L16 Bacteria Host Interactions & Immune Responses 2024 PDF

Bacteria and Host Interactions Moses T. Bility, PhD Associate Professor, Microbiology Howard University Contact for Office Hours at [email protected] September 2024 Acknowledgement to Dr. Kunle Kassim  Learning Objectives...

Bacteria and Host Interactions Moses T. Bility, PhD Associate Professor, Microbiology Howard University Contact for Office Hours at [email protected] September 2024 Acknowledgement to Dr. Kunle Kassim  Learning Objectives Explain concepts of normal flora, pathogenicity and virulence and host barriers Discuss the diversity and endogenous regulation of bacterial floras Discuss the immunological benefits of normal floras to the host Identify and describe the host factors that contribute to onset of opportunistic infections Describe the bacterial factors that promote pathogenesis and enhance virulence Review clinical cases of host-pathogen interactions and pathogenesis Describe the roles of gut microbiota, microbiome and the gut brain axis in the modulation of neurogenerative diseases Check on Knowledge: USMLE-Step 1 Style Questions Innate Immune Response to Bacterial Infection A 28-year-old man is hospitalized for a severe skin infection. Cultures from the lesion grow Staphylococcus aureus, a Gram-positive coccus that is resistant to phagocytosis due to the presence of a thick capsule. Despite this, the immune system mounts an effective response, eventually clearing the infection. Which of the following innate immune mechanisms is primarily responsible for clearing this infection? A) Natural killer cell activation B) Phagocytosis by neutrophils C) Cytotoxic T cell response D) Complement-mediated lysis Answer: B) Phagocytosis by neutrophils Explanation: Neutrophils are key players in the innate immune response to bacterial infections, especially pyogenic (pus-forming) bacteria like Staphylococcus aureus. They engulf and destroy the bacteria, despite its capsule. Check on Knowledge: USMLE-Step 1 Style Questions Intracellular Bacteria and Immune Evasion A 45-year-old man is diagnosed with tuberculosis. Mycobacterium tuberculosis evades immune detection by inhibiting phagosome- lysosome fusion within macrophages, allowing the bacteria to persist inside the host cells. Which of the following immune cells is primarily responsible for containing the spread of the infection by activating the infected macrophages? A) B cells B) CD4+ Th1 cells C) CD8+ cytotoxic T cells D) NK cells Answer: B) CD4+ Th1 cells Explanation: CD4+ Th1 cells release interferon-gamma (IFN-γ), which activates macrophages to destroy Mycobacterium tuberculosis. This is crucial for controlling intracellular bacterial infections. Check on Knowledge: USMLE-Step 1 Style Questions Bacterial Capsule and Phagocytosis A 67-year-old man with a history of splenectomy is more susceptible to infections by encapsulated bacteria such as Streptococcus pneumoniae. What is the primary reason for the increased susceptibility to encapsulated bacteria in asplenic patients? A) Reduced phagocyte function B) Defective complement activation C) Lack of T-cell response D) Impaired opsonization Answer: D) Impaired opsonization Explanation: The spleen plays an essential role in filtering blood and opsonizing encapsulated bacteria for phagocytosis. Asplenic patients are more vulnerable because they lack this important opsonization mechanism, which tags bacteria for immune clearance. Check on Knowledge: USMLE-Step 1 Style Questions Immune Evasion by Biofilm Formation A 55-year-old man presents with a chronic prosthetic joint infection. Cultures reveal Staphylococcus epidermidis, a common cause of prosthetic device infections. This organism is difficult to eradicate because it forms a biofilm on the surface of the prosthesis. What is the primary function of biofilms in bacterial survival? A) Enhancing motility B) Increasing toxin production C) Protecting bacteria from the immune response D) Facilitating bacterial division