, moves through circulation Rigid paralysis, lock jaw Require Zn Neurotoxin: splits carboxy terminal to gangliosides on neuronal membranes. Moves to CNS Interfere with normal inhibitory function = painful muscle spasms Different binding regions than botulinum BMS 1.24 Gram Positive Bacteria vs BMS 1.24  Catalase ▪ Enzyme found on nearly all living organisms exposed to oxygen ▪ Catalase positive catalase enzyme used by bacteria that respire using oxygen enzyme protects them from toxic by-products of oxygen metabolism BMS 1.24  Pathogenicity: Staphylococcus ▪ “Staph” infections result when staphylococci break through the body’s physical barriers ▪ Gram-positive cocci in clusters ▪ Low “Infectious Dose”: Entry of only a few hundred bacteria can result in disease ▪ Virulence Factors: Pathogenicity results from three generalized virulence factors 1. Evades phagocytosis by capsule production (capsule inhibiting phagocytosis) 2. Produces enzymes: surface proteins that promote colonization of host tissues 3. Produces exotoxins: toxins that damage host tissues BMS 1.24  Staphylococcus species ▪ Two species are commonly associated with staphylococcal diseases in humans 1. Staphylococcus aureus More virulent strain Some people are “carriers” in nose and on skin 2. Staphylococcus epidermidis Normal microbiota of human skin Coagulase-negative: normally less virulent Can cause opportunistic infections BMS 1.24  Streptococci ▪ Normal flora ▪ Gram-positive cocci, occur in pairs or chains ▪ Non-motile ▪ Virulence factors lipoteichoic acid for attachment hyaluronic acid capsule that inhibits phagocytosis ▪ Catalase negative Facultative anaerobe (only ferment & do not respire using oxygen) or anaerobes BMS 1.24 Streptococci BMS 1.24  Gram Positive Bacteria complete clearing partial hemolysis no hemolysis Streptococci – facultative anaerobe – Gram-positive – usually chains (sometimes pairs) – catalase negative (staphylococci are catalase positive) BMS 1.24  Lancefield Groups Membrane Antigen Group D Group A Strep pyogenes E. faecalis Group B Strep bovis Strep agalactiae Strep equines Group C, G Viridans Strep equisimilis Strep mutans Strep Strep mitis zooepidemicus Strep sanguis Strep anguinosus Pneumococci A, B and D: frequent C, G, F: less frequent BMS 1.24  Gram Negative Bacteria Rickettsia rickettisii BMS 1.24  Rickettsia rickettisii ▪ Rickettsia rickettisii (RMSF) Very tiny, non-motile, weak gram-negative bacteria (need special stain) Obligate intracellular pathogens Cannot survive or multiply outside of a host cell Cannot carry out metabolism on their own Transmitted via bite: wood tick Rickettsia rickettisii – Rocky Mountain spotted fever Rickettsia typhi – endemic typhus BMS 1.24  RMSF: Pathophysiology ▪ R. rickettsia organisms inoculated into the dermis after 6-10 hrs Spread lymphohematogenously ▪ Leads to inflammation/edema increased vascular permeability loss of barrier function consumption of platelets (thrombocytopenia) BMS 1.24  Spirochetes: Treponema, Borrelia and Leptospira ▪ Elongate, motile, flexible SPIRAL-shaped bacteria ▪ Spirochetes not classified as either gram+ or gram- exception: Borrelia burgdoferi cell wall may stain weakly for gram- negative ▪ Genus: Treponema pallidum causes syphilis disease of blood vessels leads to diffuse (multiple) organ chronic inflammation Borrelia burgdoferi (most common) causing Lyme disease Leptospira causing Leptospirosis (Weil’s Disease) BMS 1.24  Lyme Disease: Pathophysiology ▪ Borrelia burgdorferi = most common in the US ▪ Transmitted via tick saliva when bitten (vector-borne disease; deer tick) ▪ B. burgdorferi tightly controls protein expression to minimize antigenic targets for immune recognition – evades early host immunity ▪ B. burgdorferi do not produce toxins, secreted proteases, or other destructive models ▪ Symptoms are secondary to the elicited host immune response Spread via lymphatics and/or blood to organs BMS 1.24  Nontypical Bacteria Cell Walls ▪ “Fungus-like bacteria” ▪ Hydrophobic ▪ Some bacterial groups lack typical cell wall ▪ Fungus-like pellicles structure, i.e., Mycobacterium and Nocardia ▪ Fungal properties can Gram-positive cell wall structure with lipid make them difficult to mycolic acid (cord factor) treat Mycoplasma pneumoniae Pathogenicity and high degree of resistance to certain chemicals and dyes Basis for acid-fast stain used for diagnosis of infections caused by these microorganisms BMS 1.24  Acid fast: Mycobacteria ▪ Aerobic ▪ Typically non-motile, rod-shaped ▪ Slow grower ▪ Have an outer membrane but not a cell wall ▪ Contains gram-positive rods ▪ Do not have capsules ▪ Adapt to grow on simple substrates ▪ Difficult to treat Mycobacterium tuberculosis ▪ It is a causative agent for human tuberculosis ▪ Leprosy is also the result of a myobacterium BMS 1.25  Acid fast: Mycobacteria Aerobic – grow where oxygen is present ▪ Obligates – REQUIRE oxygen to thrive Gram positive = Nocardia, Bacillus Gram negative = Pseudomonas aeruginosa Acid fast = Mycobacterium tuberculosis ▪ Facultative/Microaerophile Gram positive = Staphyliococci, Corynebacterium, Listeria Gram negative = E. Coli Also yeasts BMS 1.25  Mycobacteria: Mycobacterium tuberculosis