Mechanisms Of Host Defense To Infection Flashcards
What are the 5 broad categories of pathogens/microbes?
EC bacteria IC bacteria Fungi Viruses Parasites
What are the 2 extreme patterns of pathology related to EC bacteria?
Toxicity (endo and exo-toxins)
Tissue invasion
[most EC bacteria are a combination of these two patterns]
Immunity to extracellular bacteria that produce a single toxin may require only what branch of immunity?
Antibodies - to neutralize the toxin
Immunity to extracellular bacteria that are invasive tissue requires what branch of immunity?
Cell mediated
Most extracellular organisms fall between the 2 pathological extremes, some local invasiveness assisted by local toxicity, and enzymes that degrade the ___________ _________. Both humoral and cell-mediated responses are needed
Extracellular matrix
Innate mechanisms to extracellular pathogens includes bacterial _______ recognition by molecules present in serum and by receptors on cells.
Activation of ______ complement pathway with consequent release of C3a and C5a.
Triggers of cytokine/chemokine release and ______ cell degranulation.
Increased blood flow in local capillary networks; increased adhesion of cells and ______ to endothelial cells
PAMP
Alternative
Mast
Fibrin
What are the adaptive immune responses to extracellular bacteria?
Ab production (neutralize and eliminate microbes and toxins)
Activation of CD4 T cells (produce cytokines that stimulate B cells, macrophages, and inflammation)
Extracellular bacteria may be phagocytosed rather slowly, what process increases the rate of phagocytosis?
Opsonization
[using complement fragments or other opsonins]
_______ immunity is the major effector branch in fighting extracellular bacteria
Humoral
Antibodies block attachment of bacteria to host cell membranes, and may trigger ______-mediated damage to some bacteria.
Abs directly block bacterial surface _______ proteins
They also opsonize the bacteria via ____ and _____ receptors for phagocytosis
They block bacterial factors that interfere with normal chemotaxis or phagocytosis. They neutralize toxins and spreading factors that facilitate invasion
Complement
Transport
Fc; C3
Humoral immunity is the major effector branch against extracellular bacteria because the Ags are ______, they have a ___ conformation, and they are ____-linear
Soluble
3D
Non
What are the consequences of excessive release of cytokines in the host response against EC bacteria?
Diffuse intravascular coagulation with consequent defective clotting; changes in vascular permeability, loss of fluid into tissues, fall in BP, circulatory collapse, hemorrhagic necrosis (in the gut)
[occurs with gram negative LPS –> endotoxic shock]
What is the consequence of the TNF and IL-1 host response to EC bacteria?
Endothelial expression of adhesion molecules and tissue thromboplastin –> promotes adhesion of circulating cells and deposition of fibrin
Platelet activating factor enhances these effects
________ EC bacteria can induce shock by massive release of cytokines mediated by superantigens in what is called a “cytokine storm”
Gram +
How can shock be blocked in experimental models?
Addition of neutralizing antibodies to TNF, and antibodies to tissue thromboplastin
Or inhibitors of PAF or nitric oxide production
[note that these are not useful clinically]
EC bacteria and fungi can evade phagocyte killing by the following:
Secretion of repellents or toxins that inhibit _______
Capsules or outer coats that inhibit _____ by phagocyte
Phagocytosed, but release factors that block killing mechanism. May inhibit _____ pump so pH does not fall.
Secretion of _____ which breaks down hydrogen peroxide
Chemotaxis
Attachment
Proton
Catalase
EC bacteria and fungi can evade phagocyte killing by the following:
Organisms like M. leprae have highly resistant outer coats, it surrounds itself with a _______ _______, which scavenges free radicals.
Mycobacteria also release lipoarabinomannan, which blocks the ability of _________ to respond to activating effects of IFN-y.
Cells infected with Salmonella enterica, M. tuberculosis, or Chlamydia trachomatis have impaired _______-_______ function
Phenolic glycolipid
Macrophages
Antigen-presenting
EC bacteria and fungi can evade phagocyte killing by the following:
Several organisms like Listeria and Shigella can escape the ______ and multiply in the ________
The organism may also kill the phagocyte via either ______ (staphylococci) or induction of _________ (Yersinia p.)
Phagosome; cytoplasm
Necrosis; apoptosis
How would an outer capsule on a bacteria evade complement (5 main ways)?
