Disease, and Defenses Evolution Antibiotic Resistance CH … 8, 10, 11 Evolution and... · We now have a “super bug”! Resistant Strains Rare ... • Slime or capsule: ... - neurotoxins

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Evolution, Disease, and Defenses Evolution and Antibiotic ResistanceCH 8 pages 218‐220

How Does Drug Resistance Develop?• Resistance to penicillin developed in some bacteria as early as 1940

• In the 1980s and 1990s scientists began to observe treatment failures on a large scale

• Microbes become newly resistant to a drug after one of the following occurs– spontaneous mutations in critical chromosomal genes

– acquisition of entire new genes or sets of genes via horizontal transfer from another species

Development of Drug Resistance• Resistance through horizontal transfer

– Resistance (R) factors: plasmids containing antibiotic resistance genes (some have 6‐7 resistance genes!)

– Can be transferred through conjugation, transformation, or transduction

– Plasmids encoded with drug resistance are naturally present in microbes before they have been exposed to an antibiotic

Resistance plasmids can carry many resistance genes

• YIKES! We now have a “super bug”!

Resistant StrainsRare

Resistant Strains Dominant

Antimicrobial Exposure

Antibiotic Resistant Strain Propagation

• Antimicrobial exposure causes pressure to select resistant strains.

• Without antibiotics, selective pressure decreases and antibiotic resistance genes may be lost.

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Intermicrobial transfer of plasmids containing resistance genes

S. aureus

Penicillin

1950s

Penicillin-resistant

S. aureus

Clinical Implications in the Development of Drug Resistant Staphylococcus aureus

• How do we treat S. aureus infections when they become completely resistant to our last line antibiotic, Vancomycin?

Methicillin

1970s

Methicillin-resistant

S. aureus (MRSA)

Vancomycin-resistant

enterococci (VRE)

Vancomycin

1990s

1997

Vancomycin

intermediate-resistantS. aureus(VISA)

VancomycinResistant S. aureus

1997

Mechanisms Associated with Drug Resistance

1. Drug inactivation2. Decreased

permeability3. Activation of drug

pumps4. Change in drug

binding site5. Use of alternate

metabolic pathways

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Methicillin-resistantStaphylococcus aureus(MRSA)

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Vancomycin-resistantEnterococci (VRE)

Non-Intensive Care Unit Patients

Intensive Care Unit Patients

Antibiotic Resistance is Prevalent and Rising

Source: National Nosocomial Infections Surveillance (NNIS) System

Preventing Antibiotic Resistance• Prevent infection

• Stay healthy

• Diagnose and treat infection effectively

• Don’t treat viral infections with

antibiotics

• Use effective antibiotics

• Use antimicrobials wisely

• Take full course of antibiotics

• Stop feeding antibiotics to

livestock

• Prevent transmission

• Wash your hands

• Isolate infections

Take the full course of antibiotics to decrease resistance

Preventing Antibiotic Resistance

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Preventing Antibiotic Resistance

Antibiotics are sold world wide without a prescription

Development of Drug Resistance

• A wide variety of soil bacteria can not only survive in the presence of many antibiotics, but can use the antibiotics as fuel

Development of Drug Resistance• A large population of natural

environmental bacteria exists with antibiotic resistance capabilities that might be transferred to disease‐causing bacteria

• Non‐disease‐causing flora of humans and animals can also harbor antibiotic resistance genes that can jump into pathogenic bacteria with which they share space Yep, it’s a cow peeing

https://www.youtube.com/watch?v=2L82V6VPJkQ

The Nature of DiseaseCH 10 pages 259‐282

• Host• Any organism that harbors another organism or particle (virus, prion)

• Symbiosis‐ An association between 2 species (“living together”)

– Mutualism• Both members benefit from relationship

• E. coli produce useful products (Vit K) in our large intestine

– Parasitism• One member benefits, one member is harmed

– Commensalism• One member benefits, one member is not benefited nor harmed

• Microbes on our skin utilize skin products

Host-Microbe Relationships: Symbiosis

E. Coli in Lg. intestines

Giardia in intestines

Demodex folliculorum in hair follicle

Microflora

• Resident Microflora• Microbes always present on or in the body

• Transient Microflora• Microbes present for shorter periods of time (minutes to months)

• Adult human body consists of:

– 10 trillion (10 13) eukaryotic cells‐Human cells

– 100 trillion (10 14) prokaryotic cells‐Bacteria cells

– We have 10 times as many prokaryotic cells vs. our own cells!!

