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Cellular and Molecular Immunology > Antimicrobial Peptides: Defensins and antimicrobial peptides > Flashcards

Antimicrobial Peptides: Defensins and antimicrobial peptides Flashcards

1
Q

Major subdivisions of the immune system

A
  • The innate or non-specific immune system
  • The adaptive or specific immune sytem
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2
Q

Innate immunity

A
  • Natural, none-adaptive, nonspecific.
  • Phagocytes: Monocytes, macrophages, PMN neutrophils
  • Natural Killers (NK) cells
  • Complement system
  • Exterior defenses: Skin, Stomach acifdity, Mucus, Cilia, Microflora, Lysozyme in tears, Flushing of urinary tract.
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3
Q

Summary on Innate Immunity

Anatomical barriers

A
  • Epithelial surfaces, especially our skin, form a ohysical barrier impermeable to most infectious agents.
  • Mucus, tears and saliva containing (lysozyme, phospholipase and defensins) can prevent infection.
  • The normal flora can prevent the colonization of pathogenic bacteria by antimicrobial or by competing with pathogenic bacteria.
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4
Q

Summary on Innate Immunity

Humoral barriers and inflammation

Role for locally secreted small peptides

A
  • Inflammation is one of the first responses of our immune system, stimulated by chemical factors released by injured cells called chemokines,
  • Lactoferrin and transferin - Bind iron, essential for bacteria, limiting bacterial growth
  • Lysozyme - Breaks down the cell wall of bacteria.
  • Interferons - Limit virus replication in cells
  • Interleukin 1 - Induces fever and the production of acute phase proteins.
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5
Q

Summary on Innate Immunity

Complemet system

A

A group of small serum proteins (opsoins) that bind antigens and thus enhance phagocytosis.

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6
Q

Summary on Innate Immunity

Phagocytes

A
  • The neutrophils, also called granulocytes, most efficient phagocytic cells, contain toxic substances that kill or inhbit growth of bacteris and fungi.
  • Macrophages, phagocyte intracellular pathogens, regulate inflammation adn tissue healing.
  • Natural killer cells that destroy compormised cells (infected or tumorous).
  • Other cells, mast cells, eosinophils.
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7
Q

Innate vs adpative Immne Response

A

Innate immune response protect the host during the early phase of an infection.
The innate response greatly influences the formation of the subsequent adaptive response.

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8
Q

Determinants recognized by the innate immune response

A
  • PAMPs - Pathogen associated molecular patterns
  • PRRs - Pattern recognition receptors
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9
Q

PAMPs
Pattern Associated Molecular Patterns

A
  • Non-specific (not antigen specific) receptor recognition.
  • Part of innate antimicrobial defense.
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10
Q

PRRs
Pattern Recognition Receptors

A
  • Toll-like receptors on phagocytic cells
  • The nucleotide-binding oligomerization domain (NODs) - like receptors (NLRs)
  • The retinoic acid-inducible gene (RIG) - I - like receptors (RLRs)
  • Membrane C-type lectin receptors (CLRs)
  • DNA receptors (cytosolic sensors for DNA)
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11
Q

PRRs
Pattern Recognition Receptors

A

PRRs recognize conserved microbe (pathogen) - associated molecular patterns (MAMPs/PAMPs), pathogen - specific virlence factors and danger - associated molecular patterns (DAMPs; tissue injury)

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12
Q

Innate Immunity from Invertebrates to vertebrates

Learn image

A

Focus on AMPs

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13
Q

Antimicrobial Peptides
(AMPs)

A

Human host defense AMPs and proteins are key components of innate immunity, they play a critocal role in warding off invading microbial pathogens.
These peptides vary from 10 to 150 amino acids with a net charge between -3 and + 20, and a hydrophobic content below 60%.

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14
Q

Main features of AMPs

A
  • Small, cationic peptides with potent antomicrobial activity.
  • Most widely used host defense molecule in nature.
  • Produced and secreted by epithelial lined surfaces of tissues that routinely encounter microbes or cell types involved in host defense - skin, lungs, GI tract, urinary tract, etc.
  • Natural antibiotics
  • Disrup bacterial cell membrane and exert additional antimicrobial and hysiological functions.
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15
Q

Prototypic Groups of Antimicrobial Peptides

A
  • Defensins
  • Melittin
  • Cathelicidins
  • Other AMP
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16
Q

Classification of AMPs from eukaryote organisms

A

Learn image

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17
Q

Multiple functions of AMPs in host defense

A
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18
Q

AMPs selectively bind to microbial membranes

A
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19
Q

Models of AMPs antimicrobial membrane disruption

A
20
Q

Classification of AMPs

Structure

A
  • Alpha-helix
  • Beta-sheet
  • Both alpha-helix and beta-sheet
  • Linear extension
21
Q

Defensins

Definition

A

Small (18-45 amino acids) cysteine-rich cationic proteins characterzied by many Beta-sheets and a framework of disulfide-linked cysteines. They are divided into three sub-classes as alpha, beta, and omega according to their genomic organization, cysteine spacing and intramolecular disulfide bonds.
Widely expressed across various life kingdoms, including animals (vertebrate and invertebrate), plnats, and fungi.

