Week 11 Principles of Infection Notes

Learning Objectives

• Compare mucous membranes to skin in terms of vulnerability, exposure, colonization, and immune function.
• Briefly describe the methods of transmission of infectious diseases and give two common disease examples for each method.
• Describe the epidemiologic triad of infectious disease.
• Briefly describe the factors that determine an individual’s susceptibility to infection, including exposure, age, vaccination, comorbidity, and variation (anatomical anomalies, foreign bodies, stasis, etc.)

Infection and Infectious Disease

• Infection is the invasion of the body by disease-causing agents (pathogens).
• Infectious Disease (Last, JM, 1988): “An illness due to a specific infectious agent or its toxic products that arises through transmission of that agent or its products from an infected person, animal, or reservoir to a susceptible host, either directly or indirectly through an intermediate plant or animal host, vector, or the inanimate environment.”

Types of Infection

• Primary infection: Initial infection
• Reinfection: Subsequent infection by the same organism after recovery
• Secondary infection: Subsequent infection by a different organism, as a result of impaired immune defense due to pre-existing infection
• Cross-infection: Transfer of an infection from another host / external source (often referring to infection of a hospital patient with a pre-existing disease or infection)
• Community-acquired infection: Infection acquired in the community (rather than in the hospital / nosocomial)
• Subclinical infection: When infection is present but does not cause obvious symptoms
• Chronic infection: Infection cannot be cleared (hepatitis, HIV, herpes, P. aeruginosa)

Types of Infectious Pathogens

• Bacteria: Unicellular prokaryotic microorganisms. Cause strep throat, pneumonia, meningitis, and tuberculosis.
  • Typically treated with antibiotics.
• Protists: Unicellular eukaryotic microorganisms. Cause malaria, trichomoniasis, and amoebic dysentery.
• Viruses: Smallest pathogen. Cause common cold, pneumonia, chicken pox, herpes, hepatitis B, measles, warts, polio, influenza, cancers, and AIDS and many more.
• Fungi: Plantlike microorganisms, including yeasts and molds. Causes ringworm, athlete’s foot, yeast infections, and thrush.
  • Antibiotics do not kill fungi or viruses. Antifungal medications are available but are expensive and may cause liver damage.
• Parasites: Multi-cell microorganisms. Example: intestinal worms.
• Prion: Abnormally folded proteins. Cause progressive neurodegenerative diseases.

Pathogen Emergence During Human History

• Modern humans emerge in Africa ~200,000 years ago.
• Migrations within and out of Africa ~100,000-50,000 years ago.
  • Diseases: Malaria, Tuberculosis, Smallpox.
• Early agriculture (neolithic demographic transition) 12,000 years ago.
  • Disease: Leprosy
• Silk Road links Africa, Europe, and Asia 2,200 years ago.
  • Disease: Cholera
• European colonization of the Americas begins 500 years ago.
  • Diseases: AIDS, respiratory viruses
• Today: Globalization

Transmission of Infection

• Physical contact: Direct contact between an infected individual and a susceptible person (e.g., touching, kissing, sexual contact, contact with oral secretions/body lesions) (e.g., Chlamydia, HIV)
• Objects/surfaces (fomites): Touching door handles, screens, etc., and then touching a mucosal surface on your face, e.g., nose, mouth, eyes (e.g., respiratory and gastrointestinal infections)
• Inhalation: Transfer when an infected individual sneezes/coughs, spreading infectious droplets into surrounding air (e.g., Influenza virus, rhinovirus, coronavirus)
• Ingestion: Transfer through consumption of food or water contaminated with infectious pathogens and/or toxins (e.g., Salmonella, Intestinal worms)
• Inoculation: Entry of pathogen into the host’s body (e.g., needle and insert/animal bite wounds) (e.g., Hepatitis B/C, HIV)
• Congenital: Unborn fetus or newborn infant infected by their mother (e.g., Herpes, Rubella, Parvovirus, enteroviruses, HIV)
• Hospital and laboratory: Infection acquired via hospital or laboratory and related activities.