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Resident Microflora

• Which areas harbor microflora?

• Which body tissues, organs and fluids are usually microbe‐free?

The Absence of ResidentMicroflora can have Harmful Effects

• Cattle Studies:– Enlargement of cecum

– Vitamin deficiency

– Underdeveloped immune system

Microbial Antagonism:• Normal biota are unlikely to be displaced by

incoming microbes• Limited number of attachment sites• Chemical or physiological environment created

by resident biota is hostile to other microbes

•Normal biota is beneficial, or at worst, commensal to the host in good health with a functioning immune system

Resident Microbes Compete with Possible Pathogens

First Acquiring Resident Microflora

• Mother’s birth canal

• Mother’s breast milk

• Bottle‐feeding

• People

• Air

• Surfaces

• The only time that humans are sterile is when they are in the womb (in utero)

Areas of the Body that are usually Sterile

• Circulatory system• Organs• Glands• Lungs• Sinuses• Middle and inner ear• Brain• Internal eye• Muscles

• Blood

• Urine in the kidneys, ureters, and bladder

• Cerebrospinal fluid

• Saliva before oral cavity

• Semen before the urethra

Contact to Disease1. Contact: Microbes are present

2. Colonization: The presence of bacteria on body surface (skin, mouth, intestines, airway) without causing disease

3. Infection (Infestation‐larger parasites)

Multiplication of microbes (Microbes penetrate host defenses, enter tissue and multiply)

4. DiseaseDisturbance in normal homeostasis

1. doesn’t usually lead to 3. and 4.

True vs. Opportunistic Pathogen

True pathogen Causes disease in healthy individuals

Associated with a specific and recognizable disease

Opportunistic pathogen Causes disease in immune compromised host

Gain access (injury) to sterile regions

Staphylococcus aureus

Vibrio cholerae

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Opportunistic MicrobesOpportunists usually do not cause disease unless the “opportunity” arises.

Conditions that opportunists can flourish: Failure of the host’s normal defenses

Immunocompromised populations

Intro of the organism into unusual body sites E. coli normal in gut but not urinary tract

Disturbances in normal microflora Yeast infection after antibiotic use. Why?

Requirements of Infectious DiseasePathogen needs to become established by being successful at the following:

1. Survive in a reservoir

2. Transmitter from reservoir to host

3. Invade host body

4. Attach/adhere to host cells

5. Multiply

6. Surviving host defenses (at least initially)

7. Causing disease (interrupt normal host functions)

8. Leave host to another host or reservoir

If you stop a pathogen from being able to do any of these steps they will not be able to infect the host

Infectious Disease: Survive in a Reservoir

• Reservoir• The natural host or habitat (living or nonliving) of a pathogen

• There are human, animal, and environmental reservoirs

• To get from the reservoir to the host there may be a vector involved

• Zoonosis • An infectious disease humans can acquire from animals (Ex. rabies)

• 70% of all new emerging diseases worldwide

• impossible to eradicate without also eradicating the animal reservoir

• attempts have been made to eradicate mosquitoes and certain rodents

Infectious Disease: Survive in a Reservoir

• Human Reservoirs• Asymptomatic Carrier

• Symptomatic Carriers

• Animal Reservoirs• Wild animals (Rabies)

• Deer mice (hanta virus)

• Insects

• Nonliving Reservoirs• Soil (Clostridium tetani, Bacillus anthracis)

• Water (Cholera, Giardia)

• Food (E. coli, Salmonella, Listeria)

Infectious Disease: Transmission of Disease

• Biological vector• An organism which not only transports a pathogen but also plays a role in the life cycle of the pathogen (virus inside of mosquito, bacteria inside of tick)

• Mechanical vector• An organism which only transports a pathogen (fly)


• Horizontal transmission• Disease is spread through a population from one infected person to another

– Kissing, sneezing

• Vertical transmission• The disease is transmitted from parent to offspring

– Ovum, sperm, placenta, milk

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• Direct (contact)• Kissing, sex• Droplets (sneezing, coughing directly upon a person within 3 feet)

• Vertical• Vector

• Indirect– Contaminated materials

• Vehicles=Food, water, biological products (blood, serum, tissue), fomite (door knobs, toilet seats, etc.)

