MICB 211 Chapter 12 Notes

Bacterial Pathogenesis and Virulence

Pathogenicity

-bacterium’s ability to cause disease

• qualitative

Pathogen

• bacterium that is capable of harming a healthy host

• may cause harm to healthy host → doesn’t always cause harm

Healthy Host

• host whose defence mechanisms are not compromised

Compromised Host

• host whose immune defence system is weakened

Opportunistic Pathogen

• bacterium that harms a compromised host

Virulence

-measure of the pathogenicity of a microorganism

• quantitative

-expressed as the cell number that will elicit a pathogenic response in the host within a given time period

ex: infection with a relatively small number of highly virulent bacteria will kill a certain number of mice whereas an infection with much more of less virulent bacteria is required to kill the same number of mice

-extent of virulence is correlated with ability of pathogen to multiply within the host

• may be affected by

  • route of entry

  • general health/susceptibility of the host

Virulent Organism

• causes disease in most individuals with whom it comes in contact with

Avirulent Organism

• rarely causes disease in humans

-virulence of microorganisms is attributable to the fact that they possess virulence factors

• allow it to enter and colonize in the host, resist immune defences of host and cause damage in the hose

Bacterial Infections

-classified into

• primary infection

• secondary infection'

• subclinical infection

• nosocomial infection

-classified into extent of host involvement

• influenced by invasiveness of organism

  ie. ability of organism to invade beyond the original site of entry into host’s body

Primary Infection

-initial, acute infection

Secondary Infection

-second/later infection caused by an opportunistic organism after a primary infection has weakened the host defences

Subclinical Infection

-host has no apparent symptoms

Nosocomial Infection

-acquired as a consequence of hospitalization or process of receiving health care

-infection was not present before entering health care facility

Local Infection

• restricted to a relatively small area of the body

• non-invasive organisms usually cause these infections

Systemic (Generalized) Infection

• infection that is spread throughout the body

• invasive organisms cause these infections

Focal Infection

• begins in restricted area then spreads throughout the body

-host susceptibility influences outcome during infection

• interaction between microorganisms and host is affected by virulence of microorganisms and anti-bacterial defences of the host

-susceptibility to infection is increased if anti-bacterial defences of host are compromised

• bacteria with low virulence may cause disease in compromised host

-host may be more susceptible to infection if there are factors that compromise immune defences

1. underlying disease or infection

   • AIDS, cancer, inherited immunodeficiencies

2. stress

3. poor nutrition

   • lack of essential vitamins/minerals

4. age

   • underdeveloped immune defenses of newborn and infant

   • degeneration of immune response for old people

5. immunosuppressive therapy

   • drugs used in treatment of certain cancers

   • maintenance of transplanted organs

6. genetics of host’s defence system

   • individuals in population respond differently to infection

   • genetic diseases can affect susceptibility to infection

     ex: cystic fibrosis, lung infection

   • some individuals more resistant/susceptible to infections than others

Infecting the Host

Mode of Infection

1. bacterium has to come in contact with host’s body

2. bacterium has to adhere to (and transiently colonize) or invade the host

3. bacterium has to multiply

4. bacterium has to evade the host’s innate immune defense system

-for bacterium to cause disease → must

• possess chemical/molecular mechanisms that damages the host

• trigger a chronic inflammatory response

-invasive organisms may cause systemic infections

• infection can be disseminated throughout the body

  *bacteremia → presence of bacteria in blood

Koch’s Postulates

-Robert Koch established a set of postulates that allow one to determine whether a relationship exists between a particular organism and disease

-proved a causative relationship between most bacterial pathogens and their respective diseases

1. certain bacterial pathogens can’t be cultivated in vitro

2. sometimes there are no animal models for a specific disease

Molecular Version of Koch’s Postulates

1. gene(s)/factor should be present in pathogenic strains of the organism and absent from non-pathogenic strains

2. molecular disruption (eg. deletion of genes) should reduce the virulence of bacterial strains and introducing the cloned gene(s) into an avirulent strain should render the strain virulent

3. gene(s) must be expressed at some point during the infectious process in experimentally infected animals

4. antibody raised against the virulence factor should offer some protection against infection in an experimentally infected animal