Caused by Mycobacterium tuberculosis ▪ Inhaled aerosol droplets ▪ Can infect (disseminate) many different body locations such as: 1. Meninges 2. Brain 3. Bone 4. Kidney 5. Essentially any organ (lung primary target) BMS 1.25 Primary Tuberculosis (TB) in summary ▪ The organisms are transmitted among human via aerosol. ▪ TB bacilli lodge in the alveoli or lung alveolar ducts and most of bacilli are phagocytosed by alveolar macrophages. ▪ Macrophages migrate to the lymph node and generate T cell-mediated immune response. BMS 1.25  Atypical Mycobacteria: Pathophysiology ▪ Initially phagocytosed by macrophages ▪ Macrophages produce IL-12 which up-regulates IFN ▪ IFN (interferon) activates neutrophils and macrophages ▪ Neutrophils and macrophages destroy pathogen BMS 1.25  Mycobacteria: Mycobacterium leprosy Leprosy: disfiguring skin sores; nerve damage to extremities Caused by Mycobacterium leprae ▪ Multiples slowly, incubation period on average of 5yrs ▪ Transmitted via droplets from nose/mouth with untreated individual i.e infectious ▪ Can infect skin, eyes, peripheral nerves, mucosa of upper respiratory tract BMS 1.25  INFECTIOUS DISEASES: CATEGORIZATION ▪ Bacterial Diseases – includes disease due to gram positive, gram negative, spirochetal, atypical and mycobacterial organisms ▪ Viral Diseases – includes infections due to DNA, RNA and retroviral agents ▪ Fungal Diseases – includes superficial and systemic mycoses and candida ▪ Parasitic Diseases – includes protozoal and helminthic infections BMS 1.26  Overview: Chapter 6 Sherris Microbiology ▪ Viruses are the smallest form of replicating intracellular microorganisms that are comprised of sets of genes either DNA (DNA viruses) or RNA (RNA viruses) packaged in a protein coat, capsid (naked capsid viruses) or in a nucleocapsid/capsid, and an outer lipid bilayer envelope (enveloped viruses). ▪ Viruses have spikes on their outer surface that bind to the receptors on host cells and antibodies generated against the spikes neutralize the virus. ▪ Viruses are dependent upon host structural components and metabolic functions. ▪ DNA viruses replicate in the nucleus by using host RNA polymerase for transcription and either host or viral DNA polymerase for replication (exception are poxviruses that replicate in the cytoplasm). ▪ RNA viruses replicate in the cytoplasm using its own viral RNA-dependent RNA polymerase for both transcription and replication (exception are influenza viruses and retroviruses that replicate in the nucleus). ▪ Naked capsid viruses are assembled inside the cell and released upon cell death, whereas enveloped viruses acquire lipid bilayer membrane mainly from plasma membrane and in some cases from nuclear or cytoplasmic membranes.  Overview: Chapter 6 Sherris Microbiology ▪ Viral-infected cells may result in cell death and tissue damage (pathology) generally seen in acute infections ▪ A viral infection can persist in hosts (humans) causing a chronic or latent infection with little or no pathologic changes in target cells or tissues. ▪ Since most viruses use their own enzymes (RNA or DNA polymerases) which could be a target for antivirals, they are prone to genetic changes due to lack of proofreading ability of these enzymes. ▪ The major genetic changes that viruses undergo are mutation and recombination that allow viruses to escape the immune response and cause damage or persist in the host. ▪ During viral latency, viral genome persists in host and may not be eliminated by antiviral drugs. ▪ It is difficult to develop strategies to eliminate latent viral infections by antiviral drugs.  Viruses ▪ Interrupt host cellular activity (infect healthy cells) ▪ May result in destruction of host cell or modification of certain host cell functions, and release of particles outside the cell called virions virion causes viral spread ▪ Difficult to treat. May elicit dramatic immune response which limits and eradicates the infection. ▪ Can exhibit latency or minimal initial immune response, resulting in chronic recurring illness Virus is integrating itself into the host cell genetic material ▪ Does not respond to Antibiotics BMS 1.26  Viruses Definition of Viruses: ▪ Smallest infectious particle ▪ Obligate intracellular parasite Viruses cannot make energy or proteins independent of a host cell Characters of Viruses ▪ Size ▪ Shape ▪ Structure capsid envelope nucleic Acid BMS 1.26  Viruses: Shapes Shapes: ▪ Spherical/Icosahedral Viruses equilateral triangles fused together in a spherical shape ▪ Helical Viruses protein subunits & nucleic acid arranged in a corkscrew ▪ Polyhedral Viruses protein subunits assemble into a symmetric shell that covers the nucleic acid-containing core ▪ Complex Viruses often consist of both helical & polyhedral parts confined to different structural components BMS 1.26  Viruses ▪ Nucleic acid surrounded by one or more proteins ▪ Viruses may have an outer membrane envelope ▪ Encode proteins for replication (rest of material needed for replication is found within host cell) Viruses do not have the genetic capability to multiply by division Viruses must be infectious to endure in nature; viruses are non-living entities ▪ Structure: Genomes have one of the following: DNA or RNA but not both Single-strand (ss) or double-strand (ds) DNA Single-strand sense (positive-strand) RNA Single-strand or segmented antisense (negative-strand) RNA Double-strand segmented RNA genome BMS 1.26  Components of a Virus Viral Component Role in Viral Life Cycle Example Nucleic acid Encodes all the information necessary to DNA or RNA produce new progeny virions Red strings Capsid Protein “shell” that contains/packages viral Icosahedral, helical, or (rarely) nucleic acid, protecting it between infections; complex Small inner green and may contain VAP blue spheres Structural Proteins which form the capsid, package the Matrix, nucleocapsid, VP1-VP4 proteins genome, and/or are attachment proteins (reovirus), hexon and fiber Capsid + outer green (adenovirus), gp41/120 (HIV), stalks and large blue HA (influenza), F (measles) spheres Non-structural Proteins which are required for replication, for Polymerase, helicase, protease proteins assembly, or which facilitate disease (flu N), transcription factors, progression immunomodulatory factors Black beads Envelope Lipid bilayer which is an anchoring surface for viral attachment proteins, facilitates Orange coat penetration of the host cell membrane BMS 1.26 Viral Life Cycle BMS 1.26  Viral Life Cycle/Replication Sherris & Ryan Chapter 6 Khan Academy video: Viral Replication Citation: Chapter 6 Viruses—Basic Concepts, Ryan KJ. Sherris & Ryan's Medical Microbiology, 8th Edition; 2022. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3107&sectionid=260922934 Accessed: January 15, 2024 Copyright © 2024 McGraw-Hill Education. All rights reserved BMS 1.26 Properties of Naked (non-enveloped) Viruses: Pathogenesis ▪ Stable in hostile environment ▪ Not damaged by drying, acid, detergent & heat (typically damage envelope) ▪ Released by lysis of host cells ▪ Can sustain in dry environment ▪ Can infect the GI tract and survive the acid and bile ▪ Can spread easily via hands, dust, fomites, etc. ▪ Can stay dry and still retain infectivity ▪ Neutralizing mucosal and systemic antibodies are needed to control the establishment of infection BMS 1.26  Viral Infection Stages of infection: ▪ Attachment to cell surface Cells without the appropriate receptors are not susceptible to the virus. ▪ Penetration of cell membrane – either fusion or endocytosis Virons are either engulfed into vacuoles by “endocytosis” or the virus envelope fuses with the plasma membrane to facilitate entry Entry by fusing with the plasma membrane. Some enveloped viruses fuse directly with the plasma membrane. Thus, the internal components of the viron are immediately delivered to the cytoplasm of the cell ▪ Release of viral nucleoprotein into cell cytoplasm ▪ Viral genome is copied and reproduced. Viral proteins are made by the host cell, and a new virus forms BMS 1.26  Course of Viral Infection ▪ Primary Replication The place of primary replication is where the virus replicates after gaining initial entry into the host. This frequently determines whether the infection will be localized at the site of entry or spread to become a systemic infection. ▪ Systemic Spread Apart from direct cell-to-cell contact, the virus may spread via the blood stream and the CNS. ▪ Secondary Replication Secondary replication takes place at susceptible organs/tissues following systemic spread. BMS 1.26  Routes of Viral Entry ▪ Skin: Most viruses which infect via the skin require a breach in the physical integrity of this effective barrier, e.g. cuts or abrasions. Many viruses employ vectors, e.g. ticks, mosquitos or vampire bats to breach the barrier. ▪ Conjunctiva and other mucous membranes: Rather exposed site and relatively unprotected (easy target for entry) ▪ Respiratory tract: In contrast to skin, the respiratory tract and all other mucosal surfaces possess sophisticated immune defense mechanisms, as well as non-specific inhibitory mechanisms (cilliated epithelium, mucus secretion, lower temperature) which viruses must overcome. ▪ Gastrointestinal tract: A hostile environment; gastric acid, bile salts, etc. Viruses that spread by the GI tract must be adapted to this hostile environment. ▪ Genitourinary tract: Relatively less hostile than the above, but less frequently exposed to extraneous viruses. BMS 1.26  Classification of DNA Viruses STUDY AID! DNA viruses are HHAPPPPY! H = Hepadnaviridae H = Herpesviridae A = Adenoviridae P = Parvoviridae P = Poxviridae P = Papillomaviridae Py = Polyomaviridae STUDY AID! All DNA viruses have double-stranded genomes EXCEPT Parvoviridae. In “genome-speak”, ds = double-stranded and ss = single-stranded. http://pathmicro.med.sc.edu/mhunt/intro-vir.htm BMS 1.26  Herpesvirdae Family: dsDNA viruses Herpesviruses: ▪ More than 100 know herpesviruses ▪ Eight routinely infect only humans: Five discussed in this lecture (HHV 1-5) ▪ All can establish latent infections within specific tissues (characteristic for each virus) ▪ Double-stranded DNA genome ▪ Icosahedral outer shell BMS 1.26  Human Herpesvirdae Family: HHV HHV-1 Herpes Simplex Type 1 HSV-1 HHV-2 Herpes Simplex Type 2 HSV-2 HHV-3 Varicella-Zoster Virus VZV HHV-4 Epstein-Barr Virus EBV