Immunity to Infection Flashcards
The microorganisms that are capable of
causing disease can be categorized into 4
main categories based upon organism type
and/or infectious niche. What are they?
Extracellular (bacteria - gram positive and gram negative, parasites, fungi)
intracellular (bacteria, parasites)
viruses
parasitic worms
What are the physical barriers that protect from infection, and what are their features?
skin: thick, multilayered, low moisture, acidic
mucosal surfaces: mucosal secretion, ciliated epithelium, secretory IgA
mucosal surfaces are a major site of infection (viral, bacterial, fungal, parasitic)
What does lysozyme do?
degrades the peptidoglycan layer that is unique to bacterial surfaces and is required for their survival
What is lysozyme a potent antimcrobial against?
mostly gram positive (Staphylococcus aureus, Streptococcus pyogenes, Clostridium difficile)
some gram negative (Salmonella, Pseudomonas aeruginosa, Escherichia coli)
What is lysozyme secreted in?
saliva and tears
what are antimicrobial peptides (AMPs)?
charged molecules (Defensins, Cathelicidins, Histatins) that insert themselves into the membrane of target cells and form pores
What are AMPs secreted by?
epithelial cells and phagocytes
What do defensins and cathelicidins act on?
broadly, on bacteria, fungi, and viruses
What do histatins predominantly act on?
on pathogenic fungi (e.g Cryptococcus neoformans)
when will a disease progress?
only when physical (eg skin, mucous) and chemical (eg lysozyme, AMPs) have been breached
What are toll-like receptors, and what do they do?
rapid-responding cell surface receptors that recognize PAMPS and initiate signaling cascades that promotes inflammatory cytokine secretion and promotes immune cell recruitment/activation
What does TLR2 bind?
lipoteichoic acid, lipoproteins
What are lipotechoic acid and lipoproteins signatures of?
gram positive and gram negative bacteria
What does TLR4 bind?
lipopolysaccharide (LPS)
What are lipopolysaccharides signatures of?
gram negative bacteria
What does TLR9 bind?
bacterial/viral DNA (both bacteria and herpesvirus)
What does TLR3 bind?
double stranded RNA
What is double stranded RNA signature of?
viral infection
What does TLR5 bind?
flagellin
What is flagellin a signature of?
bacteria (the bacteria motility element)
What does TLR7/8 bind?
single stranded RNA
What is single stranded RNA a signature of?
viral infection
What does TLR1 and TLR6 form a dimer with, and why?
TLR2 to alter lipoprotein specificity
What are NOD-like receptors?
cytosolic PAMP receptors
What are NOD-like receptors important for?
recognition of intracellular bacterial infections (eg Listeria monocytogenes, Mycobacterium tuberculosis)
What does NOD1 bind?
peptidoglycan breakdown products of primarily gram negative bacteria that reach the cytosol (eg Salmonella)
What does NOD2 bind?
peptidoglycan breakdown products of many bacteria (gram positive, gram negative, and Mycobacterium Tuberculosis)
Where is NOD2 especially found?
in cells of the gut
what can a mutation in NOD2 result in?
Some Crohn’s Disease patients have mutations in NOD2 linked to the intestinal permeability and inflammation associated with disease due to improper recognition of bacterial by-products.
What do glucan receptors bind?
recognize beta-glucans that comprise the fungal cell wall (e.g. acapsular Cryptococcus neoformans).
What do scavenger receptors bind?
recognize bacterial cell wall components
Together, what do PAMP receptors promote?
a number of critical responses including:
induction of inflammatory cytokine secretion
mobilization of immune cells (recruitment of inflammatory monocytes and neutrophils)
initiation of adaptive immunity via T cell activation
promote bactericidal killing by activation of antibacterial functions [antimicrobial peptide (AMP) production, reactive oxygen species (ROS) production]
What bacteria does the MAC complex act on?
acts on gram negative bacteria, but not gram positive
opsonization with C3 and recognition by the C3 receptor (C3R) can effectively opsonize what?
GRAM POSITIVE/NEGATIVE and most other foreign pathogens (i.e. the mechanism is broad and generalizable), which promotes phagocytosis by immune cells.
how does complement work on fungi?
FUNGI are also highly resistant to the MAC, but are efficiently opsonized by C3 to promote phagocytosis.