• Fecal‐oral (aka oral‐fecal)

– Air (greater than 3 feet away)• Droplet nuclei (dried microscopic residue)

• Aerosols (dust or moisture particles)

A sneeze can release enormous amounts of moist droplets, and the dry droplets form droplet nuclei. (so cover your

mouth with your elbow )


Infectious Disease: Invade Host Body

• Portal of entry: the route that a microbe takes to enter the tissues of the body to initiate an infection

• Exogenous: microbe originating from a source outside the body from the environment or another person or animal

• Endogenous: microbe already existing on or in the body from normal biota or a previously silent infection

• The majority of pathogens have adapted to a specific portal of entry

• Usually if pathogens enter the “wrong” portal, they will not be infectious

• Inoculation of the nasal mucosa with the influenza virus will result in infection, but if the virus contacts the skin, no infection occurs


• Occasionally, an infectious agent can enter by more than one portal

• Mycobacterium tuberculosis can enter through both the respiratory and gastrointestinal tracts

• Streptococcus and Staphylococcus can enter through the skin, urogenital tract, and the respiratory tract


- Gain a stable foothold on host tissues

- Dependent on binding between specific molecules on both the host and pathogen

- Pathogen is limited to only those cells (and organisms) to which it can bind

- Firm attachment is almost always a prerequisite for causing disease since the body has so many mechanisms for flushing microbes from tissues

Infectious Disease: Adhesion

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Structures

– Pili or fimbriae

– Hooks

– Spikes

Infectious Disease: Adhesion Infectious Disease: Multiply in Host

•Microbes not established as normal biota will likely encounter the host immune defenses when first entering

•Phagocytes: cells that engulf and destroy host pathogens by means of enzymes and antimicrobial chemicals WBC engulfing S. cerevisiae

Infectious Disease: Evade Host Defenses

•Antiphagocytic factors:• Virulence factors that help pathogens avoid

phagocytes• Leukocidins: kill phagocytes; Streptococcus and

Staphylococcus• Slime or capsule: makes it difficult for the

phagocyte to engulf the pathogen; Streptococcus pneumoniae and Salmonella typhi

• Some bacteria survive inside the phagocyte; Legionella, Mycobacterium

Infectious Disease: Evade Host Defenses

• Pathogen: Disease causing agent

• Pathogenicity: The ability to cause disease

• Virulence: The degree of pathogenicity

• Virulence of a microbe is determined by its ability to

- establish itself in a host

- cause damage

• Virulence factor: any characteristic or structure of the microbe contributes to its ability to establish itself in the host and cause damage

Infectious Disease: Cause Disease

• Virulence factors are adaptations a microbe uses to establish itself in a host

• Three ways that microorganisms cause damage to their host

A. directly through the action of enzymesB. directly through the action of toxins (both

endotoxins and exotoxins)C. indirectly by inducing the host’s defenses to

respond excessively or inappropriately


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•Exoenzymes- enzymes secreted by microbes that break down and

inflict damage on tissues- Often dissolve the host’s defense barriers to promote

the spread of disease to other tissues

•Examples of exoenzymes- hyaluronidase: digests the ground substance that

cements animal cells together- coagulase: causes clotting of blood or plasma

Infectious Disease: Cause Disease Infectious Disease: Cause Disease

•Toxin: a specific chemical product of microbes, plants, and some animals that causes cellular damage in other organisms

•Toxins are named according to their target- neurotoxins act on the nervous system- enterotoxins act on the intestines- hemotoxins lyse red blood cells- nephrotoxins damage the kidneys