Answer: C) Protecting bacteria from the immune response Explanation: Biofilms provide a physical barrier that protects bacteria from immune system components (like antibodies and phagocytes) and antibiotics, making infections with biofilm-forming bacteria, like Staphylococcus epidermidis, more resistant to treatment. Check on Knowledge: USMLE-Step 1 Style Questions Bacterial Superantigens-host interactions A 35-year-old woman presents with fever, vomiting, hypotension, and a desquamating rash. She was diagnosed with toxic shock syndrome (TSS) caused by Staphylococcus aureus. The bacterium produces toxic shock syndrome toxin-1 (TSST-1), which is a superantigen. How do superantigens like TSST-1 contribute to the pathogenesis of TSS? A) They form pores in the cell membrane, leading to cell lysis B) They directly activate macrophages, leading to cytokine release C) They non-specifically activate T cells, causing massive cytokine release D) They inhibit neutrophil migration, reducing immune response Answer: C) They non-specifically activate T cells, causing massive cytokine release Explanation: Superantigens like TSST-1 bind directly to MHC class II molecules and T-cell receptors, non-specifically activating a large proportion of T cells, which leads to the release of excessive amounts of cytokines (such as IL-1, IL-2, TNF), resulting in the systemic symptoms of TSS. Distribution & Composition of Bacterial Floras Front. Microbiol., 05 October 2015, Sec. Evolutionary and Genomic Microbiology, Volume 6 - 2015 | https://doi.org/10.3389/fmicb.2015.01050 Distribution & Composition of Bacterial Floras Diversity of Bacterial Floras Dynamics of coexistence in: GI Skin Oral cavity GI tract Tooth Urogenital tract enamel Respiratory tract Skin  Oral Bacterial Flora Viridans streptococci Anaerobic streptococci Bacteroides fragilis Fusobacterium sp Lactobacillus species Candida albicans  Colon Flora Bacteroides fragilis Fusobacterium nucleatum E. coli Clostridium difficile Lactobacillus acidophilus and other species Bacterial floras – regulation and advantages Skin bacteria Fatty acids Intestinal bacteria Bacteriocins, colicins B & K vitamins Antigenic stimulation Competent immunity Oral & Vaginal floras Lactobacillus keeps acid environment & flora intact Disruption of Normal Flora Trauma 1. Intestinal perforation 2. Appendix rupture 3. Dental extraction 4. Injury Excessive antibiotic use Immune dysregulation Disruption of Normal Flora Dental extraction Streptococcus viridans (mutans, mitis, salivarius) Septicemia, bacterial endocarditis Urinary tract infection E. coli, Klebsiella pneumoniae, Proteus mirabilis Traumatic Injury -- Strep. epidermidis, Pseudomonas aeruginosa, -- Clostridium tetani § Appendix rupture -- E.coli, Bacteroides fragilis Bacterial endocarditis (dental extraction) Urinary Tract Infections (Interaction of host factors and commensal bacteria) -- Tumors -- Kidney stones -- Ureteric reflux -- Prostatic hypertrophy Bladder incontinence -- Short female urethra -- Catherization Poor hygiene/ GI Urethral Contamination E. coli, Klebsiella infections  Excessive Antibiotic Use Promotes Infections Normal vaginal flora in upper slide Candida albicans yeast overgrowth (thick white discharge, but no smell) in lower slide Treatable with clotrimazole (lotrimin) gel  Excessive Antibiotic Use Promotes Infections Long-term or excessive antibiotic use (e.g. clindamycin) Clearance colon flora, except: Clostridium difficile Growth + toxin production Pseudomembranous colitis (note whitish plaques (pseudomembrane) over colon tissue (metronidazole is effective)  Bacterial Vaginosis Loss of flora regulation Flora disruption Physiological imbalance Compare normal flora in upper slide and overgrowth of gram negative associated bacteria in lower slide Gardrenella vaginalis Bacteroides species, Mobiluncus species  Bacterial Vaginosis Occurs when the normal balance of bacteria in the vagina is disrupted and replaced by an overgrowth of certain bacteria. Common