Microbiology Test 4

Disease

Disease

a disturbance in normal functioning of an organism

Infectious disease

is caused by a microbe and can be transmitted from host to host

• influenza, HIV, hepatitis B

Zoonotic Diseases

are infectious diseases of animals that can cause disease when transmitted to humans

• rabies, West Nile fever

Pathogens

microbes frequently associated with disease production

Pathogenesis

the mechanism a microbe uses to cause the disease state

Infection

refers to the replication of a pathogen in or on its host

Sign

objectively measurable and defined disease manifestation

Symptom

pathological effect experienced but not easily quantified

Primary Pathogens

tend to produce disease readily in healthy hosts

Opportunistic Pathogens

generally only cause disease when displaced to an unusual site or when the host has a weakened immune system

Virulence

measure of the severity of disease a pathogen can induce

Case-to-Infection (CI) Ratio

proportion of infected individuals who develop the disease

Genetic Differences

pathogens can weaken over time or show different virulence levels due to

Attenuated

strains show virulence

• may be useful for vaccine development

Avirulent

strains can no longer cause disease

Carrier

individual infected with a pathogenic microbe who never exhibits overt signs or symptoms of the disease (asymptomatic)

• the asymptomatic host may still be able to transmit the microbe to others

To cause infection, most pathogens must

• gain entry to the host

• attach to and invade specific cells and/or tissues within the host

• evade host defenses

• obtain nutrients from the host

• exit the host

Attachment

may occur through specific protein interactions

• viruses often utilize a specific host cell receptor

occasionally, may occur through more generalized interactions

• rice blast fungus spores adhere to most hydrophobic surfaces, including cells

Host Range

the group of organisms that the pathogen can infect

• determined by the pathogen’s ability to replicate within a host

Evading Host Defenses

after attachment and invasion, pathogens must still avoid elimination by host defenses

Antigenic Variation

some microbes employ this, shifting their surface protein structures

Latency

can be used by herpes viruses

• may be the ultimate evasion method

  • the virus inserts its genome into host cells

  • replication stops

  • periodic reactivation may occur

Capsules

on bacteria make them hard to phagocytose

Bacteria

use restriction endonucleases to digest phage DNA

Different Microbial Pathogens

cause disease in different ways

• most posses multiple properties that collectively lead to disease induction

• production of toxins is common

  • exotoxins

  • endotoxins

Viruses

typically don’t produce toxins

• instead, their replication induces either cell death or induced cell death (apoptosis) via immune responses to reduce the viral spread

Exotoxins

are proteins produced and secreted that can have negative effects on host cells

Endotoxins

are a part of the microbial structure itself

Transmission

spread of an infectious agent from one host to another

• may also occur from a pathogen’s natural source (reservoir) to a host

Contact

direct

indirect

Direct Contact

physical contact between infected/susceptible hosts

Indirect Contact

object carries agent between infected and susceptible individual

• object is often a fomite (inanimate object)

Vectorborne

transmitted via another species

Horizontal Transmission

transmission of a pathogen between members of a species other than parent to offspring

Vertical Transmission

passing of a pathogen from parent to child (often in utero, during birth, or shortly after birth)

Zoonotic Transfers

pathogen moves from its natural (reservoir) host to a human

• humans are often “dead-end” hosts, where the pathogen isn’t efficiently transferred from person to person

Epidemiology

study of patterns of disease in populations

Morbidity Rate

rate of disease in a population

Mortality Rate

death rate of disease

Centers for Disease Control and Prevention (CDC)

the federal epidemiology body

World Health Organization (WHO)

a global epidemiology center

Case

• must be defined carefully

• may include individuals infected and exhibiting the disease

• may also include infected individuals not showing signs or symptoms of the disease state (asymptomatic or subclinical)

Incidence

number of new cases appearing in a population during a specific time period

Incidence Rate

number of new cases/number of people

Prevalence

total number of cases in a population at a particular time

Endemic Disease

habitually present in the population

• often results in cyclical patterns of increased incidence

• rabies is endemic to North American foxes, bats, etc

• incidence rates may change with the seasons

Incidence Rate Increases

as more susceptibles join the population

Incidence Rates Decrease

as outbreaks result in more immune individuals

Epidemic

incidence of a diseases rises significantly above the normally expected value

Outbreak

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

Pandemic

a global epidemic

Koch’s Postulates

can be used to show a specific microbe causes a specific disease

Koch’s Postulate

• the suspected microbe is identified in every person with the disease, but not those without the illness

• a pure culture of the suspected microbe is obtained

• experimental inoculation of the suspected microbe into a healthy test host causes the same illness

• the suspected microbe is recovered from the experimentally inoculated host organism

Gastric Ulcers

• sores on the lining of the stomach thought to be caused by excess acid

• in the 1980s, researchers isolated a microbe (Helicobacter pylori) from ulcerated tissue

