Lecture_21_Digestive_System_ch22_Part1.pdf

CHAPTER 22 Infections of the Digestive System – Part 1 Copyright © 2021 W. W. Norton & Company Infections of the Digestive System Chapter Objectives § Correlate the anatomy and physiology of the digestive system with the infectious diseases affecting them. § Distinguish gastrointestinal infection...

CHAPTER 22 Infections of the Digestive System – Part 1 Copyright © 2021 W. W. Norton & Company Infections of the Digestive System Chapter Objectives § Correlate the anatomy and physiology of the digestive system with the infectious diseases affecting them. § Distinguish gastrointestinal infections by their presenting signs and symptoms. § Relate the virulence mechanisms of gastrointestinal microbes to the presentation of diseases they cause. § Discuss effective prevention and treatment for different infectious diseases of the gastrointestinal system. 2 Dehydration: A Toddler’s Plight ‒ 1 Scenario § Dao Ming is a 2-year-old who woke up lethargic with watery, nonbloody diarrhea. § By the next morning, Ming’s eyes started to appear sunken and his diarrhea persisted. His parents rushed him to the emergency department (ED) of a nearby hospital. When asked, Ming’s parents said their son had not received any vaccinations. 3 Dehydration: A Toddler’s Plight ‒ 2 Signs and Symptoms § Ming had a fever of 39.5°C (103.1°F), an elevated heart rate, and rapid breathing à dehydrated. The doctor ordered a complete blood count (CBC). Labs § The lab reported Ming’s white cell counts were normal, so the doctor began to suspect Ming’s diarrhea had a viral origin. § An enzyme immunoassay of the boy’s stool sample identified the presence of rotavirus, a virus that can be prevented by vaccination. 4 Dehydration: A Toddler’s Plight ‒ 3 Resolution § The boy was admitted to the hospital, where he received intravenous fluids to help rehydrate him and oxygen to help his breathing. § With the supportive therapy, Ming’s diarrhea disappeared within a day and by week’s end he was back playing in day care. 5 22.1 Anatomy of the Digestive System ‒ 1 Section Objectives § List the structural components of the digestive system and describe the relationships between them. § Name the functions of different structures of the digestive system. § Explain the roles of specialized cells of the intestinal tract (chief cells, M cells, parietal cells, and mucous neck cells). 6 22.1 Anatomy of the Digestive System ‒ 2 Overview of Digestive System § oropharynx (mouth) § stomach § biliary tract • § § pancreas small intestine (~250 m2!) • § Liver, Gall bladder, Bile ducts Duodenum, Jejunum, Ileum large intestine • • • • • • • cecum ascending colon transverse colon descending colon sigmoid colon rectum anus 7 22.1 Anatomy of the Digestive System ‒ 3 § The gastric mucosa and gastric pits 8 22.1 Anatomy of the Digestive System ‒ 3 § The gastric mucosa and gastric pits 9 22.1 Anatomy of the Digestive System ‒ 3 § The small intestine (crypts and villi) *you are not expected to label this diagram from memory, but you should understand difference between villi and crypts 10 22.1 Anatomy of the Digestive System ‒ 3 § Structure of large intestine (no villi, just crypts) 11 22.2 Infections of the Oral Cavity Section Objectives § List microbes found in the normal microbiota of the oral cavity. § Analyze how biofilms contribute to infections of the oral cavity. § Compare the signs and symptoms of common oral cavity infections. § Explain how oral cavity infections impact diseases elsewhere in the body. 12 Tooth Decay. OVERVIEW § Normal oral flora include • Streptococcus • Lactobacillus • Peptostreptococcus • Veillonella • Diphtheroid species § Dental plaque begins as biofilm. • Bacteria undergo metabolism. • Produce acids that can dissolve tooth enamel § Dental caries = tooth decay 13 Tooth Decay (Details) § § Attachment to teeth is via bacterial adherence to dental pellicle: a coating of sticky macromolecules, mainly proteins Bacteria also