HHV-5 Cytomegalo Virus CMV HHV-6 Roseola HHV-7 Can also cause Roseola HHV-8 Kaposi Sarcoma-associated Herpes Virus KSV  HHV-1 or Herpes Simplex Virus 1 (HSV-1) HHV-1 or Herpes Simplex Type 1 (HSV-1): ▪ Herpesvirdae family ▪ Enveloped, double-stranded DNA virus ▪ Icosahedral outer shell ▪ Herpes labialis or ‘cold sores’ primary infection of epithelial cells ▪ Recurrent infection: virus lives in a latent state in ganglion neurons (moves from epithelial cells to sensory nerves) o can reactivate to cause acute disease BMS 1.26  HHV-2 or Herpes Simplex Virus 2 (HSV-2) HHV-2 or Herpes Simplex Type 2 (HSV-2): ▪ Herpesvirdae family ▪ Enveloped, double-stranded DNA virus ▪ Icosahedral outer shell ▪ Genital herpes ▪ Primary infection: infection of epithelial cells in patient without any pre-existing antibodies Recurrent infection: re-activation of genital HSV with existing antibodies of corresponding infection BMS 1.26  HHV-3 or Varicella-Zoster virus (VZV) HHV-3 or Varicella-Zoster (VZV): ▪ Herpesvirdae family ▪ Enveloped, double-stranded DNA virus ▪ Icosahedral outer shell ▪ Primary infection (Varicella): chickenpox replicates in the nasopharynx, latency established in dorsal root ganglia highly contagious ▪ Secondary infection after true latency (Zoster): Shingles reactivation of latent VZV infection within a sensory ganglia (travels down sensory nerves from dorsal root ganglia) BMS 1.26  HHV-4 or Epstein-Barr virus (EBV) HHV-4 or Epstein-Barr virus (EBV) ▪ Herpesvirdae family ▪ Enveloped, double-stranded DNA virus ▪ Icosahedral outer shell ▪ Replicates in the epithelial cells of the oropharynx and in B lymphocytes transmitted particularly via the exchange of salvia ▪ Primary agent of infectious mononucleosis ▪ Asymptomatic EBV shedders: silent subclinical infection for life ▪ The virus replicates continuously in the body at a very low level (persistence) down-regulates cell adhesion molecules (CAMS) involved in immune recognition (LFA-3 & ICAM-1) BMS 1.26  HHV-5 or Cytomegalovirus (CMV) HHV-5 ▪ Herpesvirdae family ▪ Enveloped, double-stranded DNA virus ▪ Icosahedral outer shell ▪ Replicates mainly in the salivary glands and kidneys (shed in saliva & urine) replication is slow ▪ Chronic infection: silent subclinical infection for life ▪ The virus replicates continuously in the body at a very low level (persistence) BMS 1.26  Papillomaviridae family: Human Papillomavirus (HPV) HPV: more than 170 types classified; 40+ can infect human genital tract ▪ Papillomaviridae family ▪ Non-enveloped, double-stranded DNA virus (dsDNA) ▪ Icosahedral outer shell Associated with various diseases from skin warts to cervical cancer ▪ low risk: genital warts, benign cervical cancer: HPV-6, HPV-11 & others ▪ high risk: cervical cancer: HPV-16, HPV-18 & others BMS 1.26  DNA vs RNA Virus Do you see a possible negative relationship? Some factors influencing mutation rate: ▪ Genome size ▪ Single vs double stranded ▪ Polymerase activity ▪ Proof-reading naked RNA ▪ Post-replicative repair BMS 1.26  Classification of RNA Viruses Multiple combinations of genome and capsid structure Some patterns: –RNA viruses are typically single-stranded except for Reoviridae. –All non-enveloped viruses have icosahedral capsid structure. In “genome-speak”, ds = double-stranded and ss = single-stranded. BMS 1.26  Filoviridae RNA Virus: Ebola (Why so feared?) Ebola virus disease (EVD) or Ebola hemorrhagic fever (EHF) ▪ Filoviridae family: long, sometimes branched virus ▪ Enveloped, ssRNA, helical shape very virulent pathogen causing hemorrhagic disease capable of rapid mutations very adaptable to evade host defenses and environmental change BMS 1.26  Ebola Pathophysiology ▪ Virus animal reservoir is the fruit bat transmission to humans require contact with animal tissues, body fluids or ingestion of plants/water contaminated with bat feces or bodily fluids ▪ Human-to-Human transmission: direct mucous membrane or percutaneous exposure to infected body fluids ▪ Virus infects monocytes, macrophages & dendritic cells via a surface glycoprotein travel to lymph nodes lymph to blood stream, to spleen & liver leads to system-wide inflammation & fever ▪ At its worse: can infected cells can no longer act as antigen-presenting cells (APCs) leads to failure of adaptive immune response BMS 1.26  Rhabdoviridae RNA Virus: Rabies Infectious rabies ▪ Enveloped, ssRNA (Rhabdoviridae family) ▪ Distinct “bullet” shape; helical ▪ Entry: infected saliva ▪ Encephalitic rabies: inflammation of the brain, perivascular infiltrates throughout CNS (Lyssavirus genus) causes cytoplasmic eosinophilic inclusion bodies (Negri bodies) in neuronal cells ▪ Pathophysiology: virus replicated for months in the muscle cells; then used nerves from muscles to travel to central nervous system (CNS); can then travel to skin, cornea, salivary glands ▪ Paralytic rabies: muscle weakness Source: http://www.cdc.gov BMS 1.26  Orthomyxoviridae Family: Influenza Influenza A or B viruses = acute respiratory illness ▪ Orthomyxoviridae Family ▪ consists of four types: A, B, C & D ▪ Greek: ‘ortho’ means straight & ‘myxa’ means mucus ▪ Enveloped, negative-stranded RNA virus glycoprotein spikes: haemagglutinin (HA) & neuraminidase (NA) o give it its antigenic properties (many subtypes) & annual epidemic in humans o allow virus to bind to host cells (membrane fusion glycoproteins) ▪ Self-limiting infection ▪ Transmitted in respiratory secretions BMS 1.26  Orthomyxoviridae Family: Influenza Why does it vary year to year? ▪ 4 types of influenza virus (A, B, C, and D) Human influenza A & B cause seasonal epidemics Influenza A cause pandemics ▪ Surface proteins of the virus: Hemagglutinin (H) – 18 subtypes o 3 major (H1, H2, and H3) Neuraminidase (N) – 11 subtypes o 2 major (N1 and N2) BMS 1.26  Coronaviridae Family: COVID-19 SARS-CoV-2 or COVID-19 ▪ Coronaviridae Family ▪ Binds to ACE2 (and other proteins) and virus binds to Many different cell types, esp. respiratory epithelial cell ▪ Coronaviruses are a large family of viruses common in many species SARS-CoV (Severe acute respiratory syndrome) MERS-CoV (Middle East respiratory syndrome) ▪ A novel coronavirus was identified at the end of 2019 (COVID-19) BMS 1.26  Coronaviridae Family: COVID-19 ▪ SARS-CoV-2 = from no to mild to severe respiratory illness Severe Acute Respiratory Syndrome (SARS) Enveloped, positive- single stranded RNA virus (Coronaviridae Family) Has glycoprotein surface E2 spike protein o give it its antigenic properties o allow virus to bind to host cells (membrane fusion glycoproteins) ▪ Transmitted in respiratory secretions BMS 1.26  Flaviviridae Family: Zika Virus Zika Virus (flavivirus) ▪ Flaviviridae Family ▪ Enveloped, single-stranded RNA virus Icosahedral outer shell ▪ Closely related to dengue, yellow fever & West Nile virus (carried by Aedes mosquito) ▪ Bite of infected Aedes species of mosquito (female) Aedes aegypti BMS 1.26  Flaviviridae Family: Zika Pathophysiology ▪ Suspected link with Guillain-Barre syndrome muscle weakness & numbness of limbs due to damage of nerve cells infectious pathogen most likely is composed of amino acids which mimic the peripheral nerve myelin protein; when immune system responds to attack pathogen, now attacks real myelin protein BMS 1.26  Retroviruses Family of RNA viruses: They have an enzyme (reverse transcriptase or RT) needed to make a complementary DNA copy of the viral RNA. This needs to occur so the virus is integrated into a host cell’s DNA BMS 1.26  Retroviridae Family: HIV Virus HIV-1 (more virulent) & HIV-2 ▪ Enveloped retrovirus ssRNA genome but a retrovirus o technically not a ‘RNA virus’ because uses DNA intermediates to replicate (lipid bilayer envelope surrounds the cylindrical core of RNA (appears spherical) ▪ Target cell or tropism – CD4 helper T cells (T- tropic) and macrophages and dendritic cells ▪ Enters host cells via CD4 receptor & chemokine co-receptors (primarily CCR5 & CXCR4) ▪ Transmission – sexual, blood, semen, vaginal secretions, maternal-fetal, breast milk BMS 1.26  Overview of HIV life cycle HIV life cycle: 1. Binding and Fusion 2. Entry: Viral attachment protein (VAP) = gp160 (gp120 + gp41) 3. Reverse transcription (unique to retroviruses) 4. Integration 5. Viral RNA and protein expression 6. Assembly and budding 7. Maturation HIV targets host cells: CD4 T cells, macrophages & Dendritic cells BMS 1.26  HIV Life Cycle HIV-1 gp120 attaches to CD4 receptor and CCR5 or CXCR4 coreceptor gp41 protein mediates fusion of viral and cellular membranes Sherris & Ryan Chapter 18 Retroviral (HIV-1) life cycle. A. Viral entry and postentry (reverse transcription, DNA synthesis, and integration) events; B. Viral gene expression (transcription and protein synthesis); C. Virus assembly and release. Citation: Chapter 18 Human Retroviruses: HTLV, HIV, and AIDS, Ryan KJ. Sherris & Ryan's Medical Microbiology, 8th Edition; 2022. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3107&sectionid=260925136 Accessed: January 23, 2024 Copyright © 2024 McGraw-Hill Education. All rights reserved BMS 1.26 Overview of HIV life cycle BMS 1.26  HIV Pathogenesis ▪ The profound immunosuppression seen in AIDS is due to the depletion of T4 helper lymphocytes. ▪ In the immediate period following exposure, HIV is present at a high level in the blood (as detected by HIV Antigen and HIV-RNA assays). ▪ It then settles down to a certain low level (set- point) during the incubation period. During the incubation period, there is a massive turnover of CD4 cells, whereby CD4 cells killed by HIV are replaced efficiently. ▪ Eventually, the immune system succumbs and AIDS develops when killed CD4 cells can no longer be replaced (witnessed by high HIV- RNA, HIV-antigen, and low CD4 counts). BMS 1.26 HOST CD4+ LYMPHOCYTES DECLINE BMS 1.26  Viral Infection and the Immune System ▪ Viruses cause disease when they breach the host’s primary physical and natural protective barriers; evade local, tissue, and immune defenses; spread in the body; and destroy cells either directly or via bystander immune and inflammatory responses. ▪ Viral pathogenesis comprises of several stages: (1) Transmission and entry of the virus into the host: including food and water, aerosol, respiratory, gastrointestinal, break in the skin, via mucosal or blood, insect or animal bite, and urogenital, anal or sexual routes (2) Spread in the host: Viruses