  • by applying classic Koch’s postulate rules, this microbe was found to be the causative agent of stomach ulcers

Molecular Koch’s Postulates

a more modern take on these “rules” includes adaptation for today’s molecular biology tools

• the virulence factor should be present in the pathogen

• experimental inactivation of the virulence factor gene should decrease virulence

• reversion of the inactivating change should restore virulence

• the virulence factor gene should be expressed during an infection

• immunity to pathogen must provide protection

Virulence Factors may include

• adhesion

• invasion

• secretion factors

• toxins

Emerging or Reemerging Diseases

may occur when a pathogen encounters a new population

examples

• transfer of simian immunodeficiency virus (SIV) into humans as HIV is an example

• Lyme disease

Lyme Disease

caused by the bacterium Borrelia burgorferi

• normally resides in deer and mice

• can be transmitted to humans through the black-legged tick (lxodes scapularis), a vector organisms

• induces a characteristic rash in early stages

Why does some E. coli become dangerous?

• acquisition of virulence factor genes via horizontal gene transfer

• E. coli O157:H7 produces a toxin derived from Shigella species

• this toxin allows it to destroy host cells by shutting down protein production, making this strain much more dangerous

Methicillian-resistant Staphylococcus aureus

selective pressures of antibiotic overuse have led to acquisition of resistance traits against the drugs

• a “normal” microbe becomes significantly more dangerous to humans as strains able to resist elimination drugs are selected

What are we doing to learn more about emergence of new diseases?

• surveillance may be the best weapon

  • when we know an epidemic is getting started, we can most effectively stop its progress

  • organizations such as the CDC and WHO, as well as the Pan American Health Organization (PAHO) and the Border Infectious Disease Surveillance Project (BIDS), track cases and incidence of certain diseases

Polio Vacination

has been very effective

• in 1952, there were 58,000 cases in the United States

• by 1964, with immunizations, there were only 121 cases

• the last wild case occurred in the United States in 1979

Immunology

the study of the components and processes of the immune system

Innate Immune Defenses

• found in all multicellular organisms

• provide a first line of defense against microbes

• usually recognize biochemical differences between microbes

• while microbes can be recognized as “foreign,'“ this system cannot discern the precise identity of the microbe

  • it simply responds to an entire group of similar microbes in the same manner

  • it is therefore “nonspecific” in the nature of its responses

Adaptive Immune Defense

• found only in vertebrates

• works with innate responses to achieve a stronger level of defense

• recognizes specific pathogens rather than broad classes of microbes

• response is mediated my molecules that bind to specific pathogens

• retains memory after response is used and can initiate it more quickly upon re-exposure

Skin

generally inhospitable to foreign microbes

• cool, dry, acidic (pH 5.0)

• dead layer of cells on top proves an “armor”

• a layer of antimicrobial oil (sebum) lies on top

• sweat secretions can also provide an antimicrobial barrier

Normal Flora Microbes

colonize the skin and can “crowd out/starve out” potential invaders

Mucosal membranes

interior surfaces coated with wet mucus

• moved along the surface to prevent microbe attachment

• contain antimicrobial molecules:

  • defensin proteins

  • lysozyme

  • lactoferrin

• competitive exclusion by normal flora

Inflammation

important, early physiologic response to microbial invasion and damage

• triggered by release of proinflammatory molecules (such as histamine and cytokines) from local cells

Consequences of Local Inflammation

• vasodilation

• extravasation

• increase in vessel permeability

Cytokines

are often used to communicate the status of an infection by:

• producing fever

• enhancing inflammation

• stimulating further immune responses

Consequences of Systemic Inflammation

happens when microbes or their products get into the bloodstream

• septic shock

• toxic shock

Septic Shock

widespread presence of bacteria in the body induces system-wide inflammation

Toxic Shock

overstimulation of immune responses by bacterial exotoxins in the blood

Pathogen-Associated Molecular Patterns

• receptors on our cells that can bind to these to begin the responses against them

• evolutionarily ancient: found in invertebrates, vertebrates, and plants

• don’t recognize molecules on individual pathogens but rather common molecules found on entire groups of pathogens (nonspecific)

Toll-Like Receptors (TLRs)

• a form of pattern recognition receptors found in vertebrates/invertebrates

• originally describes in fruit fly embryos

• transmembrane proteins that recognize PAMP ligands and trigger an internal signaling reaction in self cells

Mannose-Binding Lectin and C-reactive Protein

examples of opsonizing-secreted PRRs

• MBL coats the mannose-rich surface of yeasts and bacteria

• C-reactive protein binds to phospholipids found in bacterial and fungal plasma membranes

Opsonization

coating of a microbe, enhancing destruction or uptake by other cells

Complement

• a group of 30+ serum proteins involved in antimicrobial activities

• nine particular complement proteins become activated in a cascade in the presence of PAMPs

