Ch. 31: Innate Host Resistance

human microbiome

• contains bacteria as well as yeast

• can harbor opportunistic pathogens

• unique to each individual

most pathogens must overcome

• surface barriers

• resistance by host

  • nonspecific resistance (innate immunity)

  • specific immune response (adaptive immunity)

immune system

• composed of widely distributed cells, tissues, and organs

• recognizes foreign substances or microbes

  • acts to neutralize or destroy them

immunity

ability to resist a particular disease or infection

nonspecific immune response (innate)

• natural

• first line

• resistance to any microbe

• lacks memory

• ex: epithelial barriers, phagocytes, dendritic cells, plasma proteins, NK cells

specific immune response (adaptive)

• acquired

• resistance to a particular foreign agent

• has memory

• ex:

  • naive B cell → antibodies

  • naive T cell → effector T cell

antigens

• antibody generators

• haptens: too small to be recognized by immune system, needs carrier molecule

• immunogen: recognized by immune system + elicits immune response

  • large and complex

• epitopes, valence, affinity, avidity

epitopes

on outside of antigens

valence

number of epitopes

affinity

how strong antigen binds to antibody

avidity

number of binding sites and overall antibody-antigen interaction

physical barriers

• part of first line of defense

• skin, mucuous membranes, respiratory system

skin

• consists of stratified layers of epidermis

• mechanical barrier

• pathogens enter through a break in the skin

mucous membrane

• line internal structures

• connected to respiratory and GU tract

• forms protective layer to resist microbe penetration

• layer of cells secrete antimicrobial molecules (lysozyme)

what mechanism does the respiratory system use

mucociliary escalator

• moves particles away from lungs towards mouth

innate resistance

• chemical mediators

• involve antimicrobial peptides and proteins

  • most ancient primary defense mechanism

  • Mostly amphipathic 

  • examples: lysozyme, lactoferrin and granzyme

    • Lactoferrin circulates in blood and sequesters iron, preventing microbes from getting blood

    • Granzyme makes hole in membranes of microbes → cell lysis

Two major types of antimicrobial peptides

• cationic antimicrobial peptides (CAMPs)

  • produced by humans

• Bacteriocins

  • Produced by bacteria - part of microflora

cationic peptides produced by

• host cells

first class of cationic peptides

• includes cathelicidin

  • membrane disruption

  • secreted as inactive proteins

    • Activated by proteolytic cleavage

  • broad spectrum, produced by a variety of cells

  • Found in respiratory, genital epithelial cells, and neutrophils

second class of cationic peptides

• α- and β-defensins

  • released as a precursor protein, broad spectrum

    • Activated by proteases

  • found in neutrophils, intestinal Paneth cells, intestinal and respiratory epithelial cells

  • Defensins bind to membranes, form a pore, and kill the cells

third class of cationic peptides

• histatin

  • large peptides found in human saliva

  • has anti-fungal activity due to its target being the mitochondria

bacteriocins

• antimicrobials produced by normal microbiota

• Lethal to related species

• Produced by Gram-positive and Gram-negative cells

  • Colicins produced by E. coli

  • lantibiotics by Streptococcus, Bacillus, Staphylococcus and Lactococcus spp.

• Break down cell wall and inserts into cell membrane, releasing more molecules to break cell wall

complement system

• Composed of >30 serum proteins

• Three major activities:

  • stimulating inflammatory response

  • cell lysis

    • Other complement proteins are activated and cause lysis of the cell (break down membrane)

  • Opsonization (C3b)

• 3 different pathways

3 different pathways of complement system

• Alternative pathway

• Lectin pathway

• Classical pathway

• Lectin and classical pathway almost intertwined depending on activation

alternative pathway

• first to activate

• Activated when pathogens have repetitive surface proteins

• activated by C3b - sticks to bacteria

lectin pathway

• activated by fungi enveloped

• Detects mannose → inflammatory responses

classical pathway

• Associated with antibodies

• Activated by antibody complexes

  • C1q activate C4 and C2

  • triggers inflammatory pathway

what is the cell of the immune system

leukocyte (WBC)

• involved in both specific and nonspecific immunity

• all arise from pluripotent stem cells

• each has specialized role in defending host

  • mast cells, granulocytes, monocytes + macrophages, dendritic cells, lymphocytes

