10. Pathogens vs Immune System
Diapositivas del conjunto (31)
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- You should be able to discuss and provide specific examples of (with key molecules and outcomes):
- Pathogen immunosuppression
- Pathogen immune avoidance
- Pathogen immune evasion
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- Parasites must combat or avoid immune systems of hosts:
- Immune suppression- disabling the opposition
- Immune avoidance- intracellular parasites
- Immune evasion- masters of disguise
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Immune Sup: Bacteria Manipulate Host
- E.coli bacteria manipulating host: extra Pathogenicity Island (PAI) DNA in pathogenic strain:
- Different genes encoded on PAI in bacteria:
- Toxins
- Adhesins (host specificity/tissue tropism)
- Siderophores (living in free iron limiting conditions)
- Immune modulatory factors eg IgA protease
- Type 3 secretion system (T3SS)- pathogen delivery system and its effector molecules to modulate host cell properties
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Immune Sup: Bacteria Manipulate Host
- Examples of proteins encoded by PAIs:
- Gram -ve bacteria T3SS
- Complex molecular syringe to insert proteins in the host cell
- Alters host cell in diverse ways, depending on specific effector proteins
- E.coli immunomodulator expression (Shiga toxin)
- Extracellular cytotoxin that targets host ribosome (modifies rRNA), inhibits translation
- Induces apoptotic signalling pathway
- Hemolytic uremic syndrome (HUS)- kidney damage
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- Pathogens obstruct T cell activation of host:
- Bacteria: Heliobacter pylori (H.pylori)
- Causes gastric ulcers
- Can block transcription of T cell growth factor IL-2
- Viruses: Human Immunodeficiency Virus (HIV)
- Prevents phosphorylation of TCR cascade
- Prevents formation of Immunological synapse- presentation of antigens between cells
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Immune Supression: HIV Replication
- HIV mainly targets infection of T cells and macrophages
- Progressively destroys immune cells, impairs their function and reduces numbers
- Weakens immune system-> increased susceptibility to other opportunistic infections
- Inability to battle secondary infections-> death and disease
- How they infect: HIV attaches to CD4 on surface of T cells
- Macrophages: interaction between viral gp120 with CD4 and CCR5 (coreceptor)
- T cells: interaction between viral gp120 with CD4 and CXCR4 (co-receptor)
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Immune Sup: Helminths Manipulate Host
- Helminths manipulate host immune response:
- Large extracellular helminths interact with host through their immunomodulators- surface molecules and secreted molecules
- Helminths and hygiene hypothesis:
- Helminth infection ubiquitous throughout human evolution- so immune system evolved in presence of worms (used to immunosuppression in their presence)
- Helminth infection now rare in western world- lead to increase in inflammatory diseases, autoimmunity disorders in their absence: . Allergies, autoimmunity (T1D, MS), intestinal inflammation, metabolic syndrome, obesity
- Hygiene hypothesis states rise in "Western inflammatory diseases" is the direct result of reduced pathogen exposure- i.e helminths essential for correct education of our immune system
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Immune Sup: Helminths Manipulate Host
- Large extracellular helminths modify host with their secreted molecules= Excretory/secretory (ES) molecules
- Worms produce parasite immunomodulatory molecules
- These molecules bias host immune system/ limit inflammation (suppressing immune cells)
- Worm prevents/ limits immune attack i.e chronic infection
- Commensal bacteria can promote survival of worms or compete against them
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Immune Sup: Helminths Manipulate Host
- Does worm infection prevent inflammatory disease?
- Asthma- allergic lung inflammation (using mouse model to represent)
- Induce inflammation by giving mouse ovalbumin protein-> generates OVA specific Th2 cells
- OVA delivery to lungs-> accute inflammation mimicing asthma
- Inject worms before hand, do they prevent?
