Infection and immunity Flashcards
List some indirect mechanisms of damage by a pathogen.
How can the immune system distinguish between pathogenic and non-pathogenic candida?
The two forms of candida, yeast and hyphae, are recognised by different immune receptors. There is an anti-fungal response against candida hyphae PAMPs. Immune receptors that recognise yeast are very distinct from those that recognise the hyphae.
Normally it is a commensal fungus that colonizes on genital/gastrointestinal mucosa without causing disease, and only in immunosuppressed hosts can C. albicans become pathogenic.
Host innate immunity to C. albicans critically requires pattern recognition receptors (PRRs). PRRs are involved in the recognition of C. albicans in epithelial cells, neutrophils, endothelial cells, monocytes/macrophages, dendritic cells (DCs), etc. The present known PRRs of C. albicans include:
- Toll-like receptors (TLRs)
- C-type lectin receptors (CLRs)
- Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), among which CLRs and TLRs are major.
Dectin-1, one of the CLRs, recognizes β-glucans on cell wall of C. albicans, and the rest CLRs recognize different mannose-relative structures. Ligation of Dectin-1 can stimulate a variety of cellular responses, including activation of nuclear transcription factor NF-κB and IRF5, ERK-MAPK pathway, NLRP3 inflammasome, phagocytosis, respiratory burst and Rubicon. Interestingly, Dectin-1 can collaborate with TLRs to orchestrate antifungal immunity.
Outline the immune response to an inhaled virus in the lungs.
First wave innate immune response, and adaptive immune response (cytokine and antibodies), and then resolution of inflammation after pathogen clearence.
- Innate response (0-4 hr): INF-α and INF-β production from endothelial cells, natural killer cells become active because there is ‘missing self’, activated macrophages in the lungs produce TNF-α and IL-12, which triggers TH1 response to produce INF.
- Early adaptive response: antibody immune response starts to take place, antigen presentation and immunological synapse formation, B cells make antibodies.
- Late adaptive response: memory cells are generated, IL-10 suppressed proliferation.
List some macrophage receptors and their targets.
The innate immune receptors are essential in the first wave of host-pathogen interaction. Macrophage receptors and their targets include:
- SR-A: LPS, activated B-cells.
- MARCO: LPS.
- SRCL-1: Gram +ve/-ve bacteria.
- DC-SIGN: HIV-1 virus envelope gp120, hepatitis C virus envelope glycoproteins E1 and E2, H. pylori LPS containing Lewisx antigen, Leishmania mexicana mannose capped surface lipophosphoglycan.
- SIGNR1: mostly on mucosal tissue, Strep. pneumoniae capsular polysaccharide, C. albicans, HIV-1 gp120.
- Dectin-1: C. albicans β-glucan, S. cerevisiae β-glycans.
- Dectin-2: Mycobacterium tuberculosis, HIV-1.
- Mannose receptor: central for intracellular habitat of tuberculosis, C. albicans, Influenza A virus.
Pathogens can inhabit different sites of an organism, extracellularly and intracellularly. At each site there will be different immune defences, list some examples of sites of infection, organisms, and protective immunity.
Hosts posess an array of PRRs, and pathogens an array of PAMPs. Name some PRRs and the outcomes of their recognition in different cells.
The outcome of these interactions will be phagocytis, radical superoxidative production, cytokine secretion, or if it is dentdritic cells then mature DCs are phagocytic. Mature dendritic cells (APC) can recruit T cells and present peptides to T cells. Endothelial cells can produce lots of cytokines
What are the two types of phagocytic cells?
- Neutrophils
- Macrophages
List the components of the cellular branch of innate immunity and their function(s). [5]
- Skin and mucous membranes (epithelial cells): act as mechanical and chemical barriers.
- Phagocytic cells (neutrophils, macrophages): ingest and kill bacteria and fungi.
- Proinflammatory cells (macrophages, mast cells, eosinophils, basophils, platelets): induce host defences and inflammation.
