PARASITE HOST INTERACTIONS

PARASITE HOST INTERACTIONS

1. INFECTION = growth/multiplication of a microbe in a host

   • If a parasite is able to progress beyond the point of colonisation and breach the host's defeses, an infection is said to have occurred
   • Disease = injury to the host
     • Microorganism must
       • Be transmitted from host to host
       • Gain entry to and adhere to target tissues
       • Evade the host defences and multiply in the tissue
       • Obtain iron/essential nutrients
       • Produce symptoms
       • Exit host
   • Classes of infection by site
     • Localised
     • Generalised
   • Infection process
     • Entry
       • Transmission routes
         • Route depends on ability to survive in environment
         • DIRECT
           • Transmitted by person-to-person contact
           • Resp/salivary spread
             • e.g. TB
           • Venereal spread
             • Very sensitive pathogens e.g. chlamydia 
             • Host must feel well enough (and be attractive enough) to engage in sexual intercourse
             • Bacterial STDs
               • Often asymptomatic for months/years
               • Infection often restricted to mucosal tissues
               • Avoids damage to cells critical to host health
               • mechanisms to avoid immune detection
             • Viral STDs
               • Often latent
                 • Incorporate into host genome & remain silent
               • Target immune-privileged tissues
               • Not highly virulent
                 • HIV an exception
                   • Nef gene product suppresses T-cell activation and activation-induced cell death. Function lost in HIV
         • WATER-BORNE
           • Diarrhoeal pathogens have 3 modes of transmission Person-person (direct) person-to-food-to-person (indirect) Water-borne
           • Faecal-oral spread
             • Faecal environment provides some protection to parasite, as well as humidity and nutrients
           • Does not require host mobility
             • Allows evolution of virulence
               • Parasites like Vibrio cholerae has a v high percentage of outbreaks involving waterborne transmission (80%) and a high percentage of deaths per infection
               • e.g. Cholera, caused by toxin produced by parasite
                 • Aquatic parasite with >150 recognised serotypes but only 2 are toxogenic and have caused 7 pandemics since 1817. 
                 • Highly susceptible to high acidity of stomach so high dose required for infection
                   • around 10^6 bacteria
                   • Survivors colonise intestinal lumen (non-invasive) and replicate at v high rates
                     • Causes fulminant diarrhoea, up to 20L a day, faeces contain up to 10^7 bacteria per mL
                 • Growth increases transformation competence
                   • Transformation competence = ability to take up foreign DNA
                   • TfoX induces expression of T6SS
                     • type VI secretion system genes, encode a spear-like device that allows vibrios to kill nearby susceptible prey, releasing their DNA into the environment. 
                     • Other components of TfoX competence regular allow horizontal gene transfer
                       • High levels of genetic diversity in vibrios in natural environment
                 • Colonisation factor TCO
                   • TCO = toxin co-regulated pilus, hair-like projection on the surface of bacterial cells
                   • Vibrios can use chitin as a sole source of carbon and so attach to copepods via plus and feed off chitin in exoskeleton
                     • Pilus allows attachment to intestinal epithelium, leading to colonisation
                   • Originally acquired by transduction from aquatic bacteria but now acts as a receptor or CTXphi-transduction
                 • Virulence factor CTX
                   • Encoded in genome of CTXphi & enters bacteria by transduction
                     • B subunit binds to membrane poteins and allows A subunit to enter the cell
                       • Disrupts G-protein signalling
                         • increases intracellular cAMP, causing efflux of Cl- into intestinal lumen
                           • Prevents Na+ uptake into intestinal cells, water follows by osmosis resulting in severe diarrhoea
         • VECTOR-BORNE
           • Vector (biting)
             • Very sensitive pathogens e.g. malaria
           • Vertebrate reservoir
           • Reduced requirement for host mobility, so more virulent than directly transmitted pathogens
           • e.g. Plague, caused by Yersinia bacteria
             • Found in mammalian gut, typically transmitted by faecal-oral route
             • Yersinia pestis found in rodent reservoir populations
               • Diverged from an ancestor in last 1500-20,000 years