in pregnant women and women of child-bearing age accompanied by white or gray discharge, fishy- smelling odor, pain, itching, or burning urination. Increased risks include douching; new or multiple sexual partners Gut Microbiota and Microbiome Interaction and diversity of the gut microbiota in human host are now associated with: immunity, brain and cardiac functions, obesity, cardiovascular disease, inflammatory bowel diseases (Crohns’, Ulcerative colitis), colorectal cancer, neurological diseases (Parkinson’s and Alzeimer’s diseases), autism, drug metabolism and toxicity, Predominant Gut Microbiota are: Lactobacillus, Bifidobacterium (10%), Bacteroides (30%), Clostridium, Prevotella, Fusobacterium, E. coli, Actinobacteria  Gut Microbiota and Diseases Lactobacillus and Bifidobacterium species produce: - exopolysaccharides for attachment to mucous membranes - bacteriocins to regulate microbiota - extracellular proteins against inflammatory cytokines - are sold as probiotics in health food stores Bottle-fed babies lack Bifidobacteria & more prone to diarrhea Fusobacteria are associated with: - biofilm formation, periodontal diseases, Lemierre’s disease, colon cancer, ulcerative colitis F. nucleatum DNA sequences are abundant in tissue biopsies of colorectal cancer Fecal transplants from healthy people to treat recurrent pseudomembranous colitis  Gut Microbiota & Other Diseases Colorectal cancer: Clostridium and Fusobacterium species are prominent in the tumor and epithelial cells of CRC Autism: predominant population of Clostridium species in the gut Fecal Transplants for Treatments From healthy individuals to gut of individuals with IBD (Crohns’ and ulcerative colitis) and pseudomembranous colitis Transplants of probiotics (Lactobacillus & Bifidobacterium species) into patients with IBD Organization of Gut Brain Axis and Bidirectional Communication Bacterial Flora & Immune Dysregulation Proportions of Streptococcus mitis and some anaerobes in mouths of patients with oral cancer are >2X that of healthy controls Host genetic defects in colon mucosal barrier function, innate bacterial killing or immunoregulation may alter anaerobic microbial composition and result in continuous inflammation by exotoxins of Clostridium difficile and development of Crohn’s disease and ulcerative colitis Claims of vaginosis resolution with Lactobacillus acidophilus probiotic with enhanced hydrogen peroxide production Pathogenicity: the ability to cause disease Virulence: the degree of pathogenicity Microbial Mechanisms of Pathogenicity When the balance between host and microbe tips in favor of the microbe, an infection or H1N1 flu virus disease results. Learning these mechanisms of microbial pathogenicity is fundamental to understanding how pathogens are able to overcome the host's defenses. penetration or evasion of damage to host portals of entry Number of host defenses cells portals of exit invading microbes Mucous membranes Capsules Siderophores Generally the same as Respiratory tract Cell wall components Direct damage the portals of entry for a Gastrointestinal tract Enzymes Toxins given microbe: Genitourinary tract Exotoxins Mucous membranes Antigenic variation Conjunctiva Endotoxins Skin Invasins Skin Lysogenic conversion Parenteral route Adherence Intracellular growth Cytopathic effects Parenteral route KEY CONCEPTS Several factors are required for a microbe to cause disease. Clostridium After entering the host, most pathogens adhere to host tissue, tetani penetrate or evade host defenses, and damage host tissues. Pathogens usually leave the body via specific portals of exit, which are generally the same sites where they entered initially. Mycobacterium intracellulare Determinants of Pathogenicity (virulence factors) Bacterial adherence & Intracellular Growth Tissue specificity Invasiveness Toxins Antiphagocytic factors Immune complex formation Resistance to complement damage Siderophore production Antigenic variation Proteolysis of