Immune Response to Infection Flashcards
What is in mucus that protects the epithelial cells from damage and helps limit infection via chemical barrier?
Enzymes and peptides
What three tracts of the body have mucosal epithelia?
GI
Respiratory
Urogenital
How does structure correlate with function for mucosal surfaces?
Mucosal surfaces are physiological areas of gas exchange (lungs), food absorption (gut), sensory activity (eyes, nasopharynx) and reproduction so they structure of the mucus needs to be dynamic, thin and permeable.
What percent of the human immune system is comprised of the mucousal immune system?
75%
What are the two ways the common cold can be transmitted?
Directly via droplets
Indirectly via fomites
What is the driving force that has shaped the development of the immune system in vertebrates?
The “war” between pathogenic microbes and the immune system (each thing develops defenses and subversions against each other)
What cell secretes mucus? What type of barrier does the mucus form?
Epithelial cells secrete mucus to form a physical barrier. But it is also a chemical barrier because there are enzymes and peptides present in the mucus.
Where is the majority of the mucousal immune system in the gut?
The small intestine because this is where the bulk of food re-absorption takes place
there are many commensal bacteria that aid this process
What area is located just below the epithelial cell layer in case pathogens breach the physical barrier?
What four cell types are found here?
The lamina propria which contains DC, macrophages, effector T and B cells, and IgA-producing plasma cells.
What is the function of Peyer’s patches and isolated lymphoid follicles?
to monitor the contents of the intestinal lumen and initiate adaptive immune responses (it is like the LN of the mucousal system)
How are microorganisms trafficed into the lamina propria and Peyer’s patches?
they are transported across M cells which are spaced among the epithelial cells of the small intestine
What do M cells do?
transport microorganisms from the intestinal lumen into the lamina propria, peyers patches and isolated lymphoid follicles to put them in contact with APCs like DCs and T/B lymphocytes
Once a pathogen contacts a DC in peyers patches, where do they go?
Through lymphatic drainage to the mesenteric LN
An isolated lymphoid follicle is like a smaller version of ___________________ except it differs in _________because it consists mostly of _____________________.
Peyer’s patch
composition
lymphocytes
Where are Peyer’s Patches found?
Where are isolated lymphoid follicles found?
PP- small intestine
ILF- small intestine and colon
Where are the mesenteric LN located?
in the membrane of connective tissue that holds the gut in place
Naive B, T lymphocytes traffic into Peyer’s patches, isolated lymphoid follicles, and mesenteric LN via ______________________.
High endothelial venules
What three structures of the mucousal immune system do naive B and T cells traffic into via HEV?
Peyer’s patches
Isolated lymphoid follicles
Mesenteric LN
After activation in the mesenteric LN, where do effector B and T cells travel?
through efferent lymphatic drainage into the thoracic duct to reenter the blood and then they migrate back to the mucosal immune system
What is able to ensure that “mucosal T and B cells” only circulate to the mucosal immune system and not back throughout the body?
Chemokines, cytokines, homing receptors
What is the major antibody of the mucosal immune system?
What 5 roles does it perform?
IgA
- export toxins and pathogens FROM lamina propria while it is being exported
- Bind and neutralize ae ntigens internalized in endosomes
- Bind and neutralize pathogens in the gut lumen
- bind and internalize pathogens through M cells to take to lymphoid tissue
- pick up pathogens from endosomes to take to lymphoid tissue
The lymphocyte and myeloid cell lineages of the mucosal immune system derive from the _____________________ as those of other elements of the immune system but, ___________________________.
Same precursors, but when they encounter an antigen in the mucosal immune system, they become permanent members and only traffic back to these mucosal tissues
What is the incubation period of a pathogen?
The period of time from the start of infection for the pathogen to increase in numbers to a threshold where clinical disease is initiated.
What determines the length of incubation period? (4 things)
- the number of pathogens that are the initial infecting population
- the rate the pathogen replicates
- the impact of the innate and adaptive immune system on containing the growth
- the number of pathogen needed to initiate disease (threshold)
What are the three outcomes that can occur when a pathogen is encountered?
- The host’s immune system can eliminate the pathogen band it is unabated btefore disease is even initiated
- The pathogen passes threshold, but the immune system response increases and the number of pathogens decreases back below threshold
- The pathogen passes threshold, can’t be controlled by the hosts immune system and the host dies
What is the major target of the adaptive immune system?