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Immune Sup: Helminths Manipulate Host
- Result: Intestinal helminth infection prevents lung allergic reaction
- Worm induces Tregs that limit inflammation
- Naive cells- no reaction
- OVA injected- big inflammatory response (high number of eosinophils)
- Worms before- supressed inflammation
- Worm infections also prevent inflammation in models of: Diabetes, intestinal inflammation, obesity, MS
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Immune Sup: Helminths Manipulate Host
- Summary of helmith-induced immune modulation
- Studies to isolate immunomodulators to treat allergic reactions would (treat patient without infecting them with helmith)
- Suppresion of immune cells promote worm survival but also prevent western autoimmune diseases
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Immune Sup: Helminths Manipulate Host
- Hygiene hypothesis- evidence from human studies:
- Observational study- Cross-sectional comparison of human population with various levels of worm infection and/ or inflammatory diseases- Does worm infection correlate with reduced inflammatory disease? Yes
- Interventionist study- Compare incidence of inflammatory disease before and after deworming program- Does deworming lead to increased inflammatory disease?
- Deliberate human infection study- Helminth therapy- Does experimental infection with a worm reduce inflammatory disease in a patient cohort
- Helminth immunomodulatory molecules (vs live infection)- All benefits of worm-induced immunosuppression without the pathogen
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Immune Avoid: Parasites manipulate Host
- Viruses manipulate host with immunoevasins to block their proteins presented to CD8+ T cells
- TAP= transporter, delivers peptide from cytosol to ER lumen
- TAP binds tapasin and peptide (binds tapasin) is pulled through by TAP-I and TAP-II proteins and loaded on MHC-I
- Molecules/viruses block uptake of peptides, can't be presented:
- ICP47 blocks peptide binding TAP
- US6 inhibits TAP ATPase activity
- UL49.5 inhibits TAP peptide transport
- Adenovirus E19- competitive inhibitor of tapasin
- HCMV US2- degradation of MHC-1 by removing newly synthesis MHC-1 from ER to cytosol
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Viruses Block Peptide Presentation
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Immune Avoid: Parasites manipulate Host
- Leishmania control innate immune response:
- 2 forms: promastigote (human infective, dont divide), amastigote (human infection, divide and cause disease)
- Many receptors implicated in leismania uptake- DC and macrophages are main targets for infection
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Immune Avoid: Parasites manipulate Host
- Leishmania control innate immune response: Innate phagocytes can internalise Leishmania and are destroyed by it
- Neutrophils can be initially infected and present themselves to macrophages (indirect mac infection)
- Differentiates into disease causing form
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Immune Avoid: Parasites manipulate Host
- Leishmania control innate immune response: Sandfly commensal bacteria promote Leishmania human infection
- Sandfly gut microbes prime host cell inflammasome
- Sand flies have commensal bacterial in their saliva/gut, transmit bacteria with saliva + promastigote secretory gel, activate inflammasome-> draws out immune cells (neutrophil infiltration)
- Inflammasome derived IL-1β keeps neutrophils at bite sites
- Antibiotics:
- Treating sandfly with antibiotics before transmission blocks neutrophil infiltration- Antibiotic clears the commensal bacteria
- Impairs Leishmania dissemination (parasite transmission without inflammation- lower level of transmission)
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Commensals Promote Leishmania Infection
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Immune Avoid: Parasites manipulate Host
- Leishmania control innate immune response: Inhibition of phagosome maturation
- GP63= protease on surface of transmissable form of parasite
- GP63 cleaves VAMP8 which is necessary for fusion of phaogosome and gp91phox vesicle that matures phagosome (increases oxidation->alkaline pH, decreased proteolytic activity allows processing) so it can present parasite on MHC
- No cross presentation, no stimulation of T cells
- Surface of parasite impacts on phagosome and whether parasitic vesicle can fuse with phaogosome
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Inhibition of Phagosome Maturation
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Immune Avoid: Parasites manipulate Host
- Leishmania control innate immune response: Models for delivery of Leishmania virulence factors