antibodies Plasmids Microbial Transmission Patterns Respiratory transmission (aerosols from sneezing and coughing Fecal-oral Contact (lesions and fomites) Via blood Sexual contact Maternal-placental-neonatal Genetic  Transmission Patterns Aerosol Contact Surgury Food Adherence Almost all pathogens attach to host tissues in a process called adherence (adhesion) Adhesins (ligands) on the pathogen bind to receptors on the host cells Glycocalyx Fimbriae Microbes form biofilms (communities that share nutrients) Adhesion Molecules & Host Receptors  Bacterial adherence/Infection Adhesion ligands LTA-M protein Type 1 fimbriae (pili) Host cell receptors Fibronectin D-mannose Colonization Infection Strep pyogenes E. coli Tissue Affinity Streptococcus mutans tooth enamel Streptococcus salivarius surface of tongue Streptococcus pyogenes pharyngeal epithelium  Bacterial strain specificity Gel electrophoresis Outer membrane proteins of 4 strains of Hemophilus influenzae bacteria Differences in pathogenicity type b – most pathogenic due to capsular polyribitol phosphate Invasiveness Extracellular enzymes Hyaluronidase dissolves connective tissue Collagenase hydrolyses muscle connective tissue Streptokinase lyses blood clots Phospholipases damage cell membranes Lecithinase damages cell membranes Staphylokinase (fibrinolysin) dissolves fibrin clots Hemolysins lyse erythrocytes and white blood cells  Terminologies in Microbiology ID50: infectious dose for 50% of a sample population Measures virulence of a microbe LD50: lethal dose for 50% of a sample population Measures potency of a toxin  Bacillus anthracis Portal of Entry 0 Skin 10–50 endospores Inhalation 10,000–20,000 endospores Ingestion 250,000–1,000,000 endospores  Toxins Toxins LD50 Botulinum 0.03 ng/kg Shiga toxin 250 ng/kg Staphylococcal enterotoxin 1350 ng/kg Bacterial Toxins Endotoxins (LPS) Exotoxins Production of Toxins Toxins: poisonous substances produced by microorganisms Produce fever, cardiovascular problems, diarrhea, and shock Toxigenicity: ability of a microorganism to produce a toxin Toxemia: presence of toxin in the host’s blood Intoxications: presence of toxin without microbial growth Endotoxins Lipid A portion of lipopolysaccharides (LPS) of gram-negative bacteria Released during bacterial multiplication and when gram-negative bacteria die Stimulate macrophages to release cytokines Cause disseminated intravascular coagulation  Lipid portions of lipopolysaccharides (LPS) that are part Lipid A portion of of the outer membrane of the cell wall of gram-negative bacteria (lipid A). The endotoxins are liberated when the lipopolysaccharides bacteria die and the cell wall lyses, or breaks apart. (LPS) of gram-negative bacteria Released during bacterial multiplication and when gram- negative bacteria die Stimulate macrophages Salmonella typhimurium, an to release cytokines example of a gram-negative bacterium that produces Cause disseminated endotoxins intravascular Endotoxins: toxins composed of lipids coagulation that are part of the cell wall  Endotoxins and the Pyrogenic Response Macrophage Endotoxin Cytokines Hypothalamus of brain Endotoxin Prostaglandin Nucleus Fever Blood vessel Pituitary Vacuole gland Bacterium A macrophage ingests a The bacterium is degraded The cytokines are The cytokines induce the gram-negative bacterium. in a vacuole, releasing released into the blood- hypothalamus to produce endotoxins that induce the stream by the macrophages, prostaglandins, which reset macrophage to produce through which they travel to the the body's "thermostat" to a cytokines, interleukin-1 hypothalamus, the temperature higher temperature, producing (IL-1), and tumor necrosis control center of the brain. fever. factor alpha (TNF-α). Exotoxins Proteins produced and secreted by bacteria Soluble in bodily fluids; destroy host cells and inhibit metabolic functions Antitoxins: antibodies against specific exotoxins Toxoids: inactivated exotoxins used in vaccines Exotoxins Proteins produced