               • Differences between this and non-pathogenic species e.g. Y.pseudotuberculosis: Pestis is not orally toxic to fleas (ingestion usually causes acute diarrhoea and mortality) Don't usually form biofilms and cannot back fleas (persist as single cells in the gut) Usually lack pla, so cannot disseminate from the bite site
               • Transmitted by arthropod vector (flea) and can be transmitted to humans during epizootic outbreaks
                 • V virulent to rodents & humans
                   • 'Black Plague' killed 30-60% of Europe's population
                   • Why?
                     • Poor vector competence
                       • Infection of fleas required high levels of bacteremia >10^7 bacteria per mL of host blood needed to infect 50% of fleas Massive host exploitation required for this level of replication
                     • High vector density
                       • Rats are typically covered with fleas Bacteria transmitted from vector to host even if the host dies quickly
                     • Host-seeking behaviour of vector
                       • Fleas do not leave mammalian host generally Death encourages them to find new host, allowing transmission
                     • Zoonosis - humans not the preferred host
                       • Virulence in humans might be increased by lack of adaptation between host and pathogen True for other zoonotic diseases, e.g. Lyme's disease, where virulence is associated with human immunopathology, as the infection in rodent host is asymptomatic
             • Barriers to infection
               • Transition from gut to blood stream
                 • pYv plasmid encodes T3SS injectisome proteins that impair host immunity
               • Survival in fleas
                 • pFra plasmid, Yersinia murine toxin protects against antibacterial agents in flea midgut
                   • pFra plasmid - conjugation with Photorhabdus luminsecens
               • Transmission back to host
                 • hms gene product blocks flea digestive tract by forming biofilm
                   • Increases feeding and regurgitation
               • Dissemination from bite site
                 • pPst plasmid encodes plasminogen activator pla which allows bacterium to hijack host macrophages for delivery to lymph nodes
         • SIT-AND-WAIT
           • Pathogen exits current host and waits for uninfected host to arrive
             • V high replication in host results in high virulence and death. Pathogen adopts dormant state (e.g. durable spores) that is resistant to environment and waits for uninfected host to arrive before starting replication again inside the new host
             • Relies on mobility of uninfected host
             • Must be able to survive in external environment
               • e.g. Anthrax, caused by Bacillus anthracis
                 • Can survive in soil as a dormant endospore for decades and becomes metabolically active only when picked up by a new host. 
                 • Spores enter mammalian host and are taken up by macrophages & germinate
                   • Delivered to lymph nodes and multiply before entering blood stream
                     • Septicemia and toxins produced kill host
                       • Exit host in haemorrhage exuding and form durable spores on contact with oxygen
                 • Virulence factors
                   • pXO1 produces exotoxins
                     • Edema toxin increases cellular cAMP
                       • Disrupts water homeostasis, results in massive edema
                     • Lethal toxin stimulates macrophage to release cytokines
                       • Results in shock and death
                     • Toxins cooperate to shut down/suppress immune response
                   • pXO2 produces capsule proteins
                     • Exterior coat of vegetative cells
                       • Inhibits phagocytosis by host immune system
     • Attachment
       • Key factor in determining entry routes and where the parasite is localised
       • Specificity of host/ligand interaction is responsible for particular symptoms
       • e.g. Gram negative, usually adheres to cell surface via pili with adhesins
       • Receptor-ligand interactions
         • Kinetics
           • Fate of parasite-host membrane interaction is controlled by rate of attachment, detachment and invasion
             • Density of ligand and receptor is key in determining receptor-ligand interactions as this is what keeps the cell attached to the pathogen 
             • First order reaction (independent from one another)
             • Avidity = tendency for multiple receptors/ligands to combine
               • Cumulative strength of all receptor/ligand pairs
               • Selection pressure on parasite/host attachment favours interactions that result in high avidity
                 