• Two types of toxins in pathogenic bacteria• Exotoxin• Endotoxin


Exotoxins• proteins that targets a specific cell

type• affect cells by damaging the cell

membrane and initiating lysis• Don’t confuse with exoenzymes! • Ex: Hemolysins

- disrupt the membrane of red blood cells to release hemoglobin

- Ex. Streptococcus pyogenes and Staphylococcus aureus


• Endotoxin- lipopolysaccharide (LPS), part of the outer membrane of

gram‐negative cell walls- Released when cells die- has a variety of systemic effects on tissues and organs- causes fever, inflammation, hemorrhage, and diarrhea


• Portals of exits:– Respiratory

– Salivary

– Skin

– Fecal

– Urogenital

– Blood

Infectious Disease: Leave Host to Another Host or Reservoir

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• specific avenue by which pathogens exit

• shed through secretion, excretion, discharge, or sloughed tissue

• high number of microbes in these materials increases the likelihood that the pathogen will reach other hosts

• portal of exit is usually the same as the portal of entry, but some pathogens use a different route

Infectious Disease: Leave Host to Another Host or Reservoir

Vaccinations CH 11 pages 285‐290 and 303‐307

Lines of Defense

• If the First and Second lines of defense fail, then the Third line of defense is activated.

• B and T lymphocytes undergo a selective process that prepares them for reacting only to one specific antigen or immunogen

The Third and Final Line of Defense:Specific Immunity

Adaptive immunity acquired only after an immunizing event such as an infection or vaccine

Two features that characterize the specific immune response are specificity and memory:

– antibodies produced against the chickenpox virus will not function against the measles virus

– lymphocytes have been programmed to “recall” their first engagement with an antigen and rush to the attack once again

Antibodies• Epitope: portion of antigen that binds

antibody.

• Immunoglobulin (Ig): large glycoprotein molecules that serve as the antigen receptors of B cells. When secreted they are antibodies

• Immunoglobulin structure:– Antigen binding sites: pockets in the ends

of the forks of the molecules that can be highly variable in shape to fit a wide range of antigens

– Variable regions: areas of extreme versatility in aa sequence from one clone to another

– Constant regions: amino content does not vary greatly from one antibody to another

AntigensAntigens or Immunogens: • Molecules that stimulate a response by B and T cells• Protein or polysaccharide molecules on or inside cells and viruses

• Any exposed or released protein or polysaccharide is potentially an antigen

• Antigens are highly individual and stimulate specific immunity

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Lymphocytes

• All lymphocytes arise from the same basic stem cell type

• B‐ and T‐cells constantly recirculate through the circulatory system

• Some of these cells are Memory T‐ or B‐cells. These cells remember the antigens from a past invader and attack it when it is present again

Immunological Memory

• Antibody titer• Amount of antibody measured in serum

• Primary Response• Immune response after initial exposure to antigen

• Secondary Response• aka memory

• Immune response intensifies after second exposure to antigen

• Total antibody level produced during the secondary response is a much grater than the primary response. This is the beauty of memory cells mounting a strong and immediate response and preventing us from getting sick.

Antibody Titer and Infection

Latent period Variable timeinterval

Total

IgM

IgG

SECONDARYRESPONSE

Second exposureto Ag

PRIMARYRESPONSE

First exposureto Ag

An

tib

od

y T

iter

Immunization and Vaccines

• Basic principles behind vaccination– Stimulate a primary response and a memory response so that the next time your body comes in contact with this pathogen it has memory of it

– Prime the immune system for future exposure to a virulent pathogen

– If the pathogen enters the body, the response will be immediate, powerful, and sustained because the immune system now has memory of that antigen

Total

IgM

IgG

SECONDARYRESPONSE

Second exposureto Ag

Principles of Vaccine: Whole Cell Vaccines

Example of inactivated vaccines: polio, influenza, typhoid, cholera, and plague vaccines

Example of living vaccines: measles, mumps, rubella, chicken pox, oral polio vaccine, some rabies vaccines

http://youtu.be/ztkNLWFgYH8

Documents

Disease, and Defenses Evolution Antibiotic Resistance CH … 8, 10, 11 Evolution and... · We now have a “super bug”! Resistant Strains Rare ... • Slime or capsule: ... - neurotoxins