Lecture 3: Host-Microbe Interactions

The few microorganisms that cause damage to the human body are called

Pathogens

(Distinct characteristics allow avoidance of the body defenses)

Symbiosis

‘Living together’

• Ex: skin/ mucous membranes host microbes

Interactions in symbiosis

Mutualism

Commensalism

Parasitic

Mutualism

Both partners benefit

Ex: in large intestine, some bacteria synthesize vitamin K and B, in exchange bacteria get warmth and energy sources

Commensalisms

One partner benefits, other is unharmed

Ex: many microbes on skin (not harmful/helpful) get from host

Parasitic

One organism benefits at the expense of another (Pathogen)

What can ‘good’ bacteria help with resisting pathogenic microbes

Can cover binding sites to prevent pathogen attachment

Can compete for nutrients that the pathogens need

Can produce compounds toxic to other bacteria/ pathogens

What can happen when the microbiome is supressed (eg during antibiotic treatment)

Pathogens may colonize and cause disease

Ex: toxin producing clostridium difficile can overgrow in intestines when other microbes inhibited

What other things can resident microbes do

Stimulate adaptive immune system

Aid in digestion

Overall health of human → can fight pathogen more easily

How can good microbes stimulate the adaptive immune system

Antibodies generated for harmless microbes may also bind to pathogens

Some intestinal microbes can increase patrolling T cells in intestines

How do good microbes aid in digestion

Breaking down fibre, increasing nutrients, and producing vitamins

When a microbe establishes itself (multiples) in an environment we call this

Colonization

If colonization is parasitic (harms host), we call this

An infection

Classifying infections (2)

Subclinical infection

Infectious disease

Subclinical infection

No symptoms or mild symptoms

(Feeling fine, maybe runny nose)

Sometimes leading to infectious disease

Infectious disease

Symptoms prevent normal function

(Sick in bed)

Symptoms vs signs

Symptoms - subjective effects (pain, nausea)

Signs - objective evidence (rash, pus, swelling)

One infection can sometimes

Lead to another

(Primary vs secondary infection)

• ex: seasonal cold weakens immune system and turns into pneumonia

Primary infection

Initial infection

Secondary infection

Infection developed as a consequence of initial infection

A pathogen is ultimately a .. microbe

Disease-causing

Pathogenicity

A pathogens ability to cause disease

Primary pathogens

Cause disease in otherwise healthy individuals

(Plague, measles, influenza, tetanus)

Opportunistic pathogens

Cause disease when body’s immune defences are compromised or when they are in an unusual location (opportunity arises)

Ex: serratia marcescens when on medical eq

Virulence

Degree of pathogenicity

More virulence → more pathogenic (more able to cause disease)

Virulence factors

Any trait(s)/ genes that allow it to cause disease

Infectious dose (ID)

Number of microbes necessary to establish infection

How come one of two digestive system pathogens takes much less cells to result in an infection

One better survives stomach acid

(Usually has something to do with surviving the environment)

ID50

The number of cells that infect 50% of test population (compared across doses)

What do we use to calculate the ID50

Cummulative % infected (greater than and equal to this dose)

Progression of infectious disease varies

Acute

Chronic

Latent

Acute illness

Illness is short term because the pathogen is eliminated by host defences; person is usually immune to reinfection

(Seasonal flu)

Incubation period → illness → convalescence

Chronic illness

Illness persists over a long time period

(Hepatitis C)

Incubation → illness (long lasting)

Latent illness

Illness may recur if immunity weakens

(Chickenpox to shingles, tuberculosis)

Incubation period → illness → convalescence → latency (dormant) → recurrence

Pathogen distribution

Localized or systemic

Localized

Pathogen limited to small area

(Eg boil caused by S aureus)

Systemic

Pathogen spread throughout the body (eg Lyme disease)

-emia means

In the blood

Bacteremia

Bacteria circulating in blood

Can be local; if systemic inflammation → Sepsis (very dangerous situation)

Toxemia

Toxins circulating in blood

Viremia

Viruses circulating in blood

Classical Kock’s Postulates

Used to establish that a given microbe causes a specific infectious disease

(If met, can link microbe to disease)