The pathogens attachment site to the host or tissue
What are the four major attachment strategies used by pathogens to bind to hosts?
- glycocalyx polysaccharide network (strep pneumoniae)
- Fimbrae or pili short proteins (strep pyogenes A)
- Protein receptors (viruses)
- adhesive disc (giardia intestinalis)
What is glycocalyx?
What is the purpose?
What pathogen uses glycocalyx?
Network of polysaccharides that layer around the pathogen to attach to cells in the lungs.
Strep pneumonia
What are fimbrae and pili?
What pathogen utilizes this attachment?
Short proteins that extend from the cell wall of Strep Pyogenes A which allows them to attach to cells of the trachea and cause strep throat
What is Giardia intestinalis?
What adhesion strategy does it use to attach to hosts?
a flagellated protozoa that uses adhesive discs to attach to the lining of the intestine
What are the two main ways humans are able to block adhesion by pathogens?
- Commensal bacteria forces the pathogen to compete for binding space
- The adaptive immune system targets adhesion molecules
In the US, the common cold accounts for ________________ upper respiratory infections per year.
1 billion
What are the common features regardless of infecting viral pathogen of the common cold?
- Acute disease with a short incubation period (2-5 days)
2. Infects upper respiratory tract
What are the three main culprits of the common cold?
- Rhinovirus (50%)
- Coronavirus
- Influenza virus
Influenza viruses associated with the common cold are member of the _________________ group.
Epidemic influenza is associated with the _________________ group.
Common cold- paramyxovirus
Epidemic flu- orthomyxovirus
The average adult has ____ colds a year. The average child has ____. This is probably because _____________________.
2; 4
Adults have more Ab for different forms of the cold viruses (more extensive adaptive immunity and memory cells to various strains)
What common cold strain of virus was responsible for the SARS outbreaks?
Coronavirus
Describe the structure of the Human Rhinovirus.
What temperature does it replicate best at?
It is a non-enveloped, ssRNA virus with an icosahedral capsid.
It replicates best at 33 degrees celcius (the temperature of the upper respiratory tract)
How long does a typical infection from the HRV run? What branch of the immune system is activated?
5-7 days.
The innate immune system is activated through type 1 IFN and stimulation by PRRs.
Why does it make sense that IFNa-b would be activated with the common cold?
IFNa-b upregulates MHC1 to stop viral replication and spread to the cells around it
The symptoms associated with the common cold are reflective of ____________________not _____________.
The innate immune response not the virus itself
The capsid proteins that coat the HRV have a major binding site capable of binding to what 2 parts of the host?
- ICAM1- a major attachment site on human tissue
2. LDL molecules circulating
The ICAM binding site on the HRV protein capsid has been localized to where?
What other structure has binding sites in the same location of the viral capsid?
What does this show?
a deep pocket/canyon
Human antibodies have binding sites to the same area of the viral capsid showing that the Ab is trying to block the viral adhesion site
How has the HRV mutated to stop the Ab from blocking its attachment site to ICAM?
In the canyon/pocket it has a very deep pore that can bind ICAM but is too deep to be blocked by Ab
Many viral binding sites for cell receptors are designed in a fashion that limits _____________.
direct access by antibodies
Scientists studied whether viral coat gene mutations were purifying (maintaining structure ) or diversifying (changing the protein structure) but using what ratio?
Non-synonymous (changes AA)/Synonymous (doesnt change AA)
What is purifying selection?
favors the retention of a particular protein structure
What is diversifying selection?
favors a change in the protein structure
What region did scientists see a lot of nonsynonymous mutations in the HRV protein capsid genes?
At locations where host Ab were known to bind indicating that the virus was able to mutate due to selective pressure
What are the two hypotheses for how viruses escape Ab binding?
- Canyon model- they form pores that the Ab cannot access at their binding site to host tissue
- the size of the Ab binding site is much larger than the viral attachment site so mutations in regions adjacent to the ICAM can decrease Ab binding
The highest dN/dS mutations were located in specific regions of the viral genes. What genes had this bulk of non-synonymous mutations?
4 viral capsid structural genes (VP1-VP4)
How many identical binding sites are located on the viral capsid?
16
There is a strong overlap between regions of ________ and the ______________.
diversification and the Ab binding sites
What indicates that the viral evolutionary strategy to subvert Ab-binding sites by developing a canyon is not completely successful?