- Natural killer (NK) cells: kill virus-infected cells and tumour cells.
- Antigen-presenting cells (dendritic cells, macrophages): recognise, process, and present antigens to lymphocytes, and initiate adaptive immune responses.
What are the two antigen-presenting cells?
- Dendritic Cells
- Macrophages
List the different chemical barriers on the skin and mucosa, and their major function(s). [4]
- Low pH in the stomach: kills many bacteria, fungi, or parasites, and inactivates many viruses.
- Antimicrobial peptides (constitutiveand induced): kill many microbial organisms.
- Fatty acids (sebaceous glands in skin): inhibit bacterial growth.
- Enzymes (lysozyme and amidase): hydrolyse bacterial cell wall peptidoglycan.
Name some host defence mechanisms that combat pathogens.
- Antibodies can neutralise virulence factors, stopping them from binding to their cognate receptors on the cell surface. This is known as neutralisation, and there can be neutralising and non-neutralising antibodies. When the pathogen keeps mutating its virulence factor, e.g. gp120 of HIV, the antibodies can bind to the pathogen, but cannot stop the pathogen-cognate receptor interaction. This is common in chronic infections, which is why there are multiple waves of antibody production. Vaccines induce production of neutralising antibodies, allowing macrophage ingestion. Antibodies can be recognised by Fc receptors, and they broaden the range of recognition by immune cells.
- Phagocytosis is an important mechanism in host-pathogen interactions, in which antigen presenting cells (dendritic cells, macrophages, neutrophils) ‘eat’ microbes through different receptor mechanisms. Some can bind directly to the microbe without opsonins (antibodies, surfactant proteins, complement proteins), e.g. scavenger receptors can directly bind microbe, Toll-like receptors are sensors involved in inflammatory response and are not involved in uptake. Eventually the microbe is lysed and killed through superoxidative burst etc., and then can be degraded and transcytosed or presented by class II MHC molecules for recruiting CD4 cells.
- Complement is a cascade system involving 30 plasma and cell-surface components that is a humoural immune mechanism. It can be activated via three different pathways (alternative, lectin, and classical) and can lead to three different outcomes (phagocytosis, inflammation, and lysis).
- Collectins (C1q) and ficolins: MBL and other molecules recognise carbohydrate patterns (charged) unique to pathogens. Recognition using membrane TLRs has the drawback of needing the cells to approach the pathogen, whereas soluble TLRs are free-floating chemotactic molecules that recruit infiltrating cells at the site of injury. Once these cells are recruited, the collectins can opsonise the microbe. Molecules include MBL, C1q, SP-A, and SP-D.
How can a pathogen escape adaptive immunity?
- Concealment via intracellular residence
- Cyst formation
- Uptake of host antigens
- Antigen mimicry
- Antigen variation
- Immunosuppression
- Diverson of immune response
- Polyclonal activation
What are some defects of innate immunity?
- Reduced C1 esterase: hereditary angioedema.
- Low/absent C1, C2, C4: SLE
- Low/absent C5-9: disseminated gonorrhoea, meningococcal meningitis.
- Lack of C3: lethal.
- Collectin deficiency: predisposition of Mtb infection.
- INF-α deficiency: repeated viral respiratory infections.
- CCR5 chemokine receptor deficiency: resistance to HIV.
What are some organ specific pathogens?
Macrophages are the most versatile immune cells in terms of dealing with pathogens. List some of the activites of macrophages.
- Inflammation and fever
- T-cell activation: macrophages can present antigens.
- Selection of T-cell function: secretion of cytokines which can polarise T cell immune response, IL-12→TH1 cells (γ interferon), IL-10→TH2 (immunosuppressive).
- Tissue organisation
- Tissue damage
- Microbicidal activity/phagocytosis: kill and present microbes.
List some common diseases in humans caused by viruses.