inside pathogenic bacteria, most commonly gram-positive bacteria, as part of their growth and metabolism. The exotoxins are then secreted into the surrounding medium during log phase. Cell wall Exotoxins: toxic substances released outside the cell Clostridium botulinum, an example of a gram-positive bacterium that produces exotoxins Exotoxins and Endotoxins Exotoxins A-B toxins contain an enzyme component (A part) and a binding component (B part) Diphtheria toxin Genotoxins damage DNA (causing mutations, disrupting cell division, and leading to cancer) Exotoxins Membrane-disrupting toxins lyse host cells by disrupting plasma membranes Leukocidins—kill phagocytic leukocytes Hemolysins—kill erythrocytes by forming protein channels Streptolysins—hemolysins produced by streptococci Superantigens cause an intense immune response due to release of cytokines from host cells (T cells) Cause symptoms of fever, nausea, vomiting, diarrhea, shock, and death The Action of an A-B Exotoxin DNA Exotoxin Bacterium mRNA produces and A (active) releases the Exotoxin A-B toxin. B (binding) polypeptides Bacterium Receptor Plasma membrane Nucleus B (binding) component of exotoxin attaches to host cell receptor. Cytoplasm Host cell The plasma membrane of the host cell invaginates (folds inward) at the point where the A-B exotoxin and plasma receptor make contact. The exotoxin enters the cell by receptor- mediated endocytosis. A-B exotoxin and receptor are enclosed in pinched-off portion of plasma membrane during pinocytosis. A-B components of exotoxin separate. The A component alters host cell function, often by inhibiting protein synthesis. The B component is released from the host cell, and the receptor is Protein inserted into the plasma membrane for reuse. Diseases Caused by Exotoxins Exotoxins Enzymatic lysis alpha toxin—Clostridium perfringes Pore formation alpha hemolysin — Staph aureus Protein synthesis inhibition (80s ribosome) diphtheria & shigella toxins Nerve-muscle transmission-inhibition tetanus toxin-spastic paralysis botulinum toxin-flaccid paralysis Hemolysins of Group A Strep α – hemolysin (incomplete hemolysis) β – hemolysin (complete hemolysis) Bacterial Exotoxins: Modes of Action Staphylococcus aureus (toxin-induced scalded skin syndrome) Tetanus Toxin (spastic paralysis of skeletal muscles) Non-Specific Host Responses Phagocytosis Complement activation Inflammation Acute phase responses (proteins) PHAGOCYTOSIS Host cellular response In the lung Strep pneumoniae Neutrophils Pneumonia  Intracellular Killing Lysosomal enzyme degradation Oxidative/Respiratory Burst Intracellular Killing Hydrolytic Enzymes Lysozyme Lactoferrin Collagenase Acid phosphatase Cationic proteins Additional Pathogenic Factors Siderophore production for host iron Proteolysis of sIgA Plasmids Toxin production Multiple drug resistance Antiphagocytic Factors Polysacch capsule Strep. pneumoniae M protein Group A Strep K antigen in E. coli Vi antigen Salmonella Protein A in S. aureus Resistance Mechanisms to Phagocytosis Acidification of phagolysosome Capsule production Toxin release Inhibition of phagolysosome formation Escape from phagolysome Antioxidant production Complement inactivation Phagocytosis Dysfunction Complement Activation Resistance to Complement-mediated Damage Capsule production IgA coating Elastase production Polysaccharide side chains Expulsion of membrane attack complex Consequences of Complement Deficiencies  Opsonization and Phagocytosis of Bacteria Dunkelberger, J. R., & Song, W. C. (2010). Complement and its role in innate and adaptive immune responses. Cell research, 20(1), 34-50. Vandendriessche, S., Cambier, S., Proost, P., & Marques, P. E. (2021). Complement receptors and their role in leukocyte recruitment and phagocytosis. Frontiers in Cell and Developmental Biology, 9, 624025. List of Common Pathogens Staphylococcus aureus Enterococcus faecalis Neisseria gonnorhea Hemophilus influenzae Escherichia coli Pseudomonas aeruginosa