What are koch’s postulates (4)

1. Microbe is present in every case of disease

2. Organism must be grown in pure culture (only have that microbe) from diseased host

3. Same disease can be produced when pure culture is introduced into susceptible hosts

4. Organisms must be recovered from experimentally infected hosts

Limitations/ problems with koch’s postulates

Some organisms cannot grow in lab medium

Some diseases have more than one microbe involved

May be unethical to use suitable host (eg maybe its only host is human)

Molecular Koch’s Postulates

Rely on molecular techniques to study a microbe’s virulence factors

Virulence factor gene/ product found in pathogenic strains of organism

Helps get more info on specific strains

How can we reduce virulence

Mutate gene to disrupt function

How can we restore virulence

Revert mutation or replace original gene

Ways microbes can cause infection in general (4)

1. Produce toxins that are ingested by host (no colonization) (botulism - food poisoning)

2. Colonize mucous membranes + produce toxins (E coli)

3. Invade host tissues + avoid immune defences (Myobacterium tuberculosis)

4. Invade host tissues + produce toxins (Clostridium tetani)

Overview of what pathogens generally do

Get attached

Get inside cells (could be microbe or just part)

Evade immune system (initially)

Cause damage (directly/indirectly)… spread

Simple way pathogens get attached and inside skin/ mucous membranes

Accidental penetration of skin

(Eg cut, small/large injury, insect bite)

Sophisticated way pathogens get attached and inside skin/ mucous membranes

Penetrating mucous membranes

Most pathogens use this entry point

Establishing infection (getting attached/ inside)

Adhesions

Type III secretion systems

M cells

Adhesions from pathogen … to host cell receptor

Attach

(Often located at tips of pili)

Type III secretion systems (injectisomes)

Some gram-negative bacteria have these

Deliver effector proteins to host cells

Induces changes in cell’s cytoskeleton

Can induce update of bacterial cells

What is important about type III secretion systems

Can affect non-phagocytic cells

Salmonella uses type III secretion system to induce

Membrane ruffling

(Ruffles enclose bacteria, brining them into cell)

M cells

Can be used to traverse the intestinal barrier

(Sampling intestinal env in Peyer’s patches, shigella cells)

Ways to avoid host defences (evade destruction)

Prevent encounters with phagocytes

Avoid recognition and attachment to phagocytes

Survive phagocyte

Prevent encounters with phagocytes

A. C5a peptidase: degrades the chemoattractant C5a (part of complement system)

B. Make membrane damaging toxins to kill phagocytes

Avoid recognition and attachment to phagocytes

Capsules: interfere with opsonization more generally

M proteins: bind host’s regulatory proteins that inactivate C3b to avoid opsonization

Fc antibody receptors: bind ‘red flag’ end of antibodies (usually binds directly to bacteria)

Surviving phagocyte

Escape the phagosome

Prevent phagosome-lysosome fusion

Survive within the phagolysosome

Escape the phagosome

Before lysis occurs through lysosomes

(Listeria monocytogenes produces pores in membrane)

Preventing phagosome-lysosome fusion

Avoid destruction

(Salmonella sense ingestion by macrophage, produces protein that blocks fusion)

Survive within the phagolysosome

Few can do this

(Coxiella burnetti - Q fever - can withstand)

Summary of avoiding host defences/ evading destruction

Serum resistant bacteria

Microbes bind complement regulatory proteins to avoid membrane attack complex (MAC)

-eg: Neisseria gonorrhoeae can hijack mechanism that host uses to prevent their surfaces from activating the complement system

How do some microbes avoid recognition by antibodies

1. Generate IgA protease

2. Antigenic variation

3. Minimic host molecules

How can they generate IgA protease

Cleaves IgA found in mucus

(Neisseria gonorrhoeae and others can do this)

Antigenic variation

Vary your antigens

Alter structures of surface antigens

How can they mimic host molecules

Cover surface with molecules similar to those found in host cell, appear to be “self” material

(e.g. form capsule from hyaluronic acid - polysaccharide found in human tissues)

Why do pathogens want to cause damage in the cell

Damage may help pathogen to exit and spread

(Induce diarrhea to contaminate water supplies, trigger cough to release into air)

