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Flashcards in Host Pathogen Interactions Deck (15):

Pathogen vs Non-pathogen

What determines if an organism of a pathogen...
1. The characteristic of virulence (harmful in its effects).
In other words, the ability to cause infection.
Mycobacterium tuberculosis H37Rv is virulent
Mycobacterium tuberculosis H37Ra is avirulent.


Types of host-bacterial interactions

1. Infestation-distinct from bacterial infections-animal parasites such as worms.
2. Infectious disease-manifestations of the fight due to pathogenic organisms.
3. Mutualism- relation between two different organisms in which both are benefited.
4. Opportunist-Pathogens that attack persons with a compromised immune system.


Commensal microbiota

-Makeup of microbiota depends on various factors: environment, nutrition, stress, age, etc.
-Normal microbiota are important; examples: bacteria provide vitamins.
-Microbiota varies depending on anatomic sites.
-Microbiota contributes to immune defense:
If you wipe out the microbiota, you open up to human infection.
Example: C. Diff.; hypervirulent strain in hospital and with high doses of antibiotics, you wipe out normal microbiota and C Diff. can then take over.
Once C. Diff starts growing, it produces toxins and causes problems.
Disrupting normal microbiota leads to disease.


Difference between a Pathogen and a Commensal

-Pathogens can establish in areas devoid of commensal populations.
-Pathogens possess inherent ability to cross barriers and evade host defenses.
-Pathogenic characteristics are genetically encoded; sometimes in plasmids; if you can get rid of these plasmids, you can maybe get rid of pathogen.


Response to a pathogen

-Requires the distinction between self and non self.
The body relies on two types of immunity:
-Innate-early response; early recognition and pro inflammatory response.
-Adaptive immunity-later response; elimination of pathogens in late phase.


Innate Immunity

Receptors are fixed in the genome and rearrangement is not necessary.
Distribution: Non-clonal and all cells of a certain class are identical.
Recognition: PRRs and PAMPs (conserved molecular patterns like LPS, LTA, mannans, glycans).
Self-Nonself discrimination: PERFECT, selected over evolutionary time.
Action time: immediate activation of effectors.
Response: Co-stimulatory molecules, cytokines (IL-1beta, IL-6), chemokines (IL-8).
Evolutionarily conserved pathway in humans.
In order for a pathogen to really infect the human body, it hats get past the innate immune system.


Adaptive Immune System

Receptors: encoded in gene segments and rearrangement is necessary.
Distribution: clonal and all cells of a class are distinct.
Recognition: details of molecular structure (proteins, peptides, CHO).
Self-nonself discrimination: imperfect; selected in individual somatic cells.
Can have antibody cross recognition with something else in your body.
Action time: delayed activation of effectors.
Response: clonal expansion or anergy, IL-2, Effector cytokines (IL-4, IGNgamma).


3 Phases of Host Defense

1. Innate Immunity (immediate: 0-4 hours); Infection -> recognition by preformed, nonspecific and broadly specific effectors --> removal of infectious agent.
2. Early induced innate response (early: 4-96 hours); Infection --> recruitment of effector cells --> Recognition of PAMPS and activation of effector cells and inflammation --> removal of infectious agent.
3. Adaptive immune response (late: >96 hours); Infection --> Transport of antigen to lymphoid organs --> recognition by naive B and T cells --> Clonal expansion and differentiation to effector cells --> removal of infectious agent.


Innate Immunity-Physical Barriers

Barriers to infection: skin (pH ~5-6; not optimal for many organisms).
Tight junctions between cells.
Mucus lining interior epithelial surface; coated with mucin and other glycoproteins reduces ability of microbes to stick.
Antimicrobial peptides (defensins; electrostatic attraction and the transmembrane electric field bring the defense into the lipid bilayer- the defense peptides form a pore in the pathogen kill it) ;these are produced in the skin and the lower GI; peptides with positive charge.
Fatty acids are known to disrupt membranes on pathogens.
Enzymes in the gut can chew up proteins on pathogens.
Epithelial surfaces-first line of defense.