- Adenovirus: human adenovirus (e.g. types 3, 4, and 7)
- Herpesvirus: herpes simplex, VCV, EBV, CMV, HHV8.
- Orthomyxoviruses: infleunza virus.
- Rhabdoviruses: rabies.
What are the types of proinflammatory cells? [5]
- Macrophages
- Mast Cells
- Eosinophils
- Basophils
- Platelets
Acute phase proteins are an SOS response of the body in response to a pathogen entering the bodt, which results in the liver releasing these proteins. List the acute phase proteins.
The body does not immediately know what pathogen enters the body and what is specifically needed to combat it, but sensors for pathogens have been activated.
- Protease inhibitors: α1 anti-trypsin, anti-chymotrypsin degrade foreign proteins.
- Complement components: C1, C2, C3, C4, C5, C6, C9 humoral factors.
- Transport proteins: haemoglobin-binding haptoglobin, ROI-scavenging ceruloplasmin make the cells more metabolically resilient.
- Clotting factors: fibrinogen, clotting factors can trap microbes in wounds.
- Anti-bacterial: CRP (c reactive protein) can opsonise all bacteria and recruit other opsonins.
- Others: SAP, α1 acid glycoprotein.
Innate molecules come into action after these, followed by the adaptive immune response.
Almost all adaptive immune components are involved in dealing with pathogens. There is no stage of adaptive immune response that is not interfered with by pathogens, so pathogens have evolved strategies to deal with adaptive immune response better than the innate immune system. List some stages at which pathogens can interfere.
Almost all adaptive immune components are involved in dealing with pathogens. There is no stage of adaptive immune response that is not interfered with by pathogens, so pathogens have evolved strategies to deal with adaptive immune response better than the innate immune system. This is because adaptive response is slow and specific. Peptides are more specific than PAMPs, and the antibodies produced from this are very specific. If it is a TH1 response γ interferon is made which activated macrophages, which use their PRRs. Pathogens can interfere with:
- Antigen presentation
- Phagocytosis
- Production of IL-2 (clonal expansion of T cells)
- Antibody production
- T cell polarisation (TH1, TH2)
Name some of the targets of SP-A and SP-D.
Surfactant protein A is an innate immune system collectin. It is water-soluble and has collagen-like domains similar to SP-D. It is part of the innate immune system and is used to opsonize bacterial cells in the alveoli marking them for phagocytosis by alveolar macrophages.
Surfactant pulmonary-associated protein D, SP-D, is a protein which is an innate immune system collectin. Surfactant protein D interacts with hemagglutinin of influenza A virus.
Targets of these proteins include:
- HSV
- Staph aureus (peptidoglycan)
- E. coli (O minus rough LPS)
- Aspergillus fumigatus (gp45, gp55)
- Haemophilus influenzae (Omp)
What immune deficiencies can be linked to susceptibility to bacterial infection?
Complement proteins complement the action of antibodies in their clearance of pathogens from the body: C1q is the best link between cellular and humoral immunity.
- Classic pathway (C1, C4, C2) deficiency causes immune-complex diseases: SLE, pyogenic infections.
- C3 deficiency: severe bacterial infections.
- Alternative pathway (C3, FB, FD) deficiency: disseminated pyogenic infections, vasculitis, nephritis.
- Lytic pathway (C5, C6, C7, C8, C9) deficiency: Neisserial infections, SLE.
List some viruses and their host receptors used for entry.
- EBV: B cell complement receptor CR2.
- HIV: T cell, macrophage CD4 and CCR5.
- Rhinovirus CXCR4
What virulence factors can disrupt immune response?
- Proteases: destroys IgA in Neisseria.
- Protein A: Blocks IgG in Staphylococcus.
- IL-10-like molecules: inhibits cytokines and suppresses immune response in EBV infection.
- Inhibit killing mechanisms: intracellular survival in Tuberculosis.