Streptococcus pneumoniae Three lines of immune responses and protection Natural barriers/exterior defenses Innate antigen-nonspecific defenses -rapid, local responses (fever, complement, inflammation, phagocytosis, cytokines) Acquired (adaptive) antigen-specific responses -specifically target microbial pathogens that pass through first two defenses (antibodies, B and T cells) Types of Immunity Against Disease Causation  Physical and Chemical barriers that protects microbiome integrity and against pathogenic infections https://www.open.edu/openlearn/mod/oucontent/view.php?id=28153&section=4.1  Defenses against entry into the body The skin is the most important physical barrier against microbial entry into the body due to intact epithelial cover and lactic acid and fatty acids in sweat. Others include ciliary lining in trachea, HCl in stomach, lysozyme in tears and saliva, lactoferrin and lactoperoxidase in milk. Antagonistic organisms in oral, nasal, gut and vagina floras Importance of good, healthy skin Healthy , intact, immunocompetent skin does not allow exogenous invasive infections Oxygen-deprived, nerve-damaged skin as in chronic diabetes breeds diabetic ulcers from invasive infections by skin flora and can lead to amputation Morphology of cells of the immune system  Normal Blood Cell Counts Mean number / µl Normal Range WBC (leukocytes) 7,400 4,500 – 11,000 Neutrophils 4,400 1,800 – 7,700 Eosinophils 200 0 - 450 Basophils 40 0 - 200 Lymphocytes 2,500 1,000 – 4,800 Monocytes 300 0 - 800 Normal Blood Cell Counts Neutrophils: 50-70% WBCs, bacterial infections Eosinophils: 1-4% WBCs, parasitic infections Basophils: < 1% WBCs, allergic, type 1 reactions Lymphocytes: 30-40% WBCs, T&B cells, NK cells - T cells (CD4 and CD8 cells) - CD4 TH1 for inflammatory/DTH responses - CD4 TH2 for antibody production - CD8 TC kills virus infected cells, organ transplants, tumor cells Monocytes: (phagocytic) macrophages, alveolar macro, dendritic cells, Kupfer cells (liver), histiocytes (connective tissue), microglial cells (brain)  Two types of professional phagocytes (a) is a blood monocyte (macrophage),long-lived with mitochondria, antigen presenting, produces IL-1, TNF-α, IL-6 (b) is a polymorphonuclear neutrophil, short-lived without mitochondria, uses glycolysis under anaerobic conditions such as in inflammatory focus, nonantigen presenting nor cytokine production Lower picture shows various forms of mononuclear cells (kupfer cells in liver, osteoclasts in bone marrow, microglial cells in brain) Highlights of Phagocytosis and Inflammation Phagocytosis is preceded by chemotaxis which attracts phagocytes to infection sites through generation of : - C5a, C3a as chemotactic factors from complement activation - C5a, C3a as anaphylatoxins to activate mast cells to release leukotrienes, protagladins as mediators of vascular permeability - leukotrienes, prostaglandins, TNF-α upregulate production of ICAM-1 and ELAM-1 which enable phagocytes to adhere to capillary endothelium - capillary endothelial adhesion is followed by capillary dilation (erythema/reddening), exudation of plasma proteins (complement, antibodies, cytokines, C-reactive protein) and fluid (edema) and accumulation of neutrophils - all of the above are collectively termed acute inflammation - macrophages are similarly activated by bacterial toxins, C5a, etc Acute Inflammatory Response Initiated also by the following: Bacterial activation of alternative complement system Mast cell degranulation products (leukotrienes, prostaglandins) Macrophage activation products (IL-1, IL-6, TNF-α, etc) Upgraded by acute phase proteins which are released by the liver in response to IL-1, IL-6, TNF-α following infection or tissue injury All of above illustrated by following slides Activation of Acute Inflammation by Bacterial/Alternative Complement Pathway Induction of Acute Inflammatory Reaction in Response to an Infection Induction of Acute Phase Proteins in Inflammation Mast Cell Degranulation Products