Week 11 - Infectious Diseases

Disease

A disturbance in normal functioning of an organism

Zoonotic diseases + examples

Infectious diseases from animals. Humans are usually dead-end hosts (ex. rabies, West Nile fever, Ebola).

Pathogens

Microbes frequently associated with disease production

Pathogenesis

Mechanism a microbe uses to cause the disease state, including infection and specific signs/symptoms

Primary pathogens vs opportunistic pathogens

Produce disease readily in healthy hosts vs only cause disease when displaced to an unusual site or when the host has a weak immune system

Virulence

Intensity of disease that a pathogen can induce

Case-to-infection (CI) ratio

Proportion of infected individuals who develop the disease

LD50 vs ID50 vs TCID50

LD50: amount of pathogen/toxin that kills 50% of subjects

ID50: amount of pathogen that causes infection in 50% of subjects

TCID50: amount of pathogen that causes infection in tissue culture 50% of the time

Attenuated strains

Weaker versions of viruses that are useful for vaccines (train your immune system)

Avirulent strains

No longer cause disease

Carrier (asymptomatic)

Individual infected with a pathogenic microbe who never exhibits signs or symptoms of the disease (asymptomatic), can still transmit the microbe to others

How do pathogens cause infections? (3)

1. Gain access to tissues

2. Evade/overcome host defences

3. Obtain nutrients from the host

Virulence factors

Produced by pathogens to help cause infections

E. coli (disease + virulence factors + action)

• Causes hemorrhagic colitis and kidney failure

• Intimin, tir, T3SS, shiga toxins

• Attachment, receptor for attachment, injects tir for attachment, stops translation in host cells

Neisseria gonorrhoeae (disease + virulence factors + action)

• Causes gonorrhea

• Fimbriae, IgA protease, LOS (an endotoxin)

• Attachment, immune evasion, destruction of IgA antibody, evokes inflammatory damage

Attachment mechanisms

Can occur through specific protein-protein interactions (ex. viruses) or through more general interactions (ex. rice blast spores stick to most cells)

Host range + how can it be expanded?

The group of organisms a pathogen can infect. Can be expanded via mutation (ex. FPLV in cats became CPV in dogs)

Antigenic variation/drift

Shift their surface protein structures to avoid host immunity

Capsules

• Provides attachment

• Interferes with opsonization (phagocytosis), antibody binding, and antibody stimulation

Latency

Ultimate evasion method, virus inserts its genome into host cells and goes dormant. Periodic reactivation → lytic replication may occur

Restriction endonucleases

Used by bacteria to digest phage DNA, a defence mechanism

Exotoxins vs endotoxins

Toxins produced/secreted vs toxins part of the microbial structure itself, both cause inflammation

Examples of endotoxins (2)

• Lipopolysaccharide (LPS): most common endotoxin, gram-negative bacteria

  • LOS: lacks the O-antigen

• Lipoteichoic acid: found in Gram-positive cells

Examples of routes of transmission (4)

• Fecal-oral

• Respiratory

• Vector-borne

• Sexual transmission

Direct vs indirect contact

Physical contact between hosts vs an inanimate object carries the agent between infected and susceptible hosts

Horizontal route of transmission + examples

Transmission between members of the same species, often via respiratory, fecal-oral, and sexual exit + entry points (ex. rhinovirus, influenza, polio)

Vertical route of transmission + examples

Transmission from parent to child, often in utero via placenta, birth, breast milk, and germ cells (ex. HIV, hep B + C)

Epidemiology

Study of patterns of disease in populations

Morbidity vs mortality rate

Rate of disease vs rate of death due to disease in a pop.

Incidence vs prevalence

Number of new cases appearing vs total number of cases overall

Endemic disease

Always present in the population, often results in cyclical patterns due to season, immunity status, etc

Epidemic

Incidence of a disease rises much more than the normally expected value

Outbreak

Unexpected cluster of cases in a short time in a localized population

Common-source epidemics

Single source of infection which the population is exposed to, rapid increase in incidence followed by decrease, cases tend to stay near the source of the problem (ex. food poisoning)

Propagated epidemic

Infection passing from one host to another, exhibits a gradual increase in incidence over time (ex. flu, measles, tuberculosis, COVID-19)

Koch’s postulates (4)

Used to show whether a specific microbe causes a specific disease:

• Suspected microbe must be in every person with the disease, but not those without the disease

• Pure culture of the suspected microbe is obtained

• Experimental inoculation of the suspected microbe into a healthy test subject causes the same illness