generally multiply at the site of entry to establish infection in the host and can also spread through the host by infecting neighboring cells and/or reach the blood stream (systemic infection) (3) Tropism: capability of viruses to infect a discrete population of cells within an organ. Cellular or tissue tropism is most often determined by the specific interaction of viral surface proteins (spikes) and cellular receptors on the host cells Viruses such as HIV use a receptor (CD4) and coreceptor (CCR5 or CXCR4) Different viruses may use the same receptor on host cells Sherris & Ryan Chapter 7 BMS 1.26  Viral Infection and the Immune System (4) Virulence and cytopathogenicity: the relative ability of a virus to cause disease. Viral virulence is, basically, the degree of pathogenicity of a virus. A virus may be of high or low virulence for a particular host. Different strains of the same virus may differ in the degree of pathogenicity (5) Patterns of viral infection and disease: Not every viral infection results in a disease. Infection involves multiplication of the virus in the host, whereas disease represents a clinically apparent response. Infections are much more common than disease; unapparent infections are termed subclinical, and the individual is referred to as a carrier (6) Host factors: including immune status, genetic background, age, and nutrition, play important roles in determining the outcome of viral infection. Several innate immune responses (interferons α and β, natural killer (NK) cells, mucociliary responses, and others) and adaptive immune responses (antibody and T-cell responses) influence the outcome of viral infections. Individuals with weak immune systems or those who are immunocompromised or immunosuppressed often have more severe outcomes. Details of immune responses to infection are described in Chapter 2. Sherris & Ryan Chapter 7 BMS 1.26  Viral Infection and the Immune System (7) Host defense: The two major types of host defenses are nonspecific (innate) and specific (adaptive) immune responses. The innate immune response includes interferons, natural killer (NK) cells, macrophages (phagocytosis), mucociliary clearance, and fever. o Interferons are host-encoded proteins that provide the first line of defense against viral infections The adaptive immune response involves humoral immunity (B cells) and cell-mediated immunity (T cells) o cytotoxic T lymphocytes (CTL) destroy virus-infected cells o after viral infection, the first specific immune response is T-cell mediated in which CD8 T cells recognize viral antigen presented by class I MHC and kill virus-infected cells by secreting perforins and granzymes causing apoptosis of the viral-infected host cell (8) Virus-induced immunopathology: even when the host’s working immune system cannot stop a viral infection leading to disease This could be true in viral infections in which a large number of cells are infected in an individual Recent emerging SASR-CoV-2 (COVID-19) pandemic causing multiorgan diseases involves viral load and excessive cytokine release induced damage. Sherris & Ryan Chapter 7 BMS 1.26  INFECTIOUS DISEASES: CATEGORIZATION ▪ Bacterial Diseases – includes disease due to gram positive, gram negative, spirochetal, atypical and mycobacterial organisms ▪ Viral Diseases – includes infections due to DNA, RNA and retroviral agents ▪ Fungal Diseases – includes superficial and systemic mycoses and candida ▪ Parasitic Diseases – includes protozoal and helminthic infections BMS 1.27 Infectious Diseases: Five Kingdoms Animals Fungi Plants Protista BMS 1.27  Domain Eukarya (Eukaryotes) ▪ Fungi ▪ Plantae Molds Multicellular Algae Yeasts Mosses Mushrooms Plants ▪ Protista ▪ Animaliae Slime Molds Insects Unicellular Algae Worms Protozoa Sponges Vertebrates BMS 1.27 Fungi Buds vs Hyphae BMS 1.27  Fungi Mycosis (s): fungal infection of animals Mycoses (pl): ▪ Relatively large organisms with nuclear membrane, cytoplasm and organelles Yeast: unicellular Mold: multicellular ▪ Often are resident microbes that are kept at bay by competing resident bacteria Flourishes if antibiotic treatment alters resident flora balance ▪ Opportunistic pathogens Immunocompromised hosts more susceptible BMS 1.27  Mycoses (Fungi): Two Groups Yeast: unicellular, sometimes connected by pseudohyphae ▪ grows as a single-cell, typically need microscope to see if only a few cells ▪ usually oval in shape & appears more white ▪ very common ▪ can produce energy aerobically or anaerobically ▪ budding yeasts reproduce asexually by budding off a smaller daughter cell i.e. Opportunistic yeast: Candida albicans BMS 1.27  Mycoses (Fungi): Two Groups Mold: (most) multicellular filaments (hyphae); network of branching hyphae is called mycelium ▪ grows in multicellular filaments (hyphae) leading to a thread-like ‘fuzzy’ appearance; forms a single organism or colony ▪ spores (airborne): can cling to clothing/fur (remain alive in dormant state) long incubation in body and culture plate can use sexual (meiosis) or asexual (mitosis) reproduction through spores ▪ use enzymes to degrade material and use as energy ▪ Penicillium notatum is mold (1928) ▪ Opportunistic molds cause