Regulation of Genes Encoding Virulence Factors

Virulence Factors

• disease-causing genes described in molecular version of Koch’s postulates

• possession of virulence factors is what allows pathogenic bacteria to infect normal people and cause disease

-a particular bacterium may live in many different environments

• may need to regulate the expression of components needed for survival in varying conditions

-bacteria may turn on these different components which include virulence factors only when needed

Environmental Factors

• temperature

• nutrients

• oxygen

• pH inside the cell

• iron availability

• osmolarity

-common processes regulated at the genetic level includes metabolism, response to environmental stresses and conditions, and cell division

-many virulent bacteria have global regulatory systems to regulate virulence factors

• these systems are co-ordinately regulated by a two-complement system that comprises a sensor protein and a regulator protein

• common system for signal transduction

-sensor (kinase) protein detects changes in environment that indicate that the bacterium is residing inside a human host and then phosphorylates the response regulator protein

-phosphorylated regulator protein then transcriptionally activates or represses the virulence factors by binding to a DNA sequence in the regulatory regions of each of the operons for these virulence factors

Virulence Factors: Mechanism of Pathogenic Bacteria

Bacterial Adherence

-first host barrier for many invading pathogens is usually a mucosal surface

• gut or respiratory tract

-most successful pathogens have evolved specific mechanisms to adhere to host tissue

-simple attachment is mediated through a receptor on the host cell surface (glycoproteins, glycolipids) and an adhesion (pili, capsule) on the surface of the bacterial cell

-these mechanisms benefit the pathogen by facilitating colonization, preventing the removal of the bacterium by non-specific host defence systems and by localizing the bacterium to the appropriate tissue

-specificity of interaction between host and bacterium is

• host-specific

• tissue-type specific

-pili allows bacteria to mediate adherence to host cells

• pili have a range of different functions

  • motility

  • conjugation

  • host cell adherence

-host responds to adherent organisms through

• production of antibodies against bacterial surfaces

• upregulation of production of antimicrobial peptides by epithelial cells

• phagocytosis of the adherent organisms

• shedding/destruction of epithelial cells that become colonized with bacteria

Capsules

-many pathogens have evolved surface components that prevent attachment and engulfment of macrophages and other host cellular immune responses to avoid phagocytosis

• aided by

  • membrane bound proteins

  • slimy polysaccharide capsules

  • lipopolysaccharides (Gram(-)) only

• these factors prevent the deposition of antibodies and complement on bacterial surface

  • avoiding complement-mediated killing and reducing phagocytosis

Toxins

-microbial products that can damage the host

-capable of causing disease, independent of the bacterium

ex. pathogenic bacteria can be killed in a patient but disease may persist due to continued action of toxin

Exotoxins

-secreted proteins made by both Gram (+) and Gram (-) bacteria

-toxins may enter blood circulation and spread to parts of body and cause damage far from site of bacterial colonization

-3 main categories

1. cytolytic toxins

   • enzymatically attack the cell constituents causing cell lysis

2. neurotoxins

   • interfere with nerve cell function

3. enterotoxins

   • affect cells lining the GI tract

   • causes massive fluid secretion (diarrhea)

-potent molecules

• small dose can have a significant effect on host

-proteins

-usually heat labile

-immunogenic

• stimulates immune system to produce neutralizing antibodies

-vaccination against toxin-mediated diseases can be done by immunization with toxoids

Toxoids

• toxins that have been treated with heat or chemicals to make them non-toxic to patient

• still capable of stimulating production of neutralizing antibodies

Endotoxins

-released only when bacteria die or are digested by phagocytic cells

-non-protein molecules that are heat stable

-generally associated with LPS (gram (-))

-activates macrophages causing release of inflammatory cytokines

-low doses (< 1 mg) → patient might experience fever, aches, pains

-higher doses → damage to circulatory system and shock

Endotoxin Shock

• fluids leak out of blood vessels, blood coagulates, blood pressure drops, organs fail and death may result

• treatment includes supportive therapy

  • no antibiotics (aggravates LPS/endotoxin release)

  • no vaccine since endotoxins are non-protein molecules (not immunogenic)