Activation of the Complement Cascade Results in

• inflammation

• opsonization

• direct microbe killing by formation of the membrane-attack complex (MAC)

Methods of Activating the Complement Cascade

• classical (first discovered)

• alternative pathway (evolutionarily older)

• lectin (similar to classical pathway)

Complement: Opsonization/Phagocytosis

• another function of complement

• coating with activated complement increases chances for phagocytosis

Type 1 Interferons

• interferon ⍺ and β

• induced by viruses

• can initiate a natural antiviral state

• can also increase activities an antiviral cells (NK cells)

Phagocytes

• immune system cells that engulf foreign invaders

  • include neutrophils, monocytes, and macrophages

• activation through PRRs and cytokine signaling turn the cells into efficient killing machines

• opsonization prior to ingestion enhances uptake

• neutrophil granule released intracellularly attack invaders

• once the invader is ingested, a complex process takes place to destroy it.

  • often this process involves fusion with lysosomes and the use of a controlled respiratory burst

Natural Killer (NK) Cells

• useful for eliminating host cells infected with pathogens (kill one ill cell, save many healthy cells)

• not phagocytic but do make contact with target cells

  • after contact is initiated, granule components are released

    • perforin produces a pore structure in target cell plasma membrane

    • granzymes induce apoptosis (controlled cell suicide)

• also useful for eliminating abnormal self cells (cancer)

How do NK cells recognize an abnormal cell from a normal one?

• normal nucleated cells have a surface molecule known as “class 1 major histocompatibility complex” (MHC 1)

• NK cells recognize targets that lack this molecule

  • virally infected cells often turn off its expression

  • cancer cells tend to shut down expression as well

Immune Receptors and Antigen

• T cells possess the T-cell Receptors (TCRs)

• B cells possess immunoglobulin molecules

  • B-cell receptors (BCRs) when on the surface of a B cell

  • antibody is the secreted form of the BCR

Only Immune Receptors can Bind Antigen

• the smallest part of an antigen that can be recognized is an epitope

• each antigen may have multiple different epitopes, each capable of stimulating a response

Lymphocytes and Lymphoid Tissues

B and T cells originate in the bone marrow

• T cells migrate in a still immature stage to the thymus for further development

• bone marrow and thymus are generative lymphoid organs

during development, gene rearrangements produce a very large number of unique TCRs and BCRs

• this increases the chances of a reaction against pathogens

• once mature, lymphocytes are expelled into the peripheral bloodstream as mature, naive lymphocytes

• these cells migrate through lymphoid tissues distributed around the body, ready to respond to threats

Exposure

to a new infectious agent produces a primary immune response

• this can take 7 to 14 days to peak, producing memory lymphocytes as a result and clearing the pathogen

Subsequent Exposure

results in a memory or anamnestic response

• this response is faster and more potent than the primary

Central Cells in Adaptive Immunity

• initiation of adaptive immunity is complex

• multiple cell types are involved

• T cells are involved with the cell-mediated side of adaptive immunity

Activation of T cells require

• antigen presentation

• cell signaling

• production of stimulatory molecules

How can T cells be so specific?

many T cells are produced in the bone marrow

• mature in the thymus

• are screened to avoid excessive self-reactivity

• “good” T cells with anti-foreign molecule TCRs are released to the peripheral bloodstream

• co-receptors must also correctly interact with the MHC molecule

Memory Cells

differentiate during initial adaptive immune responses

• long lived

• produce a faster and more vigorous response when the same antigen is encountered again

• the speed of the 2nd (3rd or 4th) response can even prevent a repeat infection from occurring

Effector Cells

action cells

• short lived

• armed with direct immune functions

Exogenous Antigens and the Endocytic Pathway

• extracellular antigens are taken in by endocytosis

• phagocytosis: takes in large objects

• receptor-mediated endocytosis: initiated by binding of particles to cell-surface receptor molecules

• pinocytosis: “drinking” in small extracellular volumes containing macromolecules

T-cell Activation

requires binding of the TCR with the specific peptide presented on major histocompatibility (MHC) molecules of APCs

Exogenous Antigens and the Endocytic Pathway

broken down and presented on MHC class 2 molecules

• restricts presentation to cells that can bind to MHC class 2 structures

once presented, initiates activation of helper T cells

• effectors

• memory

Intracellular Antigens and the Endogenous Pathway

• proteasomes fragment intracellular antigens

  • small peptide fragments loaded into MHC Class 1 molecules

• presentation restricted to cytotoxic T cells that can bind to MHC Class 1 structures

• activation of cells produces effector and memory cells

  • killer cells recognize targets by their presentation of antigen epitope fragments on MHC Class 1

  • killing is achieved by T cell release of perforin/granzyme, inducing apoptosis in target