Pathogenicity and Infectious Disease

Topic 10 - Pathogenicity

Bacteria Are Everywhere

• We contact numerous microorganisms daily through breathing, ingestion, and skin contact.
• The vast majority of these microorganisms generate no ill effects.
• Most swallowed microbes die in the stomach or are eliminated in feces.
• Relatively few are pathogens that cause damage.
• Pathogens possess distinct characteristics that allow them to avoid some body defenses.
• Bacteria that are shed from the skin cannot colonize because they are not pathogens.

Microbes, Health, and Disease

• Most microbes are harmless, and many are beneficial.
• Normal microbiota (normal flora) are organisms that routinely reside on the body’s surfaces.
• The relationship between the host and normal microbiota is a delicate balance.
• Some normal microbiota can cause disease if the opportunity arises.
• Weaknesses or defects in innate or adaptive defenses can leave individuals vulnerable to invasion.
• Individuals with such weaknesses are said to be immunocompromised.

Anatomical Barriers as Ecosystems

• Skin and mucous membranes serve as barriers and also host complex ecosystems of microorganisms.
• This is an example of symbiosis, or “living together”.

Mutualism

• Both partners benefit.
• Example: In the large intestine, some bacteria synthesize vitamin K and B vitamins, which the host can absorb; the bacteria are supplied with warmth and energy sources.

Commensalism

• One partner benefits, and the other is unharmed.
• Many microbes living on the skin are neither harmful nor helpful but obtain food and necessities from the host.

Parasitism

• One organism benefits at the expense of the other.
• All pathogens are parasites, but medical microbiologists often reserve this term for eukaryotic pathogens (e.g., protozoa, helminths).

The Normal Microbiota

• Resident microbiota inhabit sites for extended periods.

• Transient microbiota inhabit temporarily.

• Examples of normal microbiota at various body sites:

  • Nose: Staphylococcus, Corynebacterium
  • Mouth: Streptococcus, Fusobacterium, Actinomyces, Leptotrichia, Veillonella
  • Skin: Staphylococcus, Propionibacterium
  • Large intestine: Bacteroides, Escherichia, Proteus, Klebsiella, Lactobacillus, Streptococcus, Candida, Clostridium, Pseudomonas, Enterococcus
  • Urethra: Streptococcus, Mycobacterium, Escherichia, Bacteroides
  • Vagina: Lactobacillus
  • Throat: Streptococcus, Moraxella, Corynebacterium, Haemophilus, Neisseria, Mycoplasma

The Protective Role of the Normal Microbiota

• Significant contribution is protection against pathogens.
  • Covering of binding sites prevents attachment.
  • Consumption of available nutrients.
  • Production of compounds toxic to other bacteria.
• When normal microbiota are killed or suppressed (e.g., during antibiotic treatment), pathogens may colonize and cause disease.
• Some antibiotics inhibit Lactobacillus (predominate in the vagina, suppress growth of Candida albicans), which results in vulvovaginal candidiasis.
• Oral antibiotics can inhibit intestinal microbiota, allowing overgrowth of toxin-producing Clostridium difficile.

Stimulation of Adaptive Immune System

• Important in the development of oral tolerance.
• The immune system learns to lessen response to many microbes that routinely inhabit the gut, as well as food.
• Basis of the hygiene hypothesis, which proposes that insufficient exposure to microbes can lead to allergies.
• Composition of normal microbiota is dynamic.
• Changes occur in response to physiological variations and activities in the host.
• Healthy human fetus sterile until just before birth.
• Exposed to microbes during passage through birth canal.

Vary in

• Section human microbe.

• Gestational diabetes

  • Microbes: huse role in the immune system, how we process food, hormones we make.

Principles of Infectious Disease

• Colonization refers to a microbe establishing itself on a body surface.
• The term infection can be used to refer to a pathogen.
• Can be subclinical: no or mild symptoms.
• Infectious disease yields noticeable impairment.
• Symptoms are subjective effects experienced by the patient (e.g., pain and nausea).
• Signs are objective evidence (e.g., rash, pus formation, swelling).
• Initial infection is a primary infection.
• Damage can predispose an individual to developing a secondary infection (e.g., respiratory illness impairing the mucociliary escalator).

Pathogenicity

• Primary pathogen is a microbe or virus that causes disease in an otherwise healthy individual.
• Opportunistic pathogen (opportunist) causes disease only when the body’s innate or adaptive defenses are compromised or when introduced into an unusual location.
• Virulence refers to the degree of pathogenicity.
• Virulence factors are traits that allow a microorganism to cause disease.
• Characteristics of Infectious Disease.

Communicable or Contagious Diseases

• easily spread.

Infectious Dose

• is the number of microbes necessary to establish infection.
• $ID_{50}$ is the number of cells that infects 50% of the population.
  • Example:
    • Shigellosis results from ~10–100 ingested Shigella.
    • Salmonellosis results from as many as $10^6$ ingested Salmonella enterica serotype Enteritidis.
    • Difference partially reflects ability to survive stomach acid.