Outer surface is configured so that complement receptors on phagocytes cannot obtain access to fixed C3b
Surface structures can be expressed that divert attachment of MAC from cell membrane
Membrane-bound enzyme can degrade fixed complement
Outer membrane can resist insertion of MAC
Secretion of decoy proteins that cause complement to be deposited on them instead of bacterium itself
What extracellular bacterium was used as an example that uses several strategies to avoid damaging effects of antibodies, first by failing to evoke a large Ab response, then by secreting IgA proteases, then secreting blebs that deplete local Abs?
Neisseria gonorrhoeae
Neisseria gonorrhoeae uses several strategies to avoid damaging effects of Ab:
First, fails to evoke a large Ab response, and Ab that does form tends to ______ the function of damaging Abs.
Second, it secretes an ____ _______ to destroy antibody
Third, _____ of the membrane are released, and these appear to adsorb and deplete local Ab levels
It also has 3 strategies to alter its antigenic composition.
Block
IgA protease
Blebs
Aside from its methods for avoiding damaging effects of Ab, Neisseria gonorrhoeae uses 3 strategies to alter its antigenic composition:
- LPS may be _________, so that it more closely resembles mammalian oligosaccharides and promotes rapid removal of ___________.
- It can undergo ________ _______, so that it expresses an alternative set of surface molecules.
- The gene encoding ____, the subunits of the _____, undergoes homologous recombination to generate variants.
Sialylated; complement
Phase variation
Pilin; pilus
What cells and cytokines of the innate immune system limit the growth and spread of intracellular bacteria?
Phagocytes
NK cells
IL-12 and IFN-y
Which branch of adaptive immunity is responsible for intracellular bacteria?
Cell-mediated
[T cells activate phagocytes via CD40L and IFN-y to eliminate the microbes]
Intracellular bacteria are:
_________-dependent antigens
_________ protein peptides
Recognized by ______
T cell
Linear
HLA
Normally, cytokines inhibit intracellular bacterial growth.
With a ______ knockout, you would have REDUCED ability to control growth and cells die by day 60.
With a _____ knockout, you would by INCAPABLE of controlling bacterial growth, your cells would die by day 35.
IL-12
IFN-y
[IFN-y is most critical]
Why is cell-mediated immunity the major effector branch against intracellular bacteria?
Because when IC bacteria are phagocytosed by macrophages, they may survive in phagosomes and escape into cytoplasm
Elimination of those bacteria requires adaptive immunity via CD4 and CD8 T cells
How do CD4 T cells act as effector cells against intracellular bacteria?
They respond to class II MHC-associated peptide Ags derived from intravesicular bacteria, then produce IFN-y –> activates macrophages to destroy microbes in phagosomes
How do CD8 T cells act as effector cells against intracellular bacteria?
Respond to class I associated peptides derived from cytosolic antigens and kill the infected cells directly
By what process can dendritic cells ingest virally infected cells and display Ag to CTLs AND Ths?
Cross-presentation
What are some mechanisms by which IC bacteria and fungi evade phagocyte killing?
Release of factors that block killing mechanisms
Inhibition of lysosome fusion with phagosome
Inhibition of proton pump, so pH does not fall
Resistant outer coats with phenolic glycolipid, which scavenges free radicals
Mycobacteria release lipoarabinomannan that blocks ability of macrophages to respond to activating effects of IFN -y
Impairment of Ag-presenting function
Consequences of host responses to intracellular bacteria:
________ formation due to collection of macrophages
Activated macrophages fuse to form __________ giant cells that may or may not contain ________ center
Individual _____ influence outcomes
Granuloma
Multinucleated; necrotic
Genetics
Are the following mechanisms of evasion of EC or IC bacteria?
Antigenic variation
Inhibition of complement activation
Scavenging of reactive oxygen intermediates
Extracellular
Are the following mechanisms of evasion of EC or IC bacteria?
Inhibition of phagolysosome fusion
Inactivation of ROS and NO species
Disruption of phagosome membrane
Intracellullar
Viruses are ________ intracellular pathogens that use host cellular machinery to ________
Obligate; replicate
What is a latent viral infection?
Viral DNA persists in host cells; goal is control not eradication
What is a lytic viral infection?
Cells infected by viru are lysed, complicated by budding and virion spreading
What branch of innate immunity prevents viral infection?
Type I IFNs
What branch of innate immunity eliminates virally infected cells?
NK cells
What branch of adaptive immunity blocks viral infection during the extracellular stage? What is a requirement for this?
Antibodies; must have had previous infection
What branch of adaptive immunity is responsible for killing virally infected cells?
CTLs
______ protect against viral infections and promote cell-mediated immunity. They inhibit viral replication in infected and uninfected cells by increasing class ____ HLA, promoting _____ development, and promoting lymphocyte migration and sequestering in _____ _______
IFNs; I; Th1; Lymph nodes
In a typical acute viral response, _____ and ______are detected in the blood stream and locally infected tissues.
CTLs are activated in LNs or _______, followed by appearance of neutralizing Abs in serum.
Activated T cells are _____ by the second to third week.
T and B cell _______ is established.
NK; IFN
Spleen
Absent
Memory
How would antibody alone respond to free virus?
Blocks binding, entry, and/or uncoating of virus
How would antibody + complement respond to free virus?
Damage to viral envelope, blockade of virus receptor
How would antibody + complement respond to virus-infected cells?
Lysis of infected cell, opsonization of coated virus or infected cell for phagocytosis
How would antibody bound to infected cells kill virus-infected cells?
ADCC by NK cells, macrophages, and neutrophils
What might a consequence of host responses be in persistent viral infections like HCV?
Circulating immune complexes
How might viral infections provoke autoimmunity?
Cytolytic mechanism may expose “hidden” self-Ags: epitope spreading
Molecular mimicry (s. Pyogenes)
______ can cause tissue damage in the setting of non-cytopathic viruses by infiltrating tissue
CTLs
Viruses have the following potential mechanisms for evasion of host defenses:
________: meaning that they may not cause active infection for months to years
___________ variation: mutation of regions normally targeted by Abs and T cells
________ analogs like vIL-10, vIL-6, vCCL3
_________ binding protein analogs
Latency
Antigenic
Cytokine
Complement
How might viruses inhibit antigen processing by class I HLAs?
Block peptide uptake into ER
Prevent assembly and migration of peptide:HLA
Encode their own homolog
How might viruses inhibit antigen processing by class II HLAs?
Blocking transcription
Premature targeting for degradation
Why is treating fungi difficult?
No approved vaccines, and antifungal drugs often have severe side effects
Describe the cell wall of fungi
Rigid cell wall made up of complex polysaccharides
In what 2 forms can fungi exist in humans?
Yeasts = single cells
Hyphae = long, slender branches
Fungi are highly immunogenic to what cell types?
Bs and Ts
T/F: Fungi are often pathogenic
False; very few are pathogenic
Who is at greatest risk of fungal infection?
Immunocompromised
What aspects of innate immunity are important in fungal infection?
Neutrophils
Macrophages
Defensins
What aspects of adaptive immunity are important for fungal infection?
Th1 activation of macrophages
IFN-y and IL-12 production
What is the major effector branch in fighting fungal infections?
Cell-mediated
What pathogen has greater morbidity and mortality than any other?
Parasites
Most parasites have _______ life cycles with ______ Stages
Complex; intermediate
What are the 2 types of parasites?
Protozoan
Metazoan
[immunity differs between the 2]
Areas with endemic parasitic infections require repeated _______
Chemotherapy
What are innate effector mechanisms to protozoan parasitic infections?
Phagocytosis (neutrophils, macrophages, DCs)
What are 2 innate effector mechanisms to helminthic parasitic infections?
Phagocytes secrete microbial substances to kill organisms to be internalized
Alternative complement pathway
What are adaptive effector mechanisms to protozoan parasitic infections?
Th1 activation of macrophages
Specific Ab protection
What are adaptive effector mechanisms to helminthic parasitic infections?
Th2 class switch to IgE (IL-4, 5)
IgE binding to outer cuticle, mast cell degranulation
IL-5 recruits Eos for degranulation
ADCC
Which is more toxic to helminthes, eosinophils or mast cell degranulation?
Eosinophils
What is the most important immune response against parasites that live in the blood stream, like african trypanosomes and malarial parasites?
Antibodies
These can damage parasites directly, enhance their clearance by opsonizing them, activating complement, and blocking their entry into host cells
What are some consequences of host responses to parasitic infections?
Chronic infections
Immunosuppression
Granulomas and fibrosis that physically block circulation, lymph, portals to organs, and obstruct GI
Formation of circulating complexes
Cytokine overload (mast cell and Eo mediators)
Molecular mimicry
Parasitic evasion of phagocytosis:
Parasites actively enter the cell into a membrane-bound ________. Lysosomes do not fuse with this.
Survival of parasite depends on stage of ________
Parasites multiple within the phagosome and resist digestion by the presence of a surface ________.
Vacuole
Development
Protease
Can parasites undergo antigenic variation?
Yes, parasites can change their surface Ags during their life cycle in the host
What are the 2 forms of antigenic variation utilized by parasites?
Stage specific (mature vs. infective)
Continuous (programmed expression of genes encoding major surface Ags)
