Immunity to Microbes Flashcards
What mediates the effector mechanisms that provides defense against microbes?
Innate and Adaptive Immunity
True or False:
In many infections, tissue injury and disease may be caused by the host response to the microbe (collateral damage) rather than by the microbe itself.
True
What is the survival and pathogenicity of microbes in a host critically influenced by?
The ability of the microbes to evade or resist the effector mechanisms of immunity.
True or False:
Many microbes establish LATENT, or PERSISTENT INFECTIONS in which the immune response controls but does not eliminate the microbe and the microbe survives without propagating the infection.
True
Which complement pathways do Gram negative bacteria with surface lipopolysaccharide activate?
- alternative pathway
- mannan-binding lectin pathway
How do acute phase proteins (e.g., CRP and SAP) assist in complement activation?
Acute phase proteins bind bacterial coat polysaccharides and activate complement.
What does C3a and C5a bind to in a primary extracellular bacterial infection?
C3a and C5a bind to receptors on resident mast cells and activate them.
mast cell degranulation enhances blood flow
the increased blod flow and local edema are perceived as itchiness and irritation in the inflamed area
In a primary extracellular bacterial infection, what does locally released chemokines (IL-8/CXCL8) and bacterial-derived molecules (e.g., endotoxin) activate?
Both the endothelium and neutrophils.
In primary extracellular bacterial infection, what proteins are potent neutrophil chemoattractants?
- complement fragments (C5a)
- chemokines (IL-8/CXCL8)
together with bacterial products such as formyl-methionyl-leucyl-phenylalanine tripeptide, attract neutrophils to the site (chemotaxis)
What happens when neutrophils and tissue macrophages are attracted to the site of infection by primary extracellular bacterial infections?
> opsonized bacteria are rapdily engulfed and killed by neutrophils and tissue macrophages.
immature DCs engulf and internalize bacteria via pattern recognition receptros (e.g., Toll-like receptors) - activated mature DCs migrate to the local LNs via the lymphatics
What does local inflammation caused by a primary extracellular bacterial infection lead to the up-regulation of?
Adhesion Molecules on high endothelial venules (HEV) of lymph node, and lymphocytes enter directly from the blood.
many lymphocytes become trapped, activated, and proliferate in the local inflamed LN
this leads to the consequent swelling and local hyperemia that manifested by the symptoms of swollen painful/tender LNs
Early antibacterial Ab production is of what isotype?
IgM class
this relatively low affinity interaction is enhanced by the 5 adhesion sites on IgM, leading to higher avidity of the binding
IgM is a very potent complement activator
bacteria are also opsonized with C3b via IgM-activated complement (classical pathway) that increases phagocytosis
What happens in the resolution of a primary extracellular bacterial infection?
Bacterial debris is removed by local macrophages and neutrophils, or by Ab as soluble immune complexes.
upon elimination of pathogens, the immune responses is contracted and most of effector lymphocytes die via apoptosis
What are the two principal mechanisms that infections caused by pathogenic extracellular bacteria have?
1) Tissue damage is caused by inflammation at the site of infection.
2) Bacteria produce toxins which have diverse pathologic effects.
What are bacterial toxins subdivided into?
- endotoxins - components of bacterial cell walls
- exotoxins - which are secreted by the bacteria
What is endotoxin (LPS) of Gram-negative bacteria a potent activator of?
- macrophages
- DCs
- endothelial cells
List examples of exotoxins that are cytotoxic.
- diphtheria toxin (shuts down protein synthesis in infected cells)
- cholera toxin (interferes with ion/water transport)
- tetanus toxin (inhibits neuromuscular transmission)
True or False:
Other exotoxins interfere with normal cellular functions without killing cells, and yet, other exotoxins stimulate the production of cytokines that cause disease.
True
What are the principal mechanisms of innate immunity to extracellular bacteria?
- complement activation
- phagocytosis
- inflammation
What type of extracellular bacteria activate complement by the lectin pathway?
Bacteria that express mannose on their surface bind mannose-binding lectin, which activates complement by the lectin pathway.
What components of Gram-positive and Gram-negative bacteria activate the alternative pathway?
> Gram-positive bacteria - peptidoglycans
> Gram-negative bacteria - LPS
Give an example of a bacteria that are particularly susceptible to lysis by the MAC complex.
Neisseria
What byproducts of the alternative pathway stimulate inflammation by recruiting and activating leukocytes?