Communicable or Contagious Diseases

• easily spread person -> person.

• Jetnis = environment bic deep injury from nail.

Infectious Dose for 50%

• Loverdose, fewes to get Sick vs. 4)I million (high dose) difference in disease & pathogenicity low: bad virus-Iness pathogens Hinselvel ncte-aunconser Susieon ↳ sprobumtia [

Course of Infectious Disease

• Incubation period: time between infection and onset.

• Varies considerably: few days for the common cold to even years for Hansen’s disease (leprosy).

• Illness: signs and symptoms of disease.

• May be preceded by prodromal phase (vague symptoms).

• Convalescence: recuperation, recovery from disease.

• Carriers may harbor and spread infectious agent for long periods of time in the absence of signs or symptoms.

• Acute: Illness is short term because the pathogen is eliminated by the host defenses; the person is usually immune to reinfection.

• Chronic: Illness persists over a long time period.

• Latent: Illness may recur if immunity weakens.

Duration of Symptoms

• Acute infections: Symptoms develop quickly, last a short time (e.g., strep throat).
• Chronic infections: Develop slowly, last for months or years (e.g., tuberculosis).
• Latent infections: Never completely eliminated; microbes exist in host tissues without causing symptoms.
• Decrease in immunity may allow reactivation.
  • Chicken pox (acute illness) results from varicella-zoster virus; the immune response stops, but the virus takes refuge in sensory nerves and can later produce viral particles, resulting in shingles.
  • Tuberculosis, cold sores, and genital herpes are also examples.

Distribution of Pathogen

• Localized infection: Microbe limited to a small area (e.g., boil caused by Staphylococcus aureus).
• Systemic infection: Agent disseminated throughout the body (e.g., measles).
• Suffix -emia means “in the blood”.
  • Bacteremia: Bacteria circulating in the blood.
  • Not necessarily a disease state (e.g., can occur transiently following vigorous tooth brushing).
  • Toxemia: Toxins circulating in the bloodstream.
  • Viremia: Viruses circulating in the bloodstream.
  • Septicemia or sepsis: Acute, life-threatening illness caused by infectious agents or products in the bloodstream.

Establishing the Cause of Infectious Disease

• Koch’s Postulates
  • Criteria Robert Koch used to establish that Bacillus anthracis causes anthrax:
    1. Microorganism must be present in every case of disease.
    2. Organism must be grown in pure culture from the diseased host.
    3. The same disease must be produced when a pure culture is introduced into susceptible hosts.
    4. Organisms must be recovered from experimentally infected hosts.
  • The microorganism must be present in every case of the disease, but not in healthy hosts.
  • The microorganism must be grown in pure culture from diseased hosts.
  • The same disease must be produced when a pure culture of the microorganism is introduced into susceptible hosts.
  • The same microorganism must be recovered from the experimentally infected hosts.

Koch’s Postulates continued

• Some limitations:
  • Some organisms cannot be grown in laboratory medium (e.g., the causative agent of syphilis).
  • Infected individuals do not always have symptoms (e.g., cholera, polio).
  • Some diseases are polymicrobial (e.g., periodontal).
  • Suitable animal hosts are not always available for testing.

Establishing Infection - Adhesion

• Adherence.
• Adhesins attach to host cell receptor.
• Often located at tips of pili (called fimbriae).
• Can be a component of capsules or various cell wall proteins.
• Binding is highly specific; exploits host cell receptor.
• Colonization.
• Growth in biofilms.

Establishing Infection - Invasion

• Penetrating the Skin
  • Difficult barrier to penetrate; bacteria rely on injuries.
  • Staphylococcus aureus enters via cut or wound; Yersinia pestis is injected by fleas.
• Penetrating Mucous Membranes
  • Entry point for most pathogens.
• Directed Uptake by Cells.
  • The pathogen induces cells to engulf via endocytosis.
  • Salmonella uses type III secretion system to inject effector proteins; actin molecules rearrange, yield membrane ruffling.
• Penetrating the Stomach lining
  • Invasion of Helicobacter pylori into the tissues of the stomach, causing damage as it progresses.

Infection - Damage to the Host

• Direct or indirect effects.
  • Direct (e.g., toxins produced).
  • Indirect (e.g., immune response).
• Damage may help pathogen to exit and spread.
  • Vibrio cholerae induces watery diarrhea, up to 20 liters/day, which can contaminate water supplies.
  • Bordetella pertussis triggers severe coughing; pathogens are released into the air.

Exotoxins

• Proteins with damaging effects.
• Secreted or leak into tissue following bacterial lysis.
• Foodborne intoxication results from consumption.
• Destroyed by heating; most exotoxins are heat-sensitive.
• Can act locally or systemically.
• Proteins, so the immune system can generate antibodies.
• Many are fatal before the immune response is mounted.
• Vaccines are therefore critical: toxoids are inactivated toxin.
• Antitoxin is a suspension of neutralizing antibodies to treat.