produce polysaccharides that aid adherence of itself and other microbes. • • § § Plaque formation mechanisms plaque The result: dental plaque • § Streptococcus mutans transforms sucrose into adhesive polysaccharides. They are layered on the pellicle to form a matrix that allows adherence of other organisms. S. mutans one of the densest collections of bacteria in the body. Microbial metabolism in plaque transforms dietary sugar into acids, mainly lactic acidà dental caries (cavities). Other bacteria (esp strict anaerobes), reside in the gingival crevices between the tooth and gum à evade the washing effects of saliva and normal tooth brushing. SEM: biofilm SAG, salivary agglutinin glycoprotein EPS, exopolysaccharides 14 GTFs, Glucosyltransferases, make glucose polymers (glucans) Gingivitis and Periodontal Disease § Gingivitis: inflammation of the gums • Triggered by heavy plaque build-up (tartar) § Periodontal disease: advanced inflammation causing the gums to bleed and pull away from the teeth • Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis 15 Clicker Question 1 What ultimately causes dental carries? a. Sugar degrades the tooth enamel. b. Bacterial plaques on the tooth surface directly damage the enamel. c. physical damage to the tooth from rough brushing d. acid production by bacterial metabolism 16 INFECTIONS OF THE OROPHARYNX § The bacteria of the indigenous oral flora can invade invade surrounding healthy tissue upon damage of oral mucosa • Ludwig Angina E.g. damage via gingivitis § The mouth = likely portal of entry of αhemolytic streptococci (risk factor for subacute bacterial endocarditis). § Ludwig Angina • • • a polymicrobial infection of the sublingual and submandibular spaces that arises from a tooth causing a cellulitis (an inflammation of submucosal or subcutaneous connective tissue) Infection progress rapidly, obstructs the airway, and compromise respiratory airflow. 17 Thrush Pathobiology § Candida albicans and related spp • found in the environment § Small numbers of Candida live harmlessly in the alimentary tract • Commensal role changed when balance between indigenous bacterial flora and host defenses is upset. • antibiotic therapy can kill normal oral bacteria and allow Candida to proliferate. § white patches adhering to the oral mucosa consist of “pseudomembranes” (aka “thrush”) • made up of Candida mixed with desquamated epithelial cells, leukocytes, oral bacteria, necrotic tissue, and food debris. § The adult vagina is commonly colonized with these organisms • may be acquired by infants during delivery. § Candidiasis of the mouth is usually superficial; responds to oral antifungal agents (e.g. nystatin). thrush Nystatin binds ergosterol and forms pore in fungal membrane à cell necrosis 18 22.3 Gastrointestinal Syndromes Section Objectives § List the most common signs and symptoms associated with gastrointestinal infections. § Correlate microbial pathogenic mechanisms with the presenting signs and symptoms of gastrointestinal infections. § Outline the general mechanisms of diarrhea. 19 Types of Diarrhea – 1 § Osmotic diarrhea: intestinal osmolarity is higher than internal osmolarity, causing water to leave the cells. • Pathogens that prevent nutrient absorption can cause osmotic diarrhea. § Secretory diarrhea: increased ion secretion causes electrolytes to leave, leading to imbalance. • Pathogens that cause ion secretion cause secretory diarrhea (V. cholerae) § Inflammatory diarrhea: inflammatory cytokines damage mucosal cells and prevent absorption of nutrients and water. • Shigella and Salmonella are common causes of inflammatory diarrhea. § Motility-related diarrhea: food moves too quickly through the intestinal tract and nutrients are not absorbed. • Often caused by enterotoxins and rotavirus 20 Types of Diarrhea – 2 § Other conditions of the gastrointestinal tract • Gastritis: inflammation of the stomach lining • Gastroenteritis: inflammation along the gastrointestinal tract • Enteritis: inflammation mainly of the small intestine • Enterocolitis: inflammation of the colon and small intestine • Colitis: inflammation of the colon 21 Signs and Symptoms of Hepatitis § Hepatitis is an inflammation of the liver. § Causes: • Infection • Overconsumption of alcohol • Toxic chemicals • Autoimmune reactions § Symptoms • Jaundice • Hyperbilirubinemia – urine turns brown (bilirubinuria) from excess bilirubin secreted from a damaged liver Healthy liver Diseased liver resulting from chronic hepatitis. Yellowing of the conjunctiva of the eye in jaundice 22 Clicker Question 4 Which type of diarrhea is caused by an electrolyte imbalance? a. inflammatory diarrhea b. osmotic diarrhea c. secretory diarrhea d. motility-related diarrhea 23 22.4 Viral Infections of the Gastrointestinal Tract Section Objectives § Match gastrointestinal symptoms to the viral infections that cause them. § List routes of transmission of specific viral diseases of the gastrointestinal tract. § Discuss viral pathogenic mechanisms that lead to specific disease signs and symptoms in the gastrointestinal tract. 24 Viral Gastroenteritis § Norovirus • Fecal-oral route • Nonenveloped, positive sense, ssRNA • Causes sudden onset of symptoms; can also cause fever, headache, and malaise • Outbreaks common on cruise ships 25 Clicker Question 3 What is the primary method of treatment for diarrhea caused by a virus? a. rehydration therapy b. antibiotic therapy c. antitoxin therapy d. vitamins e. There is no effective therapy. 26 Rotavirus Rotavirus Characteristics § Rotaviruses are non-enveloped double-stranded RNA (dsRNA) viruses § complex architecture: three concentric capsids that surround a genome of 11 segments of dsRNA. § Genes encode: • Structural proteins à host specificity, cell entry, viral transcription, epitopes for immune responses • non-structural proteins: involved in genome replication & interfering with innate immunity (e.g. NSP1 and viral enterotoxin NSP4) “rota” comes from wheel-like appearance The RNA segments encode: • six structural viral proteins (VP1 – 4, 6, 7,) • six non-structural proteins (NSP1 – 6) Rotavirus Relevance of Rotaviruses • Widespread Infection: Rotaviruses infect nearly every child globally by age 3–5. • Global Impact: In 2013, they caused 200,000+ child fatalities, with consistent prevalence (30– 50%) in hospitalized cases. • Low-Income Challenges: Over 90% of fatal cases are in lowincome countries due to limited healthcare, insufficient hydration, and comorbid conditions. Rotavirus VP4 :lipid raft interactions Triggered by low Ca2+ levels DLP = double layered particle VP1,3, bind newly transcribed RNA Rotavirus infectious Cycle • Rotaviruses attach to glycan receptors via VP4, concentrated at lipid rafts, initiating viral entry. • Internalization leads to low endosomal calcium, triggering the release of transcriptionally Triple-layered particle active DLP into the cytoplasm. • Viroplasms aid in packaging, and the triple-layered particle non-structural protein 4 assembly involves DLP binding to (NSP4; an intracellular receptor) NSP4, ER budding, and the acquisition of outer capsid VP2 & 6 create structural proteins VP4 and VP7. layers around new DLP (future capsid) Rotavirus Histopathological images of the duodenum of a mouse pup infected with a murine rotavirus strain (EDIM), 48 hours after infection. Vacuolization of enterocytes VP6 staining in Infected mouse enterocytes Pathology of Rotavirus Infection • Rotavirus predominantly infects mature enterocytes at the middle and top of intestinal villi – indicated by immunofluorescent labelling of rotavirus antigen viral protein 6. • Vacuolization of enterocytes in the top and middle of intestinal villi can be observed with rotavirus infection; crypt cells are unaffected. Rotavirus Mechanism of Rotavirus-induced Diarrhea • Initiation: Rotavirus non-structural protein 4 (NSP4) is released, stimulating enterochromaffin cells (EC) to release 5hydroxytryptamine (5-HT). • Effect