• Suspected microbe is recovered from the experimentally inoculated host organism

Gastric ulcers and Koch’s postulates

• H. pylori was thought to cause stomach ulcers

• But it was also found in many individuals without ulcers, and regular use of medication can also cause ulcers

Issue with Koch’s postulates

Not all individuals show the same degree of infection, and some things are genetically more susceptible to certain infections

Molecular Koch’s postulates

Sometimes, the classic postulates are not ethical or possible, so a modern adaptation was made:

• Virulence factors should be present in the pathogen

• Experimental inactivation of the vir factor gene should decrease virulence

• Vir factor gene should be expressed in an infection

• Immunity to the pathogen/resistance to the vir factor must provide protection

Virulence factors + genetic spread between pathogens

• Include adhesion, invasion, or secretion factors

• Can be passed via horizontal gene transfer, implanting pathogenicity islands

Emerging/reemerging diseases

Occurs when a pathogen encounters a new population (zoonotic transfer), ex. transfer of SIV in monkeys to HIV in humans

Lyme disease (microbe, vectors)

• Caused by B. burgdorferi

• Usually in deer and mice, but is transmitted to humans through ticks

• Spread quickly through the US when humans spread into forests

Cause of pathogenic E. coli

Acquiring vir factor genes via horizontal gene transfer, producing shiga toxins and shutting down translation

How did methicillin-resistant S. aureus (MRSA) come to be?

Selective pressure from antibiotic overuse has led to acquisition of resistance traits against the drugs

Enterococcus faecium case study

• Gastrointestinal bacteria that cause severe infections

• Resistant E. faecium (VREfm) emerged due to high antibiotic use in hospitals

• Sequenced REfm using Illumina to analyze factors contributing to resistance, found emerging strains inhibited the growth of old strains

• Bacteriocin T8 production was found to be a driving feature of global VREfm strain emergence and persistence in healthcare settings

Fibronectin-binding proteins

Bind to fibronectin via fimbriae w/ adhesive tips, repulses negative charge on the host cell

Tir and intimin

Tir is injected into intestinal cells via T3SS, producing a pedestal that bacteria latch onto and feed from via intimin. This allows them to steal nutrients from intestinal cells

Methods that microbes use to deliver virulence factors (3)

• Cell lysis (ex. C. botulinum releasing botulinum toxin)

• Secretion to environment (ex. S. aureus and a-toxin)

• Injection into host cell via T3SS and T4SS by gram-negative species (ex. E. coli and tir)

Iron-binding strategy by pathogens

• Iron is a limiting nutrient sequestered by lacto+transferrin and locked inside host cells

  • Use siderophores to compete with host lactoferrin and transferrin

  • Lower pH at site of infection, impairing lacto and transferrin

  • Produce cytolysins that lyse host cells to steal iron

Tuberculosis + iron

Caused by M. tuberculosis, which requires iron to survive + steals it from RBCs

Exotoxins (3)

• A-B toxins: B subunit binds to host cell receptors, causing a negative action in the cell

• Cytolysins: act on cell membranes to burst cells

• Superantigens: stimulate T cells to secrete lots of cytokines

A-B toxins

B binds to receptors on host cells → taken up by endocytosis → B dissociates and forms a channel into the cell → A enters through the channel and has toxic enzymatic activity inside host cells

Diphtheria toxin (bacteria + activity + disease)

• A-B toxin released by Corynebacterium diphtheriae

• Inhibits EF2 + protein translation

• Causes diphtheria

Cholera toxin and pertussis

• A-B toxin by Vibrio cholerae and Bordetella pertussis

• Increase cAMP levels by making adenylate cyclase constitutively active

• Cholera and whooping cough

Shiga toxins

• A-B toxin by Shigella dysenteriae and E. coli

• Cleaves rRNA + prevents ribosome synthesis

• Hemolytic uremic syndrome

SNARE proteins and A-B neurotoxins

Cleave SNARE proteins, preventing neurotransmitter release (ex. botulism toxin prevents muscle contractions by blocking acetylcholine, tetanus toxin produces continuous muscle contraction by blocking glycine and GABA )

Cytolysins

Form pores or degrade phospholipids (ex. hemolysins lyse RBCs, S. aureus forms pores)

Phospholipase cytolysins

Degrade phospholipids, ex. lecithinases causing gangrene

Superantigens + related syndromes

Act on T cells, releasing a massive amount of cytokines that induce systemic inflammation. Cause toxic shock syndrome + food poisoning

Streptococcus pyogenes (attachment + overcome host defences)

• Opportunistic

• Attaches with fibronectin-binding proteins

• Overcomes host defences with capsules and M proteins (bind antibodies)

Mycobacterium tuberculosis

• Surround themselves with lipoarabinomannan (LAM), superoxide dismutase, and catalase to protect themselves from oxidative damage

• Form granulomas that crack open and cause caseous necrosis, freeing the microbe

How do bacteria become pathogens?