- C3a
- C5a
complement activation results in opsonization and enhanced phagocytosis of the bacteria
What is the function of FACTOR I in the prevention of host bystander damage?
Cleavage of C3b and C4b by FACTOR I prevents them from forming active convertases and requires cofactor activity.
These cofactors include the membrane-bound membrane cofactor protein (MCP) and complement receptor 1 (CR1), Factor H (FH) and C4b-binding protein (C4BP).
In the prevention of host bystander damage, which proteins inhibit assembly of new C3 convertases and shorten the half-life of the preformed convertases, limiting their ability to participate in complement activation?
> Classical Pathway - DAF, CR1, and C4BP
> Alternative Pathway - DAF, Factor H, and CR1
In the prevention of host bystander damage, which protein inhibits the assembly of the MAC complex?
membrane-bound MAC-INHIBITORY PROTEIN (CD59) and the fluid-phase vitronectin and S protein.
- CD59
- Vitronectin
- S protein
What are the 3 steps in opsonization and phagocytosis?
1) recognition and attachment
2) engulfment
3) killing and degradation
List the 4 different phagocyte microbicidal mechanisms.
- NADPH oxidase
- inducible NO synthase (iNOS)
- iron scavengers and exporters, such as lactoferrin
- antimicrobial peptides and proteases that permeabilize and degrade the bacteria
SOD, superoxide dismutase
Name two types of extracellular bacteria that evade the host immune system by resistance to phagocytosis?
- Pneumococcus
- Neisseria meningitidis
Name an extracellular bacteria that evade the host immune system by scavenging of reactive oxygen species?
catalase-positive staphylococci
Which type of adaptive immunity controls the major protective response against extracellular bacteria?
Humoral Immunity
How does humoral immunity function against extracellular bacteria?
Functions to block infection, to eliminate the microbes, and to neutralize their toxins.
In humoral immunity against extracellular bacteria, what are the different effector mechanisms of Abs?
- toxin neutralization
- opsonization and phagocytosis
- complement activation by the classical pathway
What do antibodies respond against in humoral immunity against extracellular bacteria?
Abs directed against:
> cell wall Ags
> secreted cell-associated toxins
True or False:
Encapsulated bacteria rich in TI polysaccharide Ags are primarily eliminated by Ab-mediated immunity.
True
What kind of infections do patients with genetic defects in Th17 development have increased susceptibility to?
BACTERIAL and FUNGAL infections, with formation of multiple skin abscesses.
In the cell-mediated immunity response against extracellular microbes, what do Th17 cells induced by these microbes promote?
- local inflammation
- recruit neutrophils
- recruit monocytes
this is all done at sites of bacterial infection
Besides Th17 cells, what other type of T helper cells are induced in cell-mediated immunity by extracellular microbes?
Bacteria also induce Th1 cells - which produce IFN-gamma and activates macrophages to destroy phagocytized microbes.
In cell-mediated immunity against extracellular microbes you know that IFN-gamma produced by bacteria induced Th1 cells activates macrophages to destroy phagocytized microbes, but what else can IFN-gamma also stimulate?
Production of opsonizing and complement-fixing IgG Abs.
What are the two injurious consequences of host responses to extracellular bacteria?
- inflammation
- septic shock
inflammatory reactions are usually self-limited and controlled
What is septic shock syndrome characterized by?
Circulatory collapse and disseminated intravascular coagulation.
septic shock is a severe pathologic consequence of disseminated bacterial infection (sepsis) by some Gram-negative and Gram-positive bacteria
What is the early phase of sepsis and septic shock caused by?
Cytokines produced by macrophages that are activated by bacterial cell wall components.
cytokines secreted cause the SYSTEMIC MANIFESTATIONS of the infection and stimulate the production of acute-phase proteins
How do the same reaction of neutrophils and macrophages that to eradicate the infection also cause tissue damage?
By local production of reactive oxygen species and lysosomal enzymes.
Macrophages release a diverse range of products implicated in the pathogenesis of sepsis. What do macrophages release and what is there function?
> TNF-alpha - upregulate tissue factor (TF).
> Nitric oxide synthase (iNOS) and IL-18 - induces IFN-gamma
- IFN-gamma in turn further activates macrophages.
What effect does IL-10 have on macrophage function?
IL-10 is a global suppressor of macrophage function.
True or False:
In the mechanisms of septic shock involves a highly complex and tightly regulated network, making it difficult to predict the outcomes of blocking or inhibiting just one pathway.
True
What are the major classes of proteins that are mediators of septic shock?