22
Q

Defensins

Distribution

A

In plants and fungi, they are produced by a wide variety of tissues. In animals they are produced by cells of the innate immune system and epithelial cells.
An organism usually produces many differents defensins, some of which are stored inside the cells, and others are secreted into the extracellular medium.

23
Q

Defensins

Function

A

They are host defense peptides, with members displaying either direct antimicrobial activity, immune signaling activities, or both.
They are variously active against bacteria, fungi and many enveloped and non-enveloped viruses.

24
Q

Defensins

Structure and diversity

A
25
Q

Classification of Human Defensins

A
26
Q

Human Defensins

Expression

A
  • Ubiquitous in the animal kingdom, in human are expressed abundantly in granules of profesional phagocytes, alpha-defensins are produced by neutrophils, macrophages and instestinal Paneth cells, while beta-defensins are mainly produced by most leukocytes and epithelial cells.
  • Defensins response can be induced by insult or injury to tissues/cells (bacteria, LPS, etc.)
27
Q

Human Defensins

Expression

A

The following tissues and systmes are protected by defensins:
* Skin -HBD-1 is constitutively expressed
* Mucosal and epithelial surfaces (oral cavity)
* Lining of the gastrointestinal tract (GI)
* Lining of the genitourinary tract (UT)
* Lining of the respiratory tract (RT)

28
Q

Human Defensins

Immunomodulatory and Antimicrobial Functions

A
29
Q

Cathelicidins

Definition

A

Family of multifunctional AMPs found exclusively in vertebrates so far (>30), including mammals, birds, reptiles, amphibians and fishes.

30
Q

Cathelicidins

Distribution

A
  • Cathelicidins are small, cationic, antimicrobial peptides found in several species, including famr animals (cattle, horses, pigs, sheep, goats, chickens, rabbits and in some species of fish).
  • In humans, the CAMP gene encodes the peptide precursos hCAP-18 whihc is cleaved inot the active forms LL-37 and FALL-39 and both are primarily stored in the lysosomes of macrophages and neutrophils.
31
Q

Cathelicidins

Function

A
  • The mechanism triggering cathelicidin action involves the disintegration (damaging and puncturing) of cell membranes of organism toward which the peptide is active.
  • Cathelicidin rapidly destroys the lipoprotein membranes of microbes enveloped in phagosomes after fusion with lysosomes in macrophages.
  • These peptides show a broad spectrum of antimicrobial activity against bacteria, enveloped virsues and fungi.
32
Q

Cathelicidin LL-37 strucuture

A
33
Q

Cathelicidin antimicrobial killing mechanisms in Gram-bacteria

A
34
Q

The pleiotorpic propeties of cathelicidin LL-37 in relation to the different cells and tissues

A
35
Q

Human LL37 can cativate the inflammasome

A
36
Q

Mechanisms of microbial resistnace to AMPs

A
37
Q

Differential bacterila resistance mechanisms to AMPs

A
38
Q

AMPs as mediators of human host defense

A
39
Q

AMPs contribute to intestinal tract homeostasis and innate immune defense

A
40
Q

AMPs contribute to innate immune defense at the respitatory tract

A
41
Q

AMPs at the innate urothelial defense

A
42
Q

AMPs in thre Urinary Tract

A
  • Defensis: Defb1-/- mice exhbit increased rates of spotaneous bacteriuria. DEFA1 CNV in UTI patients.
  • Cathelicidin: Increased renal UPEC burden in Camp-/- mice after experimental UTI.
  • Lipocalin 2 (NGAL): Increased renal UPEC burden in Lcn2-/- mice after experimental UTI.
  • Ribonucleases: RNase 4, 6 and 7 have antimicrobial activity in the urinary tract.
43
Q

AMPS:
Potential for therapeutics in UTI

A

**The Good: **
* Bactericidal at micromolar concentrations
* Microbial resistance is limited
* Synergy with conventional antibiotics
* Immunomodulation
The Challenge:
* Cost of production and delivery
* Safety/tolerability

44
Q

Dysregulation of AMPs is associated with inflammatory and autoimmune diseases

Clinical Significance

A
  • The alpha defensin peptides are increased in chronic inflammatory conditions
  • Alpha defensin are increased in several cancers, inclduign colorectal cancer.
  • A reduction of ileal alpha defensins may predispose to Crohn’s disease
  • Patients with rosacea have elevated levels of cathelicidins
  • LL-37 is thought to play a role in psoriasis pathogenesis (along with other anti-microbial peptides).
45
Q

Summary

A
  • AMPs are small cationic proteins, extensively expressed along multicellular organisms and with potent capcity of killing pathogens.
  • AMPs also boost specific innate immune responses and exert selective immunomodulatory effects on the host.
  • Upon exposure to danger, AMPs create an overall balance by inhibiting microbial growth, attenuating exacerbted inflammatory resposnses.
  • Overall, AMPs functions as natural antibiotics and immune regulators.
  • AMPs are promising potential therapeutics, useful in the control of human disease.

Cellular and Molecular Immunology (15 decks)

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