Microbiology (Unit 8)

Innate Immunity

• definition: inital defenses to prevent infection & respond to pathogens

• specifity: non-spec → act in response to all pathogens

• formation: built in mechs → structures/chems present at birth

• memory: none → same response regardless of prior exposure

Adaptive Immunity

• definition: respond to pathogens

• specifity: spec → defenses act in response to bacterial strain/virus

• formation: builds over time → need Ag exposure

• memory: has → strong response w 2nd exposure to same ag

First & Second Line of Defences

1. inital barriers to prevent entry/colonization

2. response to infection once 1st line bypassed

Barriers

=phys 1st line

skin:

• tightly packed epithelial cells (w keratin)

mucus mems:

• epithelial cells bound by tight junctions

• line nose, mouth, lungs, urinary/digestive

• mucus covers/protects cell layers & trap debris/mo

endothelia:

• tightly packed cells

• ex. blood-brain barrier → very tight cell junctions, prevent pathogens from entering CNS

Mechanical Defense

= 1st line phys

flush mucus trapped mo out of body

ciliary escalator:

• in lungs, cilia propels mucus out → swallow, cough, sneeze out

shedding:

• of skin cells

flushing:

• action of urine/tears/etc.

Resident Flora

=1st line: phys

• competitive inhibition

• microbiome prevents growth of other mo → out competes pathogens for nutrients & occupies all spaces

First Line- Chemical

=substances/enzymes continously produced by body cells

sebum: by sebaceous glands in dermis, seals off pores of hair folicles

acid production: by norm flora, create mild acidic enviornment on skin → inhibit pathogen colonization

lysozymes:in salivia/sweat/tears → break down bacterial cell walls

IgA: ab protect resp tract

digestive enzymes: saliva (salivary amylase), lower digestive (pancreatic enzymes)

Antimicrobial Peptides (AMPs)

= 2nd line: chem

• broad spectrum anti-microbial activity

• produced continously or in response to infection

• by body cells (defensins) or resident (bacteriocins)

• ex. cathlicidin, dermicidin, histatin

Acute Phase Proteins

2nd line: chem

• from liver → secreted into blood (response to inflam molecules)

• ex. ferritin, fibrinogen, MBL

Complement Proteins

2nd line: chem

• group of proteins that circulate in inactive forms in blood

• activated in cascade → allows rapid respone to infection

Complement: Classical Complement Activation

1. ab binds to bacterium

2. C1 protein recruited/activated

3. eventually C3 protein recuited/activated

4. activation of C3 → split into C3A & C3B

(better for IS → longer cascade = stronger response)

Complement: MBL Activation

1. MBL binds to carbs on microbial surface

2. eventually C3 protein recruited/activated

3. activation of C3 → split into C3A & C3B

Complement: Alternative Activation

1. C3 protein directly recruited/activated

2. activation of C3 → split into C3A & C3B

Complement Activation Outcomes: Opsonization

= enhanced phagocytosis

• C3b protein coats microbe → easier identified by macrophages

Complement Activation Outcomes: Cytolysis

1. C3b recruits/activates C5 protein

2. C5 splits into → C5a & C5b

3. C5b recruits/combines w C6, C7, C8, C9 → forms mem attack complex (MAC)

4. inserts into cell mem → extracellular fluid rushes in → microbial lysis

Complement Activation Outcomes: Enhanced Inflammation

1. C3a & C5a combine + bind to mast cells

2. ↑ histamine production

How Microbes Avoid Complement System

• capsule → inhibits opsonisation & MAC insertion

• gram neg alter outer mem structure→ prevent MAC insertion

• gram pos cocci → release enzyme breaking down C5

Cytokines

=2nd line: chem

• soluble proteins, communication b/w cells

• help stim production of chem mediatiors/promote cell func

3 types:

1. interleukins: modulate parts of IS

2. chemokines: recruit WBC to infections sites, tissue damage, inflam

3. interferons: defense against viral rep

• produce in lab → treatment for viral infec

• sig side effects

Inflammation-Eliciting Mediators

=2nd line: chem

• histamine: by mast

• leukotrienes: longer lasting effects than histamine

• prostaglandins: role in fevers

• bradykinin: ↑ vascular permeability → edema

Granulocytes: Mast Cells

G= WBC w lobed nuclei & granules in cytoplasm

• in tissues

• produce histamine

Granulocytes: Basophil

produces histamine in allergic reactions

Granulocytes: Neutrophil

eliminate/destroy bacteria through:

• direct phagocytosis

• production of extracellular traps (NETs)

Granulocytes: Eosinophil

• protect against protozoan/helminthic infections

• release degradative enzymes

Agranulocytes: Natural Killer Cells

A: WBCs wo granules in cytoplasm

• use non spec mechs to recognize abnorm body cells

• → induce apoptosis

Agranulocytes: Monocytes

after movement into body tissue → differentiate into dendritic cells & macrophages

Phagocytosis: Extravasation

1st (innate)

• site of injury → release of inflam elicitors/cytokines

• through pos chemotaxis → leukocytes leave blood through capillaries

• phagocytes (N 1st, then macro) enter tissue through extravasation

Phagocytosis: Pathogen Recognition

2nd (innate)

• attachment of phagocytes plasma mem to surface of mo → interaction of PAMPs on pathogen w PRRs on phagocytes

• ex. PAMPs: peptidoglycan, flagella proteins, lipopolysacc

• enhanced by opsonization & blocked by capsule

Phagocytosis: Pathogen Degradation

3rd (innate)

1. pseudopods form around microbe → phagosome made

2. lysosome inside macrophage contains H2O2/digestive enzymes

3. L fuses w phagosome → forms phagolysosome

4. microbe digested

5. waste excreted through exocytosis

How Microbes Avoid Phagocytosis

• capsule prevents adherence of phago

• some release molecules → phago death

• some use phagocytosis as entry into cells → rep inside

• form biofilms: phago cant detach patho from biofilm

Acute Inflammation

innate

1. immediate response to injury → vasocon (minimize blood loss (brief))

2. resident mast release histamine → vasod+ ↑ perm (5 s/s → red, pain, heat, swelling, loss of func)

3. phagocytes recruited

4. pus forms as damaged tissue/pathogens cleared

5. tissue repair begins

Chronic Inflammation

innate

• IS unable to clear pathogen

• pathogens in deeper tissues, forming granulomas (pockets of infected tissue, surrounded by WBC)

• can be observed w tissue scarring

Fever

= 2nd line

• body temp regulated by hypothalamus

• bacterial/viral infection causes chems release → prostoglandins produced

• → hypothalamus “reset” → higher body temp (neg feedback)

during fever:

• vasocon of vessels → skin pale

• shivering/↑ metabolism

Fever: Enhancing Immune System & Complications

enhance:

• inhibit pathogen growth

• isolate iron from microbes (starve)

fever breaking:

• hypothalamus restored to norm body temp (vasod → release heat from body)

comps:

• tissue/organ damage, tachycardia, dehydration, death, seizure

Adaptive: Antigens

= found on pathogens, stimulate IS

• bacteria: capsule, cell wall, flagella, etc.

• viruses: spike, envelope, capsid, etc.

• spec regions on ag where ab bind = epitopes (have multiple)

4 Types of Antigens

(carbs, proteins, lipids, DNA)

• most potent: protein

• only stimulate humoral: carbs

• least antigenic: lipid/dna

Adaptive: Antibodies

immunoglobulins → by IS to target ag (2 binding sites)

5 classes: IgG, IgM, IgA, IgD, IgE

• most abundant: IgG

• resp secretions: IgA

• allergic response & defense against parasites: IgE

Cellular vs. Humoral Immunity

C:

• involves T cells

• kill infected body cells + boost immune response

H:

• involves B cells

• kill extracellular ag

T-Cell Library Formation

= stem cells formed in bone marrow → ½ migate to thymus (become naive T cells)

naive helper T cells:

• T-cell receptor (TCR) bind to spec epitope

• CD4 co-receptor

naive cytotoxic T cells:

• TCR bind to spec epitope

• CD8 co-receptor

Helper T-Cell Activation

1. pathogen/ag phagocytosed by phago (macrophage/dendritic cell)