Neurotoxins

• damage the nervous system.

Enterotoxins

• cause intestinal disturbance.

Cytotoxins

• damage a variety of cell types.

Damage to the Host - Exotoxins

• A-B toxins have two parts
  • A subunit is toxic, usually an enzyme.
  • B subunit binds to the cell, dictates cell type to be infected.
• Structure allows novel approaches for vaccines and therapies; can use B subunit to deliver medically useful compounds to specific cell type.

AB Toxin - Diptheria

• Released interferes wiribosometo stop synthesis of proteins.

Membrane-Damaging Toxins

• Cytotoxins that disrupt plasma membranes, lyse cells.
• Hemolysins lyse red blood cells.
• Some insert into membranes, form pores.
  • E.g., streptolysin O from Streptococcus pyogenes.
• Phospholipases hydrolyze phospholipids of the membrane.
  • E.g., α-toxin of Clostridium perfringens (gas gangrene).

Damage to the Host - Exotoxins

Superantigens

• Simultaneously bind MHC class II and T-cell receptor.
• The T-cell interprets this as antigen recognition.
• The toxic effect is from massive cytokine release from $T_H$ cells.
• Include toxic shock syndrome toxin (TSST) and several by Staphylococcus aureus, Streptococcus pyogenes.

Cell talks to Helper T cell.

Damage to the Host - Endotoxin

• Endotoxin, Other Bacterial Cell Wall Components.

Endotoxin

• is lipopolysaccharide (LPS).
• Lipid A triggers an inflammatory response.
• When localized, the response helps clear.
• When systemic, causes widespread response: septic shock or endotoxic shock.
• Activates innate and adaptive defenses.
• Heat-stable; autoclaving does not destroy.
• Peptidoglycans and other components also trigger.

Damage to the Host

Comparison of Exotoxins and Endotoxin

• Exotoxins:
  • From Gram-positives and Gram-negatives
  • Protein; potent; usually heat-inactivated
• Endotoxins:
  • Only from Gram-negatives
  • Lipid A component of LPS; small localized amounts yield appropriate response, but systemic distribution can be deadly; heat-stable
• $ID_{50}$ = infectious dose
• $LD_{50}$ = Lethal dose

Mechanisms of Viral Pathogenesis

• Binding to Host Cells and Invasion
  • Viruses attach to target cells via specific receptors.
• Avoiding Immune Responses
• Avoiding the Antiviral Effects of Interferons

Antibodies and Viruses

• Move cell to cell or cause cell fusion (syncytium) to avoid.
• Modify surface antigens, outpace the body’s capacity to produce effective antibodies.
• RNA virus replicases, HIV reverse transcriptase lack proofreading ability; mutations common.
• Regulating Host Cell Death.
  • Prevent or delay apoptosis.
  • Block MHC class I presentation.
  • Present “counterfeit” MHC class I molecules
• Infected cell survives and carries the viral genome.
• Because of the fake MHC class I molecules, neither $T_C$ cells nor NK cells can recognize that the cell is infected.
• Viral genome directs the cell to make fake MHC class I molecules that cannot present peptides from cytoplasmic proteins.

Mechanisms of Eukaryotic Pathogenesis

• Colonization, evasion of defenses, damage to host.

Fungi

• Most live on decaying matter; those that cause disease are generally opportunists.
• Dermatophytes cause superficial infections of hair, skin, and nails; have keratinase enzymes.
• Fungi from normal microbiota (e.g., Candida albicans) can cause disease in immunocompromised hosts.
• Most serious fungal infections are caused by dimorphic fungi.
  • Present as molds in the environment, inhaled deep into lungs, and develop into other forms (e.g., yeasts).
  • The immune system usually controls unless compromised.
• Some fungi produce toxins: mycotoxins.
  • E.g., Aspergillus flavus produces aflatoxin.

Protozoa and Helminths

• Most live within the intestinal tract or enter via arthropod bite.
• Attach to host cells via specific receptors.
• Variety of mechanisms to avoid the immune system.
  • Hide within cells (e.g., Plasmodium species produce enzyme to penetrate red blood cells; Leishmania species survive, multiply within macrophages).
  • Vary surface antigens (e.g., African trypanosomes).
• Damage variable: can come from nutrient consumption in the digestive tract; intestinal blockage; the production of enzymes; the immune response.

Schistosomiasis Life Cycle Image Explanation

• A. Miracidia penetrate snail tissue.
• B. Cercariae released by snail into water and free-swimming.
• C. Cercariae lose tails during penetration and become schistosomulae.
• D. Paired adult worms migrate to the venous plexus of bowel/rectum/bladder, laying eggs that circulate to the liver and are shed in stools/urine.