Strategies for causing damage

Produce toxins

Activate immune system

Exotoxins

Proteins with specific damaging effects

Gram +/ - can make

Released into tissue when bacteria lyse

Most destroyed by heating

Immune system can usually generate antibodies

What are the inactivated exotoxins used for vaccine development called

Toxoids

(Eg tetanus vaccine)

What are neutralized antibodies for exotoxins called that can be used to counteract effects

Antitoxins

Categories of exotoxins (based on structure/ mode of action)

A-B toxins

Membrane-damaging toxins

Superantigens

Exfoliatin

A-B toxins

A (active) subunit: toxic, usually an enzyme, later enters cytoplasm to exert effects

B subunit: binds to cell, determines cell types to be targeted

Ex: cholera, tetanus, anthrax toxin

Membrane damaging toxins

Exotoxins that disrupt eukaryotic cytoplasmic membranes, lyse cells

Hemolysins

Lyse red blood cells

Streptolysin O from Streptococcus pyogens

Forms pores

α-Toxin of Clostridium perfringens (gas gangrene)

Hydrolyze phospholipids of membrane

Superantigens

Exotoxins that stimulate high number of Th cells, causing “cytokine storm”

Simultaneously bind MHC class II and T-cell receptor

T-cell interprets this as antigen recognition

Massive cytokine release is toxic to tissues

T cells undergo apoptosis + suppresses immune response

Exofoliatin

From S. aureus, causes scalded skin syndrome

Destroys material that binds skin layers

Endotoxin

Lipopolysaccharide found in Gram - cell walls; specifically lipid A

When lipid A is systemic (throughout body) causes widespread septic shock/ endotoxic shock (Toll like receptors bind)

B cells can also become activate without helper T cells

Heat-stable toxins

Autoclaving doesn’t destroy

(Protein from horseshoe crab blood can be used to detect small concentrations)

Overall comparision of exotoxins and endotoxins

What do both exotoxins and endotoxins ultimately do

Cause damage to cells/tissues and cause inflammation

Leads to symptoms and signs of infection

Leads to spreading of pathogen

To infect a host, a virus must

Enter appropriate cell

Use host’s machinery for replication

Avoid recognition + destruction by host cell

Move to new host(s)

Damage to host may result … from viral infection or … from immune response to virus

Directly

Indirectly

How does attachment/entry tools differ between bacteria and viruses

Bacteria use adhesions, injectosomes, etc

Viruses target specific cell receptors

(HIV → CD4 on T helper cell, COVID19 → ACE2 receptor on various non immune cells)

How does avoiding immune response differ between bacteria and viruses

Bacteria deal with phagocytosis

Viruses have to deal also with interferons (induce iAVP, put neighbouring cells on alert for viral rDNA)

What mechanisms do viruses use to avoid interferons

Coat their RNA with a virally encoded protein

Shut down host gene expression/ inactivate enzymes

What does coating their RNA with virally encoded protein do

Stops host cell from detecting viral nucleic acid

What does shutting down host gene expression/ inactivating enzymes do

Prevents expression of proteins involved in interferon response

How do virus’ vs bacteria resist the adaptive immune system

Bacteria can use Fc receptors (binds Fc region)

Viruses interfere with antigen presentation by MHC I molecules (target for Tc cells)

Why is viral interference of MHC class I complicated

Tc cells won’t kill infected cell if it doesn’t see antigens on MHC I molecules

NK cells will kill infected cells if they don’t display MHC I molecules

How do virus’ trick both the MHC I and the NK cells

Viral genome directs cell to make fake MHC class I molecules that cannot present peptides from cytoplasmic proteins

How else can viruses avoid antibodies

Move cell to cell to avoid antibodies

Modify their surface antigens (usually via mutations)

What is the downstream effect of these strategies

Cause damage to cells/tissues + cause inflammation → symptons + signs of infections → spreading pathogen

Similarities with eukaryotic pathogens

Some avoid phagocytosis (capsules in Cryptococcus fungi)

Some make toxins (mycotoxins)

Some use receptors for attachment and avoid antibodies (plasmodium in RBCs)