Phagocytic cells

-Macrophages are long lived cells-abundant in areas where infections are likely to occur; they are among the first cells to encounter invading microbes.
Oxidize pathogens quite readily in phagocytic cells.
-Neutrophils are the most abundant WBC; they are short lived and NOT PRESENT in normal, healthy tissues.
-Macrophages and neutrophils unleash an armory of weapons once a pathogen has been phagocytosed.
Defensins are 15% of the protein in a neutrophil.
NADPH oxidase complex: produce highly toxic oxygen derived compounds like super oxide, hypochlorite, hydrogen peroxide, hydroxyl radicals, nitric oxide.
-The production of toxic compounds leads to respiratory hurts (increased oxygen consumption).
-Macrophages survive the process.
-Neutrophils die-major component of pus in wounds.
-Neutrophils sense CpG tracts of pathogenic DNA; common among pathogens, element in innate immunity.


Innate Immunity-Conserved Pathogenic Features

Human cells recognize conserved pathogenic features: PAMPs (some biochemical structure on pathogens that is different then what we have on our cells in our own body.
Recognition triggers innate immune response: inflammatory responses, apoptosis or autophagy (regulated destructive mechanism) of infected cell, phagocytosis by cells such as neutrophils and macrophages, compliment activation.
Lipopolysaccharide (LPS) is a conserved pathogenic features of GRAM NEGATIVE BACTERIA; composed of lipid, sugar, and antigen components.
At a specific O on the polysaccharide, a protein is attached that is an antigen.


Innate Immunity-PRRs

Responsible for detection (binding) of PAMPs.
-TLRs represent the major family and most extensively studied class of PRRs.
-TLRs are abundant on epithelial cells lining the lung and gut.
-TLRs are abundant on macrophages and neutrophils.
-TLRs act as an "alarm" system for both the innate AND adaptive immune systems.
PAMP recognition domain; leucine rich; responsible for recognizing pathogenic feature.
Membrane bound; receptor portion that detects PAMP on outside of cell and on the inside of endosomes.
Other domain allows inflammatory response to be activated.
Once PAMP is bound, there is a domain that transducers signal via Toll/IL-1 receptor homology (TIR) domain.


Cytoplasmic PAMP receptors

RIG-I-Like Receptors (RLR); RNA helicase portion, detect RNA inside cell that is non human, viral infection, also detect DNA).
NOD-Like Receptors (NLR); can detect DNA and RNA that is non self, can lead to the destruction of the cell.
Responsible for detecting PAMPs inside of cells.
Can also detect glycoproteins on viral coats.
Fungi have a lot of sugars on the outside of their cells; look different than human cells on the outside; humans don't have mannose outside of cells (manna on fungi and is a polysaccharide of mannose).
Beta glycan and manna are different.
It takes a low number of receptors to recognize a wide variety of conserved pathogenic features.


Complement Pathway

Part of innate immunity
20 interacting proteins
3 pathways
Series of proteins in high abundance throughout the body
Can ID pathogen features
Lectin Pathway:
Bacteria and fungi have different sugars on outside of cells compared to humans.
Lectins are proteins that bind sugars.
MBL=mannose binding lectin; we do not have mannose.
Binding domains can tag outside of pathogen; surveillance proteins, if they see something tagged then they can respond.
Through signaling C3b, macrophages or neutrophils may recognize this and undergo phagocytosis or MAC.
Phagocytosis; tagged by C3 fragments, single that phagocyte needs to engulf structure.
TLR, direct, fast response.
Complement, does not require cell, float around in human body and assist body in ID pathogens.


Human Health and Gut Microbiota

At least 10 times more bacterial cells than human cells.
500-1000 different species of bacteria in humans.
Normal gut microbiota helps with digestion and immunity.
Altering microbiota results in disease.
At different time points, different kinds of bacteria are much more important for colonizing the gut.
2 non adaptive immunity pathways=complement and innate.
Invaders can be attacked by neutrophils and macrophages through TLRs or complement system.
Both TLR and complement systems can allow neutrophils and macrophages to attack a pathogen; one is a bit more direct, the complement pathogen needs be tagged on the outside to be recognize.d
TLR can just be the receptor and directly determine if it is a pathogen or not=more direct!!!
Complement, TLR, innate immunity
Disrupt normal microbiota; changes our perspective on how to treat patients.