Toll-like receptors can recognice a whole host of ligands on pathogens. Name some TLRs and their ligands.
- TLR1/2 (heterodimer): triacyl lipopeptide (bacteria).
- TLR2: lipoprotein (various pathogens), peptidoglycan (gram +ve bacteria), lipoteichoic acid (gram -ve bacteria), atypical LPS (Leigionella), Zymosan (fungi), haemagglutinin (Measles virus).
- TLR3: dsRNA (viruses).
- TLR4: LPS (bacteria), zymosan (fungi).
- TLR5: flagellin (bacteria).
- TLR6/2 (heterodimer): diacyl lipopeptides (mycoplasma).
- TLR7: ssRNA (viruses), some synthetic compounds.
- TLR8: ssRNA (viruses), some synthetic compounds.
- TLR9: CpG containing DNA (bacteria, viruses).
- TLR11: profilin (Toxoplasma gondii).
List the components of the humoral branch of innate immunity and their function(s). [7]
- Antimicrobial peptides: kill microorganisms.
- Complement: enhances phagocytosis (opsonization), induces inflammation, kills some microorganisms.
- Cytokines: activate innate and adaptive defences.
- Chemokines: attract leukocytes.
- Kinins: induce inflammation.
- Acute phase proteins: enhance cellular and humoral defences.
- Enzymes: kill and digest microorganisms.
During its long evolution and coexistence with microorganisms, the innate immune system developed three recognition strategies. List these.
- Pattern recognitions receptors (PRRs)
- Detection of danger signals from damaged tissues
- Detection of missing self (host)
What are some different routes of viral infection?
How can pathogens escape innate immunity?
-
Habitat selection:
- intracellular habitat means they can avoid soluble immune factors like antibodies and complement, e.g. HIV, measles.
-
Complement:
- capsules block activation (Staphylococcus, Haemophilus)
- LPS side chains block complement (Gram -ve)
- mimicry of complement receptors (HSV)
- MAC expulsion (Leishmania)
- destruction of complement components by enzymes (Pseudomonas)
-
Phagocytosis:
- killing phagocytic cells (Staphylococcus, Streptococcus)
- production of capsules (Streptococcus pneumoniae, Haemophilus)
- prevention of opsonisation by antibody (Staphylococci Protein A)
- uptake paralysis (Yersinia)
- inhibition of chemotaxis (Clostridia)
-
Death threat avoidance
- Entry without activation
- Inhibition of phagosom-lysosome fusion
- Inhibition of ROI
- Resistance to killing mechanisms
- Inhibition of dendritic cells
- Dendritic cells
-
Cytokines
- Mimicry of cytokine receptors
- Mimicry of inhibitory cytokines
- Inhibition of interferon
- Failure to induce interferon
- Suppression of cytokines produced by macrophages
Briefly outline complement pathway.
- Classical pathway: antibody dependent.
- Lectin pathway: MBL pathway.
- Alternative pathway: C3 dependent.
- Outcomes: completion of complement cascade resulting in the formation of the membrane attack complex (MAC) that lyses the cells, C3b can act as a potent opsonin, C3a and C3b are recycled mediate inflammaton and phagocytosis.
Define opsonization.
Antibody opsonization is the process by which a pathogen is marked for ingestion and eliminated by a phagocyte.
List some antimicrobial peptides, their location and function. [4]
- Defensins (skin, intestine, mucous membranes): kills bacteria and fungi.
- Phospholipases (in intestinal Paneth cells and tears): kill bacteria.
- Dermcidin (sweat glands): kills bacteria and fungi.
- Ribonucleases (on skin): kill bacteria and fungi.
How does microbial antagonism act as a defense?
The normal microbiota (bacteria and fungi) compete for nutrients with potential pathogens and produce anti-microbial factors (bacteriocins).
List some direct mechanisms of damage by a pathogen.