• LYMPHOCYTES ARE LEUKOCYTES

• NOT ALL LEUKOCYTES ARE LYMPHOCYTES

granulocytes

• irregular shaped nucleus

• basophil

• eosinophil

• neutrophil

basophil

• stain bluish-black with basic dyes

• lowest number of cells in circulation

• Migrate from bloodstream into tissue space

• release vasoactive mediators

• Granules containing histamine →

• role in development of allergies and hypersensitivities

• found mostly in tissues

eosinophil

• stain red with acidic dyes

• defend against protozoan and helminth parasites

• release cationic proteins (hydrolytic) and reactive oxygen metabolites

• role in allergic reactions (type I hypersensitivity)

• Release histaminase (enzyme that activates histamine)

• circulate in low numbers

neutrophils

• stain the lightest at neutral pH, highly phagocytic

• circulate in blood then migrate to sites of tissue damage

• First to respond - highest in blood circulation

• kill microbes by ingesting them

• have lytic enzymes within cells

• release ROS contained in granules

• pyogenic (PUS)

monocytes and macrophages are

highly phagocytic cells

monocytes

• mononuclear phagocytic leukocytes

• Circulate in blood, once migrated outside the blood it infiltrates tissues and differentiates into a macrophage

• Granules in cytoplasm are produced in bone marrow, and mature into macrophages

• smaller/less developed

macrophages

• larger than monocytes, reside in specific tissues (“fixed”)

• variety of surface receptors 

professional phagocytes are

macrophages, neutrophils, dendritic cells (DC)

macrophages

will first encounter the microbe

neutrophils

recruited to site of infection

• phagocytose the pathogen, causing it to die

dendritic cell (DC)

• samples the microbes but do not destroy them

  • take the information to secondary lymphoid tissue (LT)

lymphocytes

• Major cells of the immune system

• Major populations include T cells, B cells, and innate lymphoid cells (ILC)

  • ILC aka cytotoxic innate lymphoid cells

  • natural killer (NK) cells are innate, are part of ILC

    • Can recognize if host cell changes d/t infection or becomes cancerous

• B and T lymphocytes differentiate in the bone marrow from stem cells 

  • Give rise to memory cells

B cells, T cells, NK cells, and ILCs are LYMPH AND LEUKO

primary organs and tissues

• Allow lymphocytes to mature and differentiate 

• thymus and bone marrow

  • Bone marrow stays active throughout life unlike thymus

secondary organs and tissues

• lymphocytes may encounter and bind antigen

• Found in spleen, lymph nodes, MALT (mucosa) & SALT (skin)

M cells

• Mucosal-associated lymphoid tissue (MALT) includes GALT (GI) and BALT (bronchial)

• M cells are at the top

  • Embedded within epithelium

  • Tests for invaders and recruits macrophages to destroy pathogens

phagocytosis

• Use macrophages, dendritic cells, and neutrophils in process of destroying invaders

• Recognition is increased by opsonization

  • Opsonization: mark antigens with antibodies and target them for phagocytosis

• two mechanisms for recognition of microbe by phagocyte

two mechanisms for recognition of microbe by phagocyte

• opsonin-independent/nonopsonic recognition

• opsonin-dependent/opsonic recognition

opsonin-independent/nonopsonic recognition

• Cells bind directly to antigen and phagocytise directly

• Common pathogen components are non-specifically recognized

  • signaling mechanism involved

• Involves nonspecific/specific receptors on phagocytes

• Microbes directly linked to interactions with phagocytic cell, no antibody is involved

• 4 main forms of interaction recognition

4 main forms of opsonin-independent interaction recognition

• recognition by lectin-carbohydrate interactions

• recognition by protein-protein interactions

• recognition by hydrophobic interactions

• detection of pathogen-associated molecular patterns (MAMPs) by pattern recognition molecules (PRM)

opsonin-dependent/opsonic recognition

C3B associated with receptor and targets the pathogen with antigen

what does MAMPS stand for

Microbe Associated Molecular Patterns

MAMPS

• Also known as Pathogen-Associated Molecular Patterns (PAMPs) 

• Patterns

• Unique to microbes:

  • LPS

  • peptidoglycan

• Recognized by pattern recognition receptors (PRR)/molecules (PRM) on/in phagocytic cells

toll-like receptors (TLRs)

• Signaling receptors 

• Recognize and bind unique MAMPs 

• MyD88 dependent pathway = indicate pro-inflammatory cytokines

  • Once triggered, neutrophils will come to area

• TRIF-dependent pathway = trigger production of interferons, chemokines and inflammatory cytokines

  • Once triggered, natural killer cells come destroy microbes