Epidemiologic Triad of Infectious Disease

• Infection occurs through an interaction between the host, agent, and environment.
• Agent: Infectious microbe or chemical.
• Host: Organism capable of being infected by the agent.
• Environment: Factors external to the host.
• Vector: Organism which transmits infection by conveying the pathogen from one host to another (e.g., the Anopheles mosquito is a vector for malaria caused by Plasmodium parasite).

Factors That Influence Susceptibility to Infection

• Agent: Infectivity, pathogenicity, virulence, immunogenicity, stability, and survival
  • Pathogenicity = Ability of a microorganism to cause disease
  • Virulence = Degree of pathogenicity
• Host: Genotype, age, sex, social behavior, nutritional status, and other health status (diabetes, chemo/radio therapy, anatomical anomalies, foreign bodies, and stasis).
• Environment: Weather, geography, accommodation, occupation, air pollution, and the quality of food and water.

Transmission of Infection - Six Essential Elements

1. Infectious agent – Sufficient quantity of disease-causing pathogen (e.g., bacteria or virus).
2. Reservoir – Environment where the pathogen can survive (e.g., human body, animal vectors, outside environment, fomites).
3. Portal of Exit – Exit from the reservoir (e.g., urine, feces, saliva, respiratory tract, skin, blood, GI tract, mucous discharge).
4. Portal of Entry – Access point to enter the host (e.g., respiratory tract, mucous layer, GI tract, skin).
5. Mode of Transmission – Contact (direct, indirect, or droplet); Vehicle (airborne, waterborne, or foodborne); Vector (biological or mechanical).
6. Susceptible Host – Host where the pathogen can survive (e.g., genetic factors, health status, hygiene, behaviors).

Virulence Factors

• Pathogens produce a range of virulence factors that modulate the ability to infect a host.
• Promote colonization, entry, proliferation, and immune evasion.
• Examples:
  • Adhesion factors, biofilms, extracellular enzymes, toxins, anti-phagocytic factors, extracellular enzymes, toxins (exo- and endo- toxins), host immune-regulating molecules (e.g., decoy receptors, immunosuppressive cytokines, growth factors, immune signaling inhibitors, apoptosis inhibitors)
• Example: Virulence factors produced by poxvirus
  • Poxvirus genome encodes 200-250 genes – approx 50% are virulence factors!

Stages of Infection

• Incubation period: Initial infection before symptom onset; useful in infectious disease surveillance and control; often estimated based on symptom onset.
• Prodromal period: Early stage of mild symptoms prior to the characteristic manifestations of acute illness.
• Period of illness: Severe symptoms; generally brief duration
• Period of decline: Reduction in symptoms as pathogen is cleared
• Convalescence period: The return to pre-infected state. Health is restored

Skin

• Consists of epidermis, dermis, basement membrane, and hypodermis.
  • Epidermis: Outermost layer of skin (keratinized stratified squamous epithelium) serves as a protective barrier over the body’s surface.
  • Dermis: Contains connective tissue, mechanoreceptors, blood vessels, and sweat glands.
  • Basement membrane: Extracellular matrix between dermis and epidermis regulates cell migration and produces cytokines and growth factors.
  • Hypodermis: Innermost and thickest layer of skin contains collagen and elastin fibers, adipocytes, fibroblasts, macrophages, mast cells, blood vessels, lymphatic vessels, glands, and muscles in some parts of the skin (e.g., face).

Skin - Barriers and Risk Factors

• Mechanical Barrier: Stratified and cornified epithelium (keratinocytes, stratum corneum) provides a barrier from the external environment.
• Colonized with a diverse range of microbes (commensal microbiota), which deter colonization by pathogenic microbes
  • E.g., Staphylococcus epidermidis, Corynebacterium species, S. aureus, Streptococcus pyogenes, Enterobacteriaceae and Enterococcus species
• Chemical Barrier: Glands secrete low pH, sebaceous fluid, and fatty acid that inhibit pathogen growth.
• Risk Factors for Skin Infection
  • Patient-related factors: Critical illness, elderly age, immunocompromised disorders, liver and kidney diseases, and vascular insufficiency.
  • Etiological factors: Diabetes mellitus, cirrhosis, neutropenia, animal/insect bite wounds, human/animal/reptile contact, water exposure, and drug abuse.