• Random mutation

• Horizontal gene transfer

  • Conjugation, transposable elements, plasmids, and temperate (lysogenic) phages

Pathogenicity islands (PAIs) (what is it + what they code for + how are they identified)

• Large DNA sequences from foreign sources via HGT, not found in non-pathogenic strains

• Adhesion/invasion molecules, toxins, T3/4SS, iron-binding proteins

• Unusually high/low GC content

Contents of pathogenicity islands related to transposons, integrated phage genomes, and phage DNA integration mechanisms

Transposons: flanking direct repeat regions

Integrated phage genomes: multiple mobile genetic elements

Phage DNA integration: adjacent tRNA genes

Transduction

Transferring toxic genes via lysogenic phages to other microbial strains

Why would phages carry toxin genes against eukaryotic cells? + diphtheria toxin example

Kills competing eukaryotic cells, providing more nutrients to microbial hosts of phages → phages can thrive. Diphtheria toxin is expressed by C. diphtheriae in the human body, where iron levels are low, so that the toxin can lyse body cells for iron

Role of protozoa in pathogen spread to human

Pathogens that can survive and thrive and protozoa often thrive inside human cells as well

Productive vs abortive infections

New infectious viral particles are produced in host cells (hijacks host cell) vs few (if any) are produced

3 types of infections

Acute, latent, and persistent

Acute infections + example

Short duration → symptoms observed → infection is cleared and immunity is gained (ex. common cold)

Persistent/chronic infections + example

New viral particles are continuously produced, so the host doesn’t clear the virus in a reasonable timeframe (but symptoms may cease). May be due to weakened immune system or mutated virus (ex. hep B or C)

Latent infections

Acute infections → latency, replication of virus shuts down and may reactivate under stress (ex. herpesviruses, lambda phage)

Mechanism of herpesvirus in latent infections

Maintains an episome (its own circular genome) during latency + latency associated transcripts (LATs) which help maintain latency

Mechanical route of transmission + example

Transfer of virus from host to host via another vector, where the vector is not a reservoir but just a transport vehicle. Some insect vectors are required for virus replication cycles, while some are just passive vectors (ex. yellow fever, myxoma virus)

Apoptosis

Cell suicide to safely kill infected cells, usually doesn’t cause inflammation. DNA is degraded into small fragments and bits of cell are released as “blebs”

Necrosis + poliovirus and bunyavirus mechanisms

Cell bursts due to overfilling with new viruses or viral impairment of normal functions. Poliovirus hijacks translation and makes a ton of viral proteins, while bunyavirus cap-snatches host cell mRNA, degrading it, and puts the cap on viral mRNA instead

Syncytia and inclusion bodies

Viruses fuse host cells together or form clumps of viral proteins inside host cells, both of which kill host cells

How are immune responses responsible for the signs and symptoms of viral infection? (cytokines + Hep B + HBV)

• Inflammatory cytokines of the common cold causes symptoms

• Killing Hep B-infected hepatocytes, impairing liver damage

• HBV antibody-antigen complexes deposited in the kidney, causing damage

Molecular mimicry + example

Viral proteins looking similar to host proteins, causing antiviral responses to target host proteins (ex. multiple sclerosis is caused by T cells destroying myelin)

3 events that occur as viruses reproduce, altering their virulence

Mutations, recombinations, and reassortments

Viral mutations

Many viruses lack DNA proofreading, leading to changes over time

Antigenic drift

Structural mutations in hemagglutinin (HA) and neuraminidase (NA) viral surface proteins that make our immune responses ineffective

Viral recombination

Fusion of two separate viral genomes to make a new hybrid genome, resulting in entirely new properties

Virus reassortment

Segmented genome from multiple viruses swapping segments to form new viruses. Causes antigenic shift, a dramatic change in antigens due to reassortment

Cultural influences on the evolution and virulence of pathogens (2)

• Nurseries: hospital attendants, who touch many babies, can serve as vectors

• WW1 trenches: extreme crowding, many sick and injured, and the monoculture of male soldiers made disease spread rampant