3) Pathogenesis & Virulence

Pathogenesis: mechanisms by which disease develops, progresses, and either persists or is resolved

Virulence: Measure of degree of pathogenicity (damage) caused by organism

Capacity of a microbe to cause damage in a host

• measure of pathogenicity of an organism

• refers to the degree of damage caused by the microbe

• Continuum -> not categorical (yes / no)

  • one end: organisms that are avirulent (not harmful)

  • other end: organisms that are highly virulent (e.g. B. anthracis)

• Process, by which a disease develops

• To cause disease, a pathogen must successfully achieve four steps of pathogenesis:

  • 1) Exposure (contact)

  • 2) Adhesion (colonisation)

  • 3) Invasion

  • 4) Infections

• Pathogen must be able to gain entry to the host

  • travel to the location where it can establish infection

  • evade or overcome the hosts immune response

  • cause damage to the host (disease)

• The cycle is complete when the pathogen exists the host and is transmitted to a new host

• product made by the organism that contributes to overall virulence (e.g. toxin)

• help bacteria to

  • 1) invade the host

  • 2) evade host defenses

  • 3) cause disease

• Capsules -> protective coatings that surround the entire bacterial cell wall -> protection from phagocytosis

• Flagella -> Long, whip-like filaments anchored in the cell wall, with rotation allowing movement (towards nutrients)

• Pili -> Short, hair-like filaments, anchored to the cell wall (adhesion)

• Spores -> small, metabolically inactive forms of bacteria that can survive for years

• Toxins -> Proteins released by certain bacteria which can dysregulate critical cellular processes —> improve the capacity of bacteria to invade tissues (e.g. LPS)

• Siderophores -> Iron-binding factors that allow some bacteria to compete with host for iron (e.g. Enterobactin)

• Virulence of a pathogen can be quantified by using controlled experiments with labratory animals

• Two important indicators of virulence are:

  • median infectious dose (ID50) -> number of pathogen cells required to cause active infection in 50% of test subjects

  • median lethal dose (LD50) -> number of pathogenic cells or amount of toxin required to kill 50% of infected animals

• Primary pathogens: can cause disease in a host regardless of the hosts immune system

• opportunistic pathogen: can only cause disease in situations that compromise the host’s defense, such as the body’s protective barriers, immune system, or normal microbiota

• Individuals susceptible to opportunistic infections:

  • Very young / elderly

  • pregnant women

  • chemotherapy patients

  • immunodeficiency

  • recovering from surgergy

  • breach of protective barriers (severe wound or burn)

• Primary pathogen: Enterohmorrhagic E. Coli (EHEC)

  • produces a virulence factor known as Shiga toxin

  • Shiga toxin inhibits protein synthesis —> severe and bloody diarrhea and inflammation, even in patients with healthy immune system

• Opportunistic pathogen: Staphyloccus epidermitis

  • among most frequent causes of hospital aquired (nosocomial) disease

  • member of the normal skin microbiota (30% carriage rates)

  • In hospitals, can grow into biofilms that form on catheters / implants -> uses the entrance to enter the body

  • Once inside the body, S. epidermidis can cause serious infections such as endocarditis

• Commensals in animals are sometimes pathogens in humans

• Zoonosis: disease transmitted to human from animals

• Example: EHEC

  • can cause serious disease in humans (especially children)

  • from cattle

1) Exposure

• encounter with a potential pathogen

• needs to be able to gain access into host tissue

• portal of entry: anatomic site through which pathogen can pass into host tissue (eye, nose, mouth)

2) Adhesion

• Following initial exposure —> pathogen adheres at the portal of entry

• capability of pathogenic microbes to attach to the cells of the body using adhesion factors

3) Invasion

• Once adhesion is successful -> invasion can proceed

• dissemination of a pathogen throughout local tissues

• pathogens may produced enzymes or toxins which serve as virulence factors —> allow them to colonise and damage host tissue as they spread deeper into the body

• may also produce virulence factors that protect them against immune system defense

4) Infection

• Following invasion, successful multiplication of the pathogen leads to infection

• can be described as local, focal, or systemic depending on the extend of the infection

• Local infection

  • confined to a small area of the body, typically near the portal of entry

  • e.g. Urinary tract infections (UTIs) confined to the bladder

• Focal infection

  • localised pathogen or toxin it produces can spread to a secondary location

  • e.g. gum disease can lead to a local infection by Streptococcus -> may then gain access to the bloodstream resulting in a secondary infection in other locations

• Systemic infection

  • disseminated throughout the body

  • pathogen must overcome host defenses to cause systemic infection

  • damage to the host can be direct (via virulence factors such as toxins)

  • or may result from host immunemediated damage (sepsis)

• Horizontal gene transfer between bacteria leads to exchange of genetic material

• Bacteria may aquires new virulence traits -> evolves into pathogens

• Virulence factors in bacteria may be encoded in

  • chromosomal DNA

  • bacteriophage DNA

  • plasmids

  • transponsons

• Pathogenicity islands:

  • Large inserts of foreign DNA into bacterial chromosomes

  • frequently encode virulence associated traits

• Examples:

  • SPI1 -> Salmonella pathogenicity island 1 -> encodes Type 3 secretion system that is key for host cell attachment

  • SPI2 -> survival within macrophages