in Acute Inflammation Cellular Components of Adaptive Immunity (Humoral & Cell Mediated) Include B cells, TH1 , TH2 , TC and TS cells B cells mature into plasma cells to produce antibodies T-1 cells and T-2 cells are CD4 helper cells T-c and T-s are CD8 cytotoxic and suppressor T cells T-1 cells produce IL-2, TNF-α , IL-12 and interferons for macrophage stimulation and intracellular killing and inhibit T-2 cytokine production T-2 cells produce IL-4, IL-6 and IL-10 cytokines, are good helpers for B cell production of antibodies and inhibit T-I cytokine production T-c cells are effective against viruses and virally infected cells T-s cells are involved in immunosuppression as in EBV infections (mononucleosis, Burkitt’s lymphoma) Integration of Humoral and Cellular Components of Immunity Classes and Functions of Immunoglobulins  General Functions of Antibodies in Immunity Antibodies are produced by B cells and are especially effective against extracellular organism's microbial pathogens for phagocytosis Opsonize for intracellular killing They neutralize microbial toxins Block virus binding to host cells Blocks microbial nutrient transport Secretory IgA blocks attachment of microbes to mucosal surfaces Interact with complement to induce granulation of mast cells and generate acute inflammatory reaction at mucosal surfaces  Additional Properties of Antibodies Primary antibody response is usually of the IgM type IgE is produced in response to allergic reactions Second time exposure to microbial antigens generates rapid, large secondary responses in specific IgG antibody production and additional cellular responses Large secondary responses to primary toxoids are useful protective outcomes of vaccination against specific and related pathogens and are due to memory B and T cells Immune Response Time Course Endotoxin and Septicemia Fever Activation of coagulation process Disseminated Intravascular Coagulation (DIC) Depression of RES Vascular collapse Sepsis Lipid A, Coagulation and RES Lipid A activates clotting mechanism, with formation of fibrin Fibrin may clog small blood vessels, causing intravascular coagulation (IVC), followed by shock Lipid A may inhibit macrophages from degrading fibrin polymers trapped in blood vessels Result from all of above is IVC and septic shock Lipid A, Fever and Vascular Collapse Lipid A activates macrophages to release IL-1, TNF-α. IL-1 goes to the hypothalamus to upregulate the thermocentric center to cause fever. TNF-α causes increased vascular permeability and dilation This results in low blood pressure (hypotension), impairing blood flow to vital organs (kidneys, liver, lung, brain), followed by shock, multiple organ failure and death Other Bacterial Factors for Septicemia and Vascular Collapse Lipoteichoic acid (LTA) in gram positives behaves like LPS to also initiate the sepsis cascade Superantigens: exotoxins of gram positives and gram negatives do not go to the macrophages. Instead, they go directly to activate T cells and cause cytokine storm which then leads to overwhelming sepsis Roles of Superantigens, C5a and Toll-like Receptors in Sepsis 1. LTA & LPS, Superantigens (microbial toxins that bypass macrophages, but directly activate T cells to produce cytokine storm) 2. Bind to TLRs on macrophages and T cells 3. Both cells are activated to produce pro-inflammatory cytokines 4. DIC, Sepsis Immunological Features of Sepsis Development Following Infection Features of Sepsis Following Infection LPS /LTA/ Superantigen and Sepsis Fever Hypoferremia Vascular permeability Hypotension Vascular collapse Activation of coagulation process Multiple organ failure Sepsis Summary of Innate and Adaptive Immunity Summary of Host Immune Responses to Bacterial Infection Reading References 1. Medical Microbiology: Patrick R. Murray et al. 2019. Eighthth edition (e). Mosby Inc. Chapters 14, 8-10. 2. www.smithsonian.com/microbes 3. Michael Bolan: Some of my best friends are bacteria. NY Times magazine of May 19, 2013