What do complement deficiencies especially render patients susceptible to?
bacterial infection, in particular meningococci (Neisseria meningiditis) and pneumococci (Streptococcus pneumonia)
Upon induction of phagocytosis by PAMP receptors or complement mediated opsonization, innate immune cells (macrophages and neutrophils) are activated to kill the pathogen. In most cases, what is this mediated by?
production of reactive oxygen species, which consist of peroxides and free radicals that cause significant damage to the microorganism – known as Respiratory Burst
What is the respiratory burst?
C3 coated bacteria are phagocytosed and reside in phagosomal compartments. The phagosome fuses with lysosomes containing bacterial damaging reactive oxygen species
What is chronic granulomatous disease?
Defective enzyme (NADPH oxidase) involved in respiratory burst leads to significant susceptibility to bacterial and fungal infections
What are innate antiviral effectors?
interferons and NK cells
What induces type I interferons?
Viral single-stranded (TLR7) and double stranded RNA (TLR3) is recognized by TLRs leading to the induction of Type I interferons
What are type I interferons?
interferon-alpha and interferon-beta
What do type I interferons do?
act on cells surrounding the infected cell and induce Interferon Stimulated Genes (ISGs) that prevent viral synthesis and contain viral spread
What is type II interferon?
interferon-gamma
how do type I and type II interferons differ?
Type I Interferons differ from Type II interferon (Interferon-γ) in that they are traditionally considered specific to
antiviral immunity
when can interferon gamma be induced?
In response to bacterial and viral pathogens (often associated with Th1 cell-mediated immune responses that lead to significant macrophage activation)
What does the antiviral interferon response lead to?
the recruitment and activation of NK-cells, immune cells that can specifically target and kill virally infected cells prior to the induction of cytotoxic T cells
What can Abs in the humoral response be specific to?
specific to a single microbe or bacterial toxin or can be specific to a common motif present on the pathogen surface (e.g. antibodies specific to bacterial surface molecules or carbohydrates)
What is crucial to effective protective immunity?
Specific antibody directed against all pathogens
What do specific antibodies mediate?
opsonization
toxin neutralization
complement activation and cell lysis by MAC
How do specific antibodies mediate opsonization?
Extracellular bacteria (e.g. Staphylococcus aureus, Vibrio Cholera, Streptococcus pyogenes, Streptococcus pneumoniae) and Fungi are opsonized by antibodies recognizing microbial cell surface determinants
Some baceteria produce toxins that can perturb antibody binding (e.g. Protein A of Staphylococcus aureus)
How do specific antibodies mediate toxin neutralization?
Toxin neutralization is specific to bacterial pathogens and not viruses
Antibodies with specificity to a bacterial-produced toxic factor (e.g. Cholera toxin of Vibrio Cholera can be neutralized by toxin-specific IgA in the gut – the site of V. cholera infection)
How do specific antibodies mediate complement activation and cell lysis by MAC?
Ab facilitate complement Activation and cell lysis by MAC (e.g. Neisseria meningiditis)
Some bacteria are opsonized less efficiently due to the production of capsular polysaccharides that interfere with C3 recognition (Streptococcus pneumonia, Group A
Streptococcus, and Staphylococcus aureus)
What is the T cell-dependent control of intracellular bacteria?
(e.g. Mycobacterium tuberculosis and Listeria monocytogenes)
Th1 cells serve to activate macrophages via the production of Interferon-γ and other pro-inflammatory cytokines
What is the T cell-dependent control of virally infected cells?
Clearance of viral infection is highly dependent on the induction of cytotoxic CD8 T cells in conjunction with antibody and NK cell-mediated responses
How are parasitic infections cleared?
Control of parasitic infections (e.g. Schistosoma mansoni) can be mediated by complement activation, but is also mediated by an IgE-dependent process known as antibody dependent cellular cytotoxicity (ADCC)
What is ADCC?
During ADCC, parasite specific IgE, bound to eosinophils via their Fc regions, recognize the invading parasite and induce eosinophil-dependent killing.
How are fungal infections cleared?
typically taken up and processed by phagocytic cells that have been activated by cytokine mediated processes.
What is Streptococcus pyogenes responsible for?
Skin infection (impetigo) Throat infection (Strep throat) Necrotizing fasciitis
What is Staphylococcus aureus responsible for?
Skin and soft tissue infections Bacteremia Endocarditis Osteomyelitis Pneumonia