2. in macro MHC-II combines w ag

3. MHC-II & ag presented on plasma mem

4. macrophage becomes APC

5. matching TCR on NHT binds to displayed ag → partially activates NHT

6. CD4 co-receptor on NHT binds to displayed ag to anchor TCR-ag complex

7. APC + NHT → release cytokines (further activates NHT)

8. NHT proliferates through mitosis + differentiate into:

• TH1: stim cells in immune response

• TH2: stim humoral immunity

• mem t-cells: remember ag (encounter → rapidly switch to TH1/TH2)

Cytotoxic T-Cell Activation

• recognition of ag presented on MHC-I

• anchoring by CD8 co-receptor

• NCT cells differentiate→ effector & mem cytotoxic t-cells

• assistance from cytokines secreted by TH1 cells → longer lasting effects

Effector Cytotoxic T-Cell Function

once activated release:

• perforin: create pores in target cell

• granzymes (proteases) enter pores & induce apoptosis

B-Cell Library Formation

stem cells formed in bone marrow

• ½ remain in bm → become B cells (coated w IgM ab → bind to single epitope)

TH2-Dependent B Cell Activation

(use of TH2 cells activated in cellular for same ag)

1. IgM of inactive B cell binds to foreign ag

2. IgM-ag complex internalized into inactive B cell

3. ag combined w MHC II → ag presented onto B cell plasma mem

4. B cell becomes APC

5. matching TH2 binds to presented Ag

6. TH2 releases cytokines → activates B cell

7. B cell proliferate through mitosis → differentiate

• plasma cells: secrete IgM → later secrete longer lasting IgG

• mem b cells: remember ag (2nd encounter → switch to plasma cells + secrete ab)

longer lasting response → leads to mem

TH2-Independent B Cell Activation

1. T-independent ag (ex. carbs) → sufficient to provide 1st activation signal

2. B cell direcly activated through binding of IgM to ag

3. B cell proliferate through mitosis + differentiate into plasma cells (→ secrete IgM)

• no mem cells

short response + needs boosting from innate

Actions of Antibodies

1. neutralization: bind to epitopes → prevent cell attachment

2. opsonization: coat pathogen → enhance phagocytosis

3. agglutination: cross link ag → create lrg clumps

4. complement: activate cascade

5. ab-dependent cell-mediated cytotoxicity: enhanced killing of pathogens too lrg to phagocytize

Adaptive Immunity: Primary vs. Secondary Response

• takes time to build adaptive response

• prim: 1st exposure to pathogen, slow response

• sec: mem allows stronger/faster response on 2nd encounter

Classifications of Adaptive: Active Immunity

= activation of own immune defenses

• active, natural: immunity through illness + recover

• active, artificial: vaccination

Classifications of Adaptive: Passive Immunity

= transfer adaptive immune defenses from another person/animal

• passive, natural: ab passed through breast milk/placenta

• passive, artifical: transfer ab harvested from person/animal (usually blood)

Herd Immunity

= too few susceptible individuals for diease to spread effectively

• achieve through vaccination programs → ↓ susceptible people

• susceptible: cant vaccinate (young, allergic to vaccine ingredient)

Function of Vaccines

• exposure of person to ag → trigger prim response wo person feeling effects of pathogen

• acc encounter pathogen → 2nd response

Vaccine Types: Attenuated

=live, weak organisms

• still replicate → boosters not needed

• challenges for storage/transport

• ex. chicken pox vaccine

Vaccine Types: Inactivated

=dead organisms

• no risks of severe infection, boosters needed

• vaccines in devloping countries (easy to store/administer)

• ex. influenza & hepatitis A vaccine

Vaccine Types: Subunit

=key ag of pathogen

• through genetic engineering/isolation from degraded pathogen

• no protection against antigenic variation

• ex. hepatitis B & HPV vaccine

Vaccine Types: Toxoid

=inactivated toxins (pathogens not included)

• least side effects → doesnt prevent pathogen infection

• ex. tetanus vaccine

Vaccine Types: Conjugate

=synthetic → combine carb ag w lrg proteins to stim cellular & humoral

• more expensive to produce

• ex. meningitis vaccine (bacterial)

Vaccine Types: Nucleic Acid

=NA injected → cells uptake + use as template to make protein ag

• ex. covid 19 vaccine