- cytokines
- chemokines
- lipid mediators
- oxygen radicals
What typical effect do the mediator chemokines IL-8, MIP-1alpha, MIP-1beta, MCP-1, and MCP-3 have in septic shock?
> Mobilize and activate inflammatory cells, especially neutrophils.
> Activate macrophages.
What typical effect do lipid mediators platelet-activating factor, prostaglandins, leukotrienes, thromboxane, and tissue factor have in septic shock?
> Activate vascular endothelium.
> Regulate vascular tone.
> Activate extrinsic coagulation cascade.
What typical effect do oxygen radical mediators superoxide and hydroxyl radicals and nitric oxide have in septic shock?
> antimicrobial properties
> regulation of vascular tone
What typical effect do cytokine mediators IL-1, IL-6, IL-12, IL-15, IL-18, TNFalpha, MIF, HMGB1, IL-10 have in septic shock?
> activate neutrophils
> activate lymphocytes
> activate vascular endothelium
> upregulate cellular adhesion molecules
> induce prostaglandins
> induce nitric oxide synthase acute-phase proteins
> induce fever
> NOTE: IL-10 is predominantly a negative regulator of these effects.
What class of MHC molecule does superantigens (SAgs) bind to?
Certain bacterial toxins called superantigens (SAgs) bind to the class II MHC outside the peptide binding groove.
Simultaneously, SAgs binds to the variable region of different TCR beta chains, regardless of the peptide specificity of the TCR.
What do T cells express that allow SAgs to activate a large number of T cells causing polyclonal T cell activation?
TCR beta chain from a particular Vbeta family.
What are staphylococcal SAgs responsible for in human disease?
FOOD POISONING - staphylococcal SAgs are potent GI toxins responsible for staphylococcal food poisoning.
What microbe causes toxic shock syndrome (TSS)?
S. aureus - can be considered as a capillary leak syndrome.
What microbe causes streptococcal toxic shock syndrome (streptococcal TSS)?
S. pyogenes - is the most severe form of invasive streptococcal infection.
What is acute rheumatic fever (ARF)?
A post-infection cause of preventable pediatric heart disease.
What disease is a post-infection cause of preventable pediatric heart disease?
acute rheumatic fever (ARF)
What is Kawasaki disease (KD)?
An acute multi-system vasculitis of unknown etiology.
What has been proposed to contribute to the pathogenesis of autoimmune disease by activating T cells that are specific for self Ags?
Autoimmune diseases - that SAgs contribute to the pathogenesis of autoimmune disease by activating T cells that are specific for self Ags.
What is the major mechanism used by bacteria to evade humoral immunity?
Variation of surface Ags.
Why is humoral immunity not effective against intracellular bacteria?
Intracellular bacteria and viruses are able to survive and replicate within host cells where they are inaccessible to circulating Abs.
elimination of these bacteria requires cell-mediated immunity
True or False:
In many intracellular bacterial and viral infections the host responses also cause tissue injury.
True
What effect does an intracellular viral infection cause?
Activation of cytokine and cytokine-receptor genes, especially the Type I interferons (e.g., IFN-alpha).
What are the local effects of IFN-alpha on a intracellular viral infection?
> Inhibition of viral gene replication.
> Up-regulation of MHC class I molecules.
List the 4 step overview of the cell-mediated immune response to a primary viral infection.
1) Viral infection results in cell death and viral replication.
2) Components of viruses (e.g., ssRNA) activate DCs and locally released cytokines and chemokines amplify the activation of macrophages and professional APCs.
3) These cells engulf cellular debris and present viral proteins.
4) Professional APCs (e.g., tissue DCs such as Langerhans cells in the skin) transport Ag to local LNs via lymphatics.
Give an example of an adhesion molecule that is up-regulated on an endothelial cell by cytokines in a primary viral infection.
ICAM-1
Give an example of chemokines that begin to attract cells through the endothelium towards the site of infection in a primary viral infection.
IL-8/CXCL 8 - which attracts neutrophils to the site of infection.
What cytokines are locally produced by macrophages and T cells that enter the bloodstream and have systemic effects on fever and arthralgia/myalgia?
IL-1 and TNF-alpha
What does the local inflammation caused by IL-1 and TNF-alpha produced locally by macrophages and T cells at the site of infection lead to up-regulation of?
Adhesion molecules on high endothelial venules (HEV) of LN, and lymphocytes enter directly from the blood.
What happens when lymphocytes become trapped in the local inflamed LN?