In protozoan infections, the early influx of inflammatory cells into the site of infection is dominated by ___________, ___________ and inflammatory __________. These cells interact directly with parasites through pattern recognition receptors such as ____-____ __________ (____), rapidly amplifying the production of pro-inflammatory cytokines. ____ on the surface and within endosomal compartments of host cells bind parasite ligands such as glycosylphosphatidylinositols (GPIs), GPI-anchored proteins and lipophosphoglycan, and trigger a signalling cascade that results in cell activation and release of cytokines such as __-__, essential for protection against Toxoplasma gondii and Trypanosoma brucei .
Helminth parasites and their products can also be recognized by ____: double-stranded RNA from the ____ of Schistosoma mansoni activates TLR3 and elicits IL-12 and TNFα production. Interestingly, the interaction between ____ and the lipid lysophosphatidylserine, expressed by both eggs and adult stages of S. mansoni, results in the development of IL-10-producing _ _____, suggesting that the TLR pathway can be exploited by helminths to suppress the host immune response.
In protozoan infections, the early influx of inflammatory cells into the site of infection is dominated by neutrophils, macrophages and inflammatory monocytes. These cells interact directly with parasites through pattern recognition receptors such as toll-like receptors (TLRs), rapidly amplifying the production of pro-inflammatory cytokines. TLRs on the surface and within endosomal compartments of host cells bind parasite ligands such as glycosylphosphatidylinositols (GPIs), GPI-anchored proteins and lipophosphoglycan, and trigger a signalling cascade that results in cell activation and release of cytokines such as IL-12, essential for protection against Toxoplasma gondii and Trypanosoma brucei .
Helminth parasites and their products can also be recognized by TLRs: double-stranded RNA from the eggs of Schistosoma mansoni activates TLR3 and elicits IL-12 and TNFα production. Interestingly, the interaction between TLR2 and the lipid lysophosphatidylserine, expressed by both eggs and adult stages of S. mansoni, results in the development of IL-10-producing T cells, suggesting that the TLR pathway can be exploited by helminths to suppress the host immune response.
How are viruses recognised by the immune system?
In most cases antibodies are good at dealing with viral response. Antibodies will bind viruses, recruit complement, will be ingested by macrophages and antigens will be presented. If this is in mucosal epithelial cells, non-phagocytic cells, the cytotoxic T cells will come into action. Only non-phagocytic cells can be targeted by cytotoxic T cells.
List the different mechanical barriers on the skin and mucosa, and their major function(s). [8]
- Keritanised epithelium (skin): offers protection against microorganisms.
- Desquamation (stratified epithelium): removes microorganisms attached to its surface.
- Epithelial cells joined by tight junctions: offers protection against microorganisms.
- Mucous-coated hair in nose: traps particles.
- Mucous-coated ciliated epithelium: removes particles from the respiratory tract.
- Mucous-coated intestinal epithelium: keeps the bulk of bacteria away from intestinal epthelium.
- Coughing and sneezing: expels particles.
- Flow of urine: cleanses the urethra.
Outline the differences in the types of hypersensitivity reactions.
- Type I (allergic) hypersensitivity is mediated by IgE and mast cell (Hay fever)
- Type II (cytotoxic) hypersensitivity is mediated by IgG, complement and phagocytes (blood transfusion rejection)
- Type III (immune-complex mediated) hypersensitivity is mediated soluble Ag-Ab complex, polymorphs, complement (glomerulonephritis)
- Type IV (cell-mediated) hypersensitivity is mediated by T cells, cytokines (TB granuloma)
List the innate immune cytokines involved with:
- Inflammation
- Differentiation
- Proliferation
- Cell movement
- Inhibition
- Anti-viral
- Inflammation: IL-1, IL-6, TNF
- Differentiation: IL-12, IL-18, INF-g
- Proliferation: IL-15
- Cell movement: IL-8, MIP-1α, RANTES, MCP
- Inhibition: IL-10, TGF β
- Anti-viral: INF α, β, and γ