- When in parasitic vcauole, release virulence factors into host cell cytoplasm via:
- Exosomes- eg contain immunomodulatory factors that fuse out into host cytoplasm and remodel actin and block lysosome (keep pH at good level for survival)
- Lipid rafts
- Translocases flipases
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Immune Avoid: Parasites manipulate Host
- Leishmania control innate immune response: Pre-emptive disabling of host cell signalling pathways by Leishmania exosome cargo
- Promastigotes manipulate host cell macrophages via exosomes and blebs from PM
- Results in:
- Blocking microbial functions; NO TNF-α, ROS
- Promote anti-inflammatory response- IL-10, leading to Leishmania persistence
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Immune Evasion: Antigenic Variation
- Influenza
- Surface proteins
- Haemagglutinin (HA)- attaches to host receptors
- Neuraminidase (NA)- breaks down sialic acid to allow budding
- Major serovars: 15 different HA, 9 different NA
- Antigenic drift/ minor mutations- epidemics, seasonal flu
- Antigenic shift/ major reassortment- host infected with 2 different flus simultaneously, pandemic
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Immune Evasion: Antigenic Variation
- Trypanosomes
- Changing surface coat: switch VSG (Variant Surface Glycoprotein) expression
- VSG switches to avoid Ab landing, recycles coat every 12 min
- If Ab lands on VSG, VSG moves Ab to flagella pocket, ingest via endocytosis, digests Ab, VSG shift back to surface
- How does it switch- T, brucei genome sequencing info
- >1000 VSG genes in genome
- Almost all are pseudogenes/ gene fragments
- Trypanosomes can create new genes by recombining fragments
- VSG repertoire for antigenic variation larger than originally thought
- Parasite kills you before runs out of different VSGs
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Immune Evasion: Antigenic Variation
- Plasmodium
- Infect RBCs, RBC develop surface knobs that contain parasite proteins
- Surface knobs cause RBCs to stick to endothelial lining and block capillaries- Prevents parasite clearance by spleen
- Stick to eachother and vessels- cause blood clots-> liver and brain inflammation and damage (cerebral malaria- why P.falciparum is so pathogenic)
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Immune Evasion: Antigenic Variation
- Plasmodium: PfEMP proteins
- Plasmodium spp. PfEMP1 protein is massive complex, 2 domains (CIDR and DBL)
- Functions of domains:
- Cytoadherence of RBC to microvascular endothelial cells in all organs to avoid spleen
- Evade specific immune responses through antigenic variation
- CIDR and DBL domains are variable and can recombine with eachother-multiple copies of these genes throughout genome
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- Trypanosoma cruzi avoid innate and acquired immune response: Receptor-ligand interactions
- Receptor-ligand interactions enable T.cruzei adherence and invasion of mammalia cells and interactions drive:
- Phagocytosis, membrane raft-dependent endocytosis, macropinocytosis, autophagy, Ca2+ dependent lysosome exocytosis
- Every life cycle phase is infective- infect any nucleated cell by triggering their own endocytosis via calcium signalling, inside cell need to escape parasitic vacuole into cytoplasm to differentiate into amastigotes
- Have multiple receptors-> multiple receptor-ligand pairs
- Complex downstream signalling
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- Trypanosoma cruzi avoid innate and acquired immune response: Surface trans-sialidases obstruct CD8+ T cell immunity
- Immune cell function dependent on sialic acid- T cell activation associated with decreased sialyation of surface proteins
- T.cruzi TS re-sialytes molecules reducing T cell-target interactions
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- Trypanosoma cruzi avoid innate and acquired immune response: Lysosomal escape by T.cruzi trypomastigotes
- Inside vesicle potent oxidants, ROS are formed (H2O2 and peroxynitrite, ONOO-)
- T.cruzi peroxidases and superoxide dismutases (SOD) neutralises lysosomal reactive oxygen species (ROS)
- Escape requires acid-activated protein TC-TOX which forms pores and rips vacuole apart
- In cytosol, ROS can promote T.cruzi growth via amastigote access to iron
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- Trypanosoma cruzi avoid innate and acquired immune response: Congenital transmission by T.cruzi trypaomastigotes
- Problem for pregnant women, foetus at risk of infection
- Complement acts as molecular bridge- C1q bidns to trypomastigote calreticulin and placental calreticulin, forming bridge
- Ab's promote assist T.cruzi uptake- were tested to block interaction but promoted it by assisting recognition of the pathogen