There are some Ab binding sites within the canyon
What has a strong influence on the evolution of pathogens? How is this evidenced in HRV?
The host immune response
Evidenced by the fact the HRV has mutated to make over 100 serological types
How do continuously mutating viruses influence the genetics of the human immune system?
selection of new HLA haplotypes
How is host selection different for the common cold and epidemic influenza?
The common cold solely targets humans but influenza can infect many different species
How many deaths per year does influenza cause?
40,000
What is the basic structure of the influenza virus?
how is the genetic info organized? what are the layers? the surface molecules?
It is a single stranded RNA virus (with 8 genomes)
It is surrounded by matrix protein, then the lipid bilayer of the host that it acquires when it buds out of the host cell.
It has neuraminidase and hemagluttinin proteins on the surface.
What structure of the influenza virus is the target of the adaptive immune response?
Neuraminidase
Hemagluttinin proteins on the lipid bilayer
What part of the body is infected by the influenza virus?
What structure on the virus binds to the host cells?
What structure on the host cells allows the virus to bind?
Upper and lower respiratory tracts
The hemagluttinin on the virus binds to sailic acid residues of carb moieties on the cell surface proteins of epithelial cells
Why are different strains of influenza characterized by the serotype of their N and H antigens?
Because N and H are what the adaptive immune system predominantly respond to
What strain of the flu preferentially infects the upper respiratory tract?
What is characteristic of the pathogenesis and spread of upper respiratory tract infections?
H1N1 (swine flu)
It is less severe, but spread more easily
What strain of the flu preferentially infects the lower respiratory tract?
What is characteristic of the pathogenesis and spread of lower respiratory tract infections?
H5N1 (avian flu)
It is more severe (even fatal) but is not as easily spread
What serotype of flu killed 20-100 million individuals in the Spanish Flu of 1918?
H1N1.
The deaths were caused by cytokine storms initiated by the innate immune response
What happened prior to the initiation of significant symptoms (1 day post-infection to about 4 days post infection) of the flu?
shedding of the virus by the nasal lavage
When did the shedding of the virus by the nasal lavage start to decrease?
Why?
About 6 days post infection due to the elimination of the virally infected host cells by CD8 T cells
When are the majority of cytokines released during infection with the flu?
What are the 4 major cytokines released?
Which is released first? By what cells are they released?
2 days after infection initiation:
IFNa-b is released first from infected epithelial cells in the upper respiratory tract.
Next, IL-6 is released by macrophages in the mucosal of the upper respiratory tract
4 days after infection:
TNFalpha and IL-8 (CXCL8) are released to attract more myloid cells and effector cells to the tissue
What symptoms of the flu correlate with IL-6 and IFNab?
Fever and upper respiratory tract inflammation (sore throat, congestion)
The ___________ virulent the influenza infection, the more _______________ are released and the more _______________the symptoms.
The more highly virulent the influenza, the more cytokines are released and the more severe the symptoms
Congestion of the ________ respiratory tract is more severe because:
lower because congestion can impair breathing and normal lung function
What two major cells are involved in the adaptive immune response to influenza?
CD8 T cells and antibodies (released from plasma cells)
What is the major strategy elicited by the influenza virus to subvert the adaptive immune system?
mutate the structure of the H and N proteins recognized by antibodies and CD8 T-cells
What is the main way that H and N mutate in structure to avoid Ab binding?
The Ab binding site is much larger than the H or N attachment site to the sailic acid on epithelial cells so mutations around the binding site can restrict Ab binding w/o affecting the host binding site
What are the two main strategies influenza viruses use to elude adaptive immune system?
- Antigenic Drift
2. Antigenic Shift
What is antigenic shift?
Two viruses infect the same host.
Inside the host, they exchange RNA segments so that they will express a novel hemagglutinin
What is antigenic drift?
Mutations alter the epitopes in hemagglutinin so neutralizing antibodies can no longer bind
Which process is more rapid, antigenic drift or antigenic shift?
Antigenic shift occurs in a host cells where a new hemagglutinin is made. It is a rapid exchange of RNA when two viruses infect the same host cell.
Antigenic drift is more gradual because it is the accumulation of mutations adjacent to the critical attachment regions until Ab can no longer recognize the virus
Which host evasion process is slower, influenza or the common cold?
What is the most likely reason?
The influenza virus process is much slower than that seen for HRV probably because it doesnt have a canyon structure like HRV