Pathogenesis of Skin Infection

• Pathogens, at low numbers, initially colonize the skin, multiply, and enter upon skin breach.
• Breach can occur through lacerations, bite wounds, scratches, needles, pre-existing skin conditions, burns and surgery, contiguous spread from an adjacent infection.
• Infection causes folliculitis, furuncles (boil), carbuncles (collection of boils), erysipelas (infection of the upper layer of skin), or cellulitis (infection of deeper tissues).
• Involvement of deeper skin structures causes fasciitis (connective tissue), myositis (muscle), or panniculitis (fat layer).

Immune Response to Skin Infection

1. Tissue damage releases factors to increase blood flow and vessel permeability.
2. Fluid influx and immune cell recruitment
   • Limits pathogen spread
3. Neutrophils rapidly migrate to the site of inflammation.
4. Phagocytes (e.g., neutrophils and macrophages) ingest pathogen.

• Release of immune mediators (e.g., inflammatory cytokines and antimicrobial molecules (e.g., reactive oxygen species ROS, neutrophil elastase)
• Limit proliferation and cause direct killing of the pathogen

Mucosal Surfaces/Tissues

• Mucous membranes are endodermal surfaces covered by various types of epithelium overlaying connective tissue.
• Involved in absorption and secretion.
• Serve as a barrier between the external environment and internal organs (e.g., respiratory tract, gastrointestinal tract, and urogenital tract).
• Note: Mucosal barriers can be infected by bacteria, viruses, fungi, and parasites.

Mucosal Defense Mechanisms

• Mucosal epithelial cells form a contiguous lining.
• Constantly renewed mucosal barriers can be rapidly adjusted to changes in the environment.
• Mechanisms of Defense:
  • Mucus production: Mucus interferes with pathogen attachment, acts as a lubricant, and contains antimicrobial molecules. Protects against chemical, enzymatic, microbial, and mechanical damage.
  • Specialized microstructures: Trap pathogens and propel them out of the body (e.g., cilia in the respiratory tract).
  • Chemical factors: Include acid pH and antimicrobial peptides to directly kill bacteria.
  • Physical movement: Peristalsis of the gut and the flow of urine limit pathogen attachment.

Mucosal Immune Response

• Healthy tissue protected by mucosal immunity through mucus.
• Bacteria gain access to the lamina propria by endocytosis, activate macrophages but do not cause inflammation.
• Local effector cells respond to limit infection; dendritic cells travel to the mesenteric lymph node to activate adaptive immunity.
• Effector B cells and T cells that are highly specific for the invading bacteria colonize the infected area.
• Infection is terminated with either minor tissue damage or no need for repair.

Mobilizing Local Innate Immunity at Mucosal Entry

• The body races to mobilize local innate immunity and contain infection at the mucosal point of entry.
• Key players: IFN-α/β, IFN-λ, IFN-β, IFN-γ, IFN-α/β.

Specialised Mucosal Tissue Structures (MALT)

• Many mucosal tissues contain specialized secondary lymphoid structures that house immune cells.
• MALT = mucosa-associated lymphoid tissue
• GALT = gut-associated lymphoid tissue (including tonsils, appendix, and Peyer’s patches)
• BALT = bronchus-associated lymphoid tissue
• MALT contains a range of immune cells that can rapidly respond to pathogens in mucosal tissues.
  • T and B cells
  • Plasma cells that synthesize and secrete antibody (IgA)

Defense in the Respiratory Tract

• Respiratory tract: Lined with airway epithelium
  • Upper Respiratory Tract: Protection by ciliar beat, mucous secretion, antimicrobial factors, normal microbial flora.
  • Lower Respiratory Tract: Protection by ciliar beat, mucous secretion.
  • Alveoli: Resident alveolar macrophages rapidly phagocytize small particles. Dendritic cells ingest pathogens and may activate adaptive immune responses.