disease by: allergic sensitivity to spores growth of mold within the body ingested or inhaled toxic compounds produced by molds (mycotoxins) BMS 1.27  Dimorphic Fungi Dimorphic fungi: having more than one appearance during their life cycle ▪ May be able to appear as yeasts or molds (important for infectivity) ▪ Change in response to the environment (able to survive in diverse environments) nutrient availability temperature changes i.e. Histoplasma capsulatum, causes histoplasmosis (lung infection) BMS 1.27  Ways to Classify Mycoses Mycoses: ▪ Site of Infection (Portals): superficial cutaneous subcutaneous systemic (deep) ▪ Route of Acquisition: airborne, cutaneous or percutaneous ▪ Type of Virulence exhibited by fungus BMS 1.27  Site of infection: Superficial & Cutaneous Mycoses ▪ The superficial (& cutaneous) mycoses are usually confined to: Outer layers of skin Hair Nails Do not invade living tissues The yeast Malassezia are part of the normal skin flora but can over-grow (pityriasis or tinea versicolor) ▪ The fungi are called dermatophytes BMS 1.27  Site of infection: Subcutaneous Mycoses Causative agent found in soil, leaves and/or organic material after typically introduced when there is injured skin. ▪ Usually remain localized at site of entry may slowly spread to surrounding tissue ▪ often asymptomatic or minimal ▪ when triggering an inflammatory response = redness (maybe itching) Almost always occur after trauma to skin (& deeper) ▪ most fungi are in tropical regions ▪ subcutaneous fungi found in temperate regions: sporotrichosis ▪ fungus called Sporothrix, lives in soil ▪ immunocomprised individual at higher risk BMS 1.27  Site of infection: Systemic (Deep) Mycoses Systemic or deep infection ▪ Caused by pathogenic & opportunistic fungal pathogens may slowly spread to surrounding tissue ▪ often asymptomatic or minimal ▪ opportunistic infections occur more likely in immunocompromised patients Infections are caused by the organisms leading to 1. Histoplasmosis: infect lungs 2. Coccidioidomycosis: infect lungs (may move to brain*, bones or other sites) 3. Blastomycosis: infect lungs 4. Candidiasis: MC opportunistic fungal infection (can be superficial or deep infection) 5. Aspergillosis: infect sinuses & lungs 6. Cryptococcosis: can cause pneumonia and/or meningitis 7. Pneumocystis jirovecii/previously pneumocystis carinii BMS 1.27  Fungi: Candidiasis ▪ Approx. 20 species that cause infection Candida albicans, most common strict aerobe, favors moist surfaces (gut, genitals, lungs) both yeast and mold qualities ▪ Superficial candidiasis: infect epidermis, mucosal surfaces lining oral pharynx, esophagus, intestines, urinary bladder, vagina ▪ Deep candidiasis: kidneys, liver, spleen, brain, heart = visceral candidiasis ▪ i.v. catheters are the major portal of entry for deep infection ▪ Entry: overcoming host barriers via adhesins immunocompromised host broad spectrum antibiotics corticosteroids chemotherapy  Candidiasis: Pathophysiology Virulence Factor & Effects ▪ cell surface hydrophobicity & adherens: promotes retention in the mouth adherens: cell-cell adhesion complexes ▪ secretory IgA destruction: promotes retention in the mouth ▪ phenotype switching & binding to complement: evasion of host defenses ▪ hydrolytic enzyme production: invasion & destruction of host tissue BMS 1.27  Fungi: Cryptococcus ▪ Cryptococcus = “hidden sphere/berry” Cryptococcus is used when referring to the yeast state of the fungi actually 17 species of Cryptococcosis ▪ Pathogenic yeasts: typically inhale microscopic fungus C. neoformans: most that inhale never become ill C. gattii: rare infection; lives in soil & certain trees (tropical/sub-tropical regions Invasive, opportunistic infection (esp. lungs) can lead to pneumonia and/or meningitis especially Encephalomeningitis in immunosuppressed patients BMS 1.27  Fungi: Pneumocystis Pneumocystis pneumonia (PCP): ▪ Pneumocystis jirovecii use to be called P. carinii & classified as a protozoa still abbrev. PCP (might see PJP) ▪ Infection spread through the air infects lungs ▪ Pathogenic yeast-like fungus most do not become ill ▪ Immunocompromised most likely to become infected HIV/AIDS BMS 1.27  Fungi: Histoplasmosis Histoplasma capsulatum: causes histoplasmosis (lung infection) ▪ dimorphic fungi can grow inside of macrophages ▪ inhale microscopic fungal spores from the air most do not become ill can move from lungs to other organs the pattern of infection are similar to TB ▪ Risk factors for severe respiratory disease: Impaired cellular immunity AIDS/HIV infection Chronic immunosuppressive therapy Neutropenic BMS 1.27  INFECTIOUS DISEASES: CATEGORIZATION ▪ Bacterial Diseases – includes disease due to gram positive, gram negative, spirochetal, atypical and mycobacterial organisms ▪ Viral Diseases – includes infections due to DNA, RNA and retroviral agents ▪ Fungal Diseases – includes superficial and systemic mycoses and candida ▪ Parasitic Diseases – includes protozoal and helminthic infections BMS 1.28 Infectious Diseases: Five Kingdoms Animals Fungi Plants Protista BMS 1.28 Entry of Parasitic Infection BMS 1.28  Parasitology Definitions: ▪ Medical parasitology: “the study and