Lymphocytes become trapped, activated, and proliferate in the local inflamed LN.
this leads to the consequent swelling and local hyperemia that manifested by the symptoms of swollen painful/tender LNs
In a primary viral infection, how do naive B cells acquire viral Ags?
attachment to surface IgM or IgD
True or False:
Antiviral IgM are produced as a result of primary Ab response.
True
Naive B cells acquire viral Ags through attachment to surface IgM or IgD. What type of T cell does Ag-activated B cells present processed viral peptides to?
Th2 cells - from which they receive positive growth and differentiation signals.
Naive B cells acquire viral Ags through attachment to surface IgM or IgD. Ag-activated B cells then process and present viral peptides to Th2 cells, which provides positive growth and differentiation signals to the Ag-activated B cell. What do these signals from Th2 T cells cause the B cells to do?
B-cells differentiate and class switch, leading later to production of high affinity antiviral IgG (secondary Ab response).
In a primary viral infection what stabilizes the interaction between viral peptides presented by class II MHC molecules to a complementary TCR on a Th cell?
Interaction is stabilized by CD4/class II MHC and CD80/86 binding to CD28, which also provides co-stimulatory signals to the Th cell.
What is the role of Th1 cells in a primary viral infection?
Th1 cells recruit and stimulate virus-specific CTLs by providing IL-2 for proliferation of CD8+ T cells.
the CTLs recognize virus peptides cross-presented by DCs
the same viral epitopes will be presented within class I MHC on the surface of infected target cells
How do Th cells and CTLs leave the LN after being activated?
Via the draining lymphatics and ultimately enter the blood.
In a primary viral infection activated Th cells and CTLs leave the LN via the draining lymphatics and ultimately enter the blood. At this stage in a cell-mediated immune response to a primary viral infection, what are the 3 key attributes at this stage?
(1) virus-specific TCRs
(2) up-regulated adhesion molecules (LFA-1), to allow migration into the inflamed tissues
(3) up-regulated production of cytokines
Once virus-specific CTLs leave the LN, what do they do next in a cell-mediated immune response to primary viral infections?
- virus-specific CTLs migrate from the blood into peripheral tissue
- CTLs recognize viral Ags presented within class I MHC on virally infected cells and kill them
- local Th1 and Th2 cells now organize the local antiviral immne response:
> Th1-derived IFN-gamma activates phagocytosis by macrophages
> Abs facilitate phagocytosis via FcR and CR1
NK cells may be recruited at two points during the primary virus infection. What are they?
(1) they exhibit an innate (early in the course of infection) antiviral role following activation by epithelium-derived IFN-alpha
(2) at a later stage of infections, NK cells are activated by cytokines IFN-gamma and IL-2 produced by Th1 cells specific for the virus
What do virus-infected cells secrete after their death?
> Secrete viral proteins after their death:
- These proteins may be neutralized or removed by Ab in the form of immune complexes.
- Ab may guide Fc receptor-expressing NK cells that culminates in Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC).
After the resolution of the primary viral infection, where do virus-specific memory T and B cells reside long term at?
- lymph nodes
- spleen
- bone marrow
What type of cell ensures long-term circulation of protective virus-neutralizing Abs?
plasma cells
How is the innate immune system activated by intracellular bacteria?
Mediated by phagocytes and NK cells interactions among which are mediated by IL-12 (DCs and macrophages) and IFN-gamma (NK cells).
May control bacterial growth, but elimination of the bacteria requires adaptive immunity.
How is the adaptive immune system activated by intracellular bacteria?
Cell-mediated immunity (CTLs) in which Th1 cell-produced IFN-gamma activates phagocytes to eliminate the microbes.
Which two cell types mainly mediate the innate immune response to intracellular bacteria?
- phagocytes
- NK cells
Before the development of adaptive immunity, what two cell types provide an early defense against intracellular bacteria?
- NK cells
- macrophages
What receptor types recognize intracellular bacteria products resulting in activation of DCs, macrophages, and neutrophils?
- TLRs
- cytoplasmic proteins of the NOD-like receptors
True or False:
The resistance of pathogenic bacteria to degradation within phagocytes is overrun by NK cell-produced IFN-gamma.
True
The resistance of pathogenic bacteria to degradation within phagocytes is overrun by NK cell-produced IFN-gamma. Which cells produce IL-12 and IL-15 to activate these NK cells?
Activated DCs and macrophages produce IL-12 and IL-15 which activate NK cells.
the NK cells produce IFN-gamma, which in turn promotes killing of the phagocytized bacteria by macrophages
What is the endogenous pathway?