Mucosal Defense in the Gastrointestinal Tract

• General Mechanisms: Mucous secretion, mucosal epithelium barrier, peristaltic motion, secretory antibodies, phagocytic cells, and a large population of commensal bacteria.
  • Stomach: Low pH.
  • Small Intestine: The upper portion contains few bacteria.
  • Colon: Enormous numbers of microorganisms, 50-60% of fecal dry weight is bacteria.
• Epithelial cell turnover: The epithelial layer is under constant renewal at a high rate, which can detach pathogens and repair damaged epithelium efficiently.
• In the gut, M (microfold) cells transfer pathogens from the gut lumen to dendritic cells and macrophages, which then present pathogens to T cells in GALT and recruit antibody-secreting plasma B cells in the mucosa for the production of sIgA.
• Gut-Associated Lymphoid Tissue (GALT)
  • Peyer’s Patches: Located in the mucosa and submucosa.
  • Lamina propria lymphocytes: Scattered in the lamina propria of the mucosa.
  • Intraepithelial lymphocytes: Reside in the epithelium but not inside epithelial cells.

Defense in the Urogenital Tract

• Male:
  • No bacteria above the urethrovesicular junction.
  • Frequent urine flushing.
  • Prostatic fluid contains anti-bacteria substances.
  • Urinary sIgA.
• Female:
  • Large microbial population (lactobacilli) which generates low pH.
  • Phagocytic immune cells and antibody production.
  • Immune surveillance.

Infection Control

• Infection control measures aim to reduce the spread of pathogens and rapidly treat infection to limit symptoms.
• Population level: Education, vaccination, and isolation of infected individuals.
• Cut-off infection route: Personal hygiene, public hygiene, insecticide, disinfection.
• Protect susceptible populations: Active/passive immunization.

Active Versus Passive Immunisation

• Passive Immunization: Transfer of preformed antibodies to at-risk individuals.
  • Prophylactic (e.g., RSV) in susceptible individuals
  • Treatment (e.g., anti-venom) following exposure
• Includes the transfer of antibodies from mother to infant via placenta or breast milk.
• Active Immunization: Stimulation of the individual’s own immune system to induce antibody production.

Types of Vaccines

• Inactivated – the pathogen is killed and administered.
• Live attenuated – low pathogenicity pathogen applied.
• Purified subunit - purified pathogen molecules are used.
• DNA vaccines – DNA vector transferred which expresses vaccine antigens.
• Viral vector – e.g. Adenovirus vector to deliver DNA encoding the vaccine antigen.
• mRNA vaccine – mRNA encapsulated in lipid nanoparticle encodes vaccine antigen
• Adjuvants: Mixed with vaccine antigens to trigger and direct adaptive immune response.
• Mechanisms of action:
  • Activation of antigen-presenting cells.
  • Promotes the persistence of antigen (slow release).

How do Vaccines Work?

• Vaccine antigens are taken up by antigen-presenting cells (APCs).
• Adaptive immunity activation depends on adjuvant:
  • B cells activated and form memory B cells and produce antibodies
  • Most vaccines are designed to induce neutralizing antibodies
  • T cells activated and form memory T cells
  • T cell vaccines are now being developed for numerous diseases (e.g., malaria, HIV, influenza, cancer, tuberculosis)
• Adaptive memory immune response is ready upon exposure to the pathogen.

Coronavirus Vaccines in Development

• Protein-based: Spike protein is purified and injected; the body produces antibodies.
• Viral vector: Adenoviral vector with purified spike protein gene is injected; the body produces the spike protein and the immune system responds.
• mRNA: mRNA that codes for the spike protein is purified and injected; the body produces the spike protein.

Vaccine Approaches – Subunit Vaccines

• Critical ‘subunit’ of the virus is used as the antigen (e.g., surface protein).
  • Purified protein subunit purified from virus culture (e.g., Flu vaccine – hen eggs or cell culture) or recombinant DNA cloning.
• Direct administration will not induce a cell-mediated response (needs to be formulated with adjuvant).
• But subunit alone is not infectious.

Vaccine-Preventable Diseases

• Pneumococcal
• COVID-19
• Influenza
• Meningococcal
• Human Papillomavirus
• Hepatitis A
• Hepatitis B
• Tetanus
• Pertussis
• Varicella
• Rotavirus
• Poliomyelitis
• Haemophilus influenza type b
• Measles
• Mumps
• Rubella

Resources

• Infection. Barbara Bannister. 3rd Edition. John, Wiley & Sons, Limited
• Oxford Textbook of Medicine: Infection. David Warrell. Oxford University Press.