medical implications of parasites that infect humans” ▪ A parasite: “a living organism that acquires some of its basic nutritional requirements through its intimate contact with another living organism”. Parasites may be simple unicellular protozoa or complex multicellular metazoa Protozoa: unicellular organisms, e.g. Plasmodium (malaria) Metazoa: multicellular organisms, e.g. helminths (worms) and arthropods (ticks, lice) ▪ An endoparasite: “a parasite that lives within another living organism” – e.g. malaria, Giardia ▪ An ectoparasite: “a parasite that lives on the external surface of another living organism” – e.g. lice, ticks BMS 1.28  Parasitology Definitions: Host: “the organism in, or on, which the parasite lives and causes harm” Definitive host: “the organism in which the adult or sexually mature stage of the parasite lives” Intermediate host: “the organism in which the parasite lives during a period of its development only” Zoonosis: “a parasitic disease in which an animal is normally the host - but which also infects man” Vector: “a living carrier (e.g.an arthropod) that transports a pathogenic organism from an infected to a non-infected host”. A typical example is the female Anopheles mosquito that transmits malaria BMS 1.28 Parasites: Protozoa BMS 1.28  Parasites: Protozoa Protozoa ▪ Complex unicellular microorganisms ▪ No cell wall, often motile ▪ Can be parasitic or live independently use term ‘parasite’ for a protozoa that cannot live in the open environment thus must invade another organism ▪ Transmission ▪ Paramecium are free-living sexual contact contaminated food or water a vector BMS 1.28  Parasites: Amoebiasis ▪ Amoebiasis (Amebiasis) or amoebic dysentery ▪ Caused by the parasitic protozoa: Entamoeba histolytica, Entamoeba dispar, Entamoeba moshovskii ▪ one-celled parasite known as amoebas Entry: fecal to oral route ▪ Pathophysiology: Has surface lectin molecules that allows it to adhere to the epithelial cells of the colon BMS 1.28  Parasites: Giardia & Malaria ▪ Giardia: Giardia intestinalis, Giardia lamblia or Giardia duodenalis tough outer shell (can survive chlorine disinfection) entry: fecal-oral route ▪ Malaria: Plasmodium falciparum entry: vector-borne liver cells and RBCs most affected BMS 1.28 Helminthic Infections (Parasitic worm) ▪ Ascariasis ▪ Trichinosis ▪ Hookworm ▪ Pinworm BMS 1.28  Helminth Infections: Generally they stimulate Eosinophila Phylum Nemathelminthes (roundworms = do have a body cavity) – “Nematodes” ▪ non-segmented worms (no complete circulatory system) Phylum Platyhelminthes (flatworms = do not have a body cavity) ▪ Class Cestoidean (segmented flatworm/tapeworms) – “Cestodes” ▪ Class Trematoda (non-segmented flatworm/flukes) – “ Trematodes” BMS 1.28  Nematode/Roundworm Intestinal Nematodes are non-segmented worms: ▪ Common GI symptoms of nausea, vomiting & diarrhea (traveling to countries with poor sanitation) 1. Ascariasis by Ascaris lumbricodies 2. Trichinosis by Trichinella spiralis food-borne via raw or undercooked meat (usually pork) typically ingested as larvae form which invade the small intestine can migrate to lymph and/or blood: prefers oxygen rich tissue (LUNG, skeletal & cardiac muscle & brain) 3. Hookworm by Ancylostoma duodenale or Necator americanus 4. Pinworm or Enterobiasis by Enterobius vermicularis: egg deposition by pregnant females direct contact with a contaminated item confined to ileum & cecum; often asymptomatic BMS 1.28  Nematode/Roundworm: Ascariasis Ascariasis Pathophysiology: ▪ Ascaris lumbricodies parasite ▪ Ingest eggs in contaminated soil ingest fertile eggs exposure to pigs, soil transmitted ▪ In duodenum of host, larvae are released & enter circulation ▪ Reaches liver and lungs. ▪ Mature in lungs, coughed-up, swallowed & re- enter GI tract. BMS 1.28  Nematode/Roundworm: Hookworm Hookworm Pathophysiology: ▪ Ancylostoma duodenale or Necator americanus parasites ▪ Immature worms enter through skin, especially feet ▪ Hookworms move several times a day to different attachment sites in the upper intestinal mucosa to ingest blood ▪ They secrete an anticoagulant which causes the old attachment sites to continue to bleed Adult male and female worms of A. duodenale BMS 1.28  Helminthic Infections (Parasitic worm) ▪ Liver fluke ▪ Lung fluke ▪ Intestinal fluke ▪ Blood fluke (Schistosomiasis) BMS 1.28  Trematoada/Fluke: Type of Flatworm Trematode (fluke, type of flatworm): ▪ Classified by location of the adult worm: liver fluke: ingesting undercooked, smoked or salted fish (esp. fresh water) lung fluke (Paragonimiasis): ingesting inadequately cooked or pickled crab or crayfish o adults live in lungs, deposit eggs in bronchi intestinal fluke: ingesting undercooked or salted fish Lung Fluke (parasitic worm) blood fluke: o Schistosomiasis: penetrate the skin by direct contact ▪ Acute infection can become a chronic infection ▪ Chronic infection leads to inflammation, ulceration and hemorrhage of small intestine. BMS 1.28  Helminthic Infections (Parasitic worm) ▪ Ascariasis ▪ Trichinosis ▪ Hookworm ▪ Pinworm ▪ Liver fluke ▪ Lung fluke ▪ Intestinal fluke ▪ beef tapeworm ▪ Blood fluke ▪ pork tapeworm (Schistosomiasis) ▪ fish tapeworm BMS 1.28