> Proteins from intracellular pathogens, such as viruses, are degraded by the proteasome and the resulting peptides are shuttled into the ER by TAP proteins.
these peptides are loaded onto MHC class I molecules and the complex is delivered to the cell surface, where it stimulates CTLs that kill the infected cells
What is the exogenous pathway?
> Extracellular pathogens are engulfed by phagosomes.
inside the phagosome, the pathogen-derived peptides are loaded onto MHC class II molecules, which activate Th cells that stimulate the production of Abs
some peptides from the exogenous pathway can also be presented on MHC class I molecules - how this cross-presentation occurs has been explained in 2003
How does M. tuberculosis survive in phagosomes?
By preventing acid-containing lysosomes from fusing with phagosomes and creating mature phagolysosomes.
CD4+ Th1 cells respond to class II MHC-associated M. tuberculosis Ags and produce IFN-gamma, which activates macrophages to destroy the microbes in phagosomes
CD8+ T cells respond to class I MHC-associated peptides derived from cytosolic Ags (cross-presenting) and kill the infected cells
What is the mechanism of immune evasion by Mycobacterium leprae (inhibited by phenolic glycolipid)?
INACTIVATION of reactive oxygen and nitrogen species.
What is the mechanism of immune evasion by Listeria monocytogenes (mediated by hemolysin protein)?
DISRUPTION of phagosome membrane, escape into cytoplasm.
What is the mechanism of immune evasion by Mycobacterium tuberculosis and Legionella pneumophila?
INHIBITION of phagolysosome formation.
True or False:
Naive CD4+ T cells may differentiate into Th1 cells, which activate phagocytes to kill ingested microbes or Th2 cells, which inhibit this classical pathway of macrophage activation.
True
Th1/Th2 balance may influence the outcome of infections, as illustrated by Leishmania infection in mice and Mycobacterium leprae in humans
What is bound to PAMPs and recognizes fungi?
Fungi are recognized by PRRs (TLRs and C lectin-like receptors) binding the PAMPs.
What is the mechanism of defenses against fungi infections?
> fungi are recognized by PRRs (TLRs and C lectin-like receptors) binding the PAMPs
> the detection of Beta-Glucan by dectin 1 is also important
> then occurs differentiation of Th1, Th2, and Th17 cells and production of cytokines
> cytokines IL-12 and IL-23 have important differentiation and activation roles for activation of Th1 and Th17 responses
> Th1 (IFN-gamma) and Th17 (IL-17, IL-22) cytokines further amplify an inflammation and innate immunity
> specific Th2 cells (Abs) are less important
> in general, Th1 responses are required for clearance of a fungal infection, while Th2 responses usually results in susceptibility to infection
What is the role of dectin-1 in fungal infections?
> Dectin-1 is a specific receptor for beta-glucans expressed on macrophages
> Dectin-1 is a recently discovered PRR that plays an important role in antifungal innate immunity
dectin-1 and TLR2/TLR6 signaling combine to enhance the responses triggered by fungi
What are beta-glucans, which bind to dectin-1 receptors expressed on macrophages?
Polysaccharide PAMPs that contain only glucose as structural components.
What is the role of dectin-1?
Binds and internalizes beta-glucans and mediates the production of reactive oxygen species (ROS), activation of NF-kappaB and subsequent secretion of proinflammatory cytokines.
dectin-1 and TLR2/TLR6 signaling combine to enhance the responses triggered by fungi
Look over slide 57 in lecture.
Chart of immune protection organized by microbe class.
Look over slide 58 in lecture.
Summary chart of protective immunity (part 1).
Look over slide 59 in lecture.
Summary chart of protective immunity (part 2).
Look over slide 60 in lecture.
Summary chart of immunocompromised patients.
List examples of live attenuated vaccines.
- oral polio
- varicella
- mumps
- measles
- rubella
- bacillus
- Calmette-Guerin (BCG)
List examples of killed or inactivated vaccines.
- inactivated polio
List examples of subunit (only some Ags) vaccines.
- diphtheria toxoid
- tetanus toxoid
List examples of recombinant subunit (Ags are recombinant) vaccines.
- hepatitis B
List examples of conjugate (polysaccharides-protein) vaccines.
- Haemophilus influenzae type b
- Streptococcus pneumoniae
List examples of polyvalent (large number of Ags) vaccines.
- Streptococcus pneumoniae