of 5-HT: 5-HT, a neurotransmitter, activates 5-HT3 receptors on intrinsic primary afferent nerves, increasing gastrointestinal motility and inducing nausea/vomiting. • Enteric Nervous System Activation: This activation leads to increased intestinal motility and stimulation of nerves in the submucosal plexus, causing the release of vasoactive intestinal peptide (VIP) from nerve endings adjacent to crypt Rotavirus Mechanism of Rotavirus-induced Diarrhea (con’td) • VIP Signaling: VIP signaling raises cellular cAMP levels, resulting in the secretion of sodium chloride (NaCl) and water into the intestinal lumen, ultimately causing diarrhea. • Vomiting Reflex: Rotavirus can activate the vomiting center in the brainstem. The virus or NSP4 stimulates vagal afferents to the vomiting center by releasing 5-HT from ECs in the gut, triggering the vomiting reflex. • Clinical Intervention: 5-HT3 receptor antagonists are employed to attenuate vomiting in children with acute gastroenteritis, disrupting the vomiting reflex induced by the rotavirus infection. Rotavirus Immune Evasion Strategies • In human cells in vitro, evasion of the innate IFN response is mediated by rotavirus non-structural protein 1 (NSP1) through inhibition of NF-κB activation • via degradation of F-box/WD repeat-containing protein 1A (BTRC; also known as β-TrCP) • NSP1 can also block type I and type III IFN responses by inhibiting STAT1 activation • Other viral proteins (VPs) might be involved in the suppression of the IFN response through inactivation of MAVS. IFNAR1, IFN-α/β receptor 1; IκB, inhibitor of nuclear factor-κB; IKK-ε, inhibitor of NF-κB kinase subunit ε; JAK1, Janus kinase 1; ISRE, IFN-stimulated response element; TBK1, TANK-binding kinase 1; TYK2, non-receptor tyrosine kinase TYK2. Rotavirus Relevance of Rotaviruses • Transmission: Mainly fecal-oral route • Diagnosis: PCR assays (for rotavirus alone or in multipathogen panels) or serologic assays • Treatment: Supportive – disease is self-limited, lasting only a few days. – oral rehydration therapy to prevent dehydration. • Prevention: Vaccination • During first year of an infant’s life, rotavirus vaccines provide up to 87% protection against rotavirus illness Stool PCR test Oral delivery of vaccine two available vaccines: RotaTeq® licensed in 2006; given in 3 doses @ ages 2, 4 & 6 months Rotarix® licensed in 2008; given in two doses @ ages 2 & 4 months Case History: “Hurling” in Hawaii § Three weeks ago, Katherine, a 17-year-old from Waikiki, Hawaii, developed nausea, fever, and aches. She initially thought it was the flu. She felt extremely tired, dozed through school auditorium events, and was unable to participate in golf tournaments or the school debating team. § About 2 days ago, Katherine could not keep food down and was taken to the emergency department (ED), where she was given an antinausea shot. The shot didn’t work; she continued to vomit and made a second visit to the ED. She noted that her urine seemed dark, and she told the physician that she had not been hospitalized before this event and had not traveled outside the United States. She denied using drugs or having any sexual partners. The practitioner noticed a yellow tinge to the white part of her eyes. A blood test showed that she was positive for anti-hepatitis A virus (HAV) antibodies. 35 Hepatitis § The A, B, Cs of hepatitis. All are RNA viruses except for B Hepatitis Strain Transmission Characteristics A Fecal-oral, food borne Self-limiting, no asymptomatic carriers or liver disease. B Exchange of blood or body fluids (sexual contact) Often no symptoms are displayed, carriers of virus are common, and liver damage is seen in 30% of cases. C Exchange of blood or body fluids (sexual contact) Mild initial disease, 70% progress to chronic infection. Risk of liver failure and cancer. D E Only causes disease if coinfection occurs with hepatitis B virus. Fecal-oral route, typically waterborne Both acute and chronic disease are possible. Very difficult to detect with current tests. Uncommon in the United States. 36 Mumps Paramyxovirus § Single-stranded RNA virus § Highly infectious, self-limiting infection § Parotid glands • Shed in saliva • Spread via sneezing and coughing § Causes massive swelling of parotid glands and can cause harm if swelling of testes occurs § Vaccination has eliminated most cases 37 22.5 Bacterial Infections of the Gastrointestinal Tract Section Objectives § Categorize GI infections by bacterial pathogenic mechanisms. § Correlate bacterial virulence mechanisms to GI disease symptoms. § Relate the treatment of GI infections to virulence of GI pathogens. § Evaluate treatment and prevention methods used for bacterial infections of the GI tract. 38 Peptic Ulcers § Helicobacter pylori • Gram-negative spirochete • Phylum Proteobacteria, Class Epsilonproteobacteria • ubiquitous and infects ~ half of the human population worldwide § Identified in 1983 by Barry Marshall and Robin Warren as causative agent of peptic ulcer disease (Nobel Prize 2005) § Since this discovery involved in stomach ulceration & gastric cancer § Symptoms – Dyspepsia, upper abdominal pain, bloating, belching, nausea 39 GASTRIC INFECTIONS Damage § H. pylori colonizes the human gastric mucosa and causes superficial gastritis within weeks. § Over years, H. pylori–induced gastritis can either remain clinically asymptomatic or lead to different disease outcomes: § duodenal ulcer via hyperacidity § gastric adenocarcinoma via chronic inflammation § MALT or non-Hodgkin lymphoma (rare) Normal Gastric Mucosa Active Gastritis 40 GASTRIC INFECTIONS Encounter and adherence 1. Initial steps of H. pylori colonization include acid adaptation, motility, and chemotaxis to the mucus layer and gastric epithelium. • urease production to neutralize stomach acid • flagella to provide motility à penetrate the mucous layer of the stomach lining. 2. H pylori also colonizes the gastric epithelium via adhesin-mediated adherence to epithelial cell receptors. • initial binding via Blood-group antigen binding adhesin (BabA) • Chronic infection via Sialic acid-binding adhesin (SabA) H pylori virulence factors associated with adherence, persistence, and damage. 41 GASTRIC INFECTIONS Encounter and adherence 3. H pylori initiates epithelial damage via release & delivery of effector proteins that induce an array of pathologic effects on the gastric epithelium. § cytotoxin-associated gene (cagA) § Secreted into cell via T4SS § Impairs epithelial barrier integrity by disrupting Tight junctions and Adherens Junctions à antigen leakage § Tyrosine Phosphorylated in vivo à increased epithelial proliferation and motility (linked to gastric cancer). § Present in 70% of H pylori infections and 90% of cases of peptic ulcer disease Formation of vacuoles or vacuole-like structures within cells § Vacuolating cytotoxin A (VacA) § Present in most strains of H. pylori § Leads to vacuolation § Forms transmembrane pores deregulating selective permeability of membrane § Causes apoptosis 42 If you are curious Both CagA and T4SS encoded with the Cag Pathogenicity Island (PAI). 43 Gastric INFECTIONS Invasive § Urease test of biopsies: tests ammonia production via pH indicator. § Culture can be problematic due to fastidious nature of H. pylori growth § Histology allows visualization of pathogen in-situ using histologic stains Non-Invasive § § § § § (ELISA – Enzyme-linked Immunosorbent Assay) § Urea breath tests: Following ingestion of carbon-labeled urea, H. pylori+ persons will produce ammonia and labeled CO2, the latter detected by breath test Good method to test eradiciaton Serology: measure levels of circulating H.pylori-specific IgG antibodies via(ELISA) sensitive and specific for primary diagnosis of H pylori infection, but limited for post-treatment assessment due to maintainience of serologic titires. Stool antigenic tests: ELISA of fecal material Accurate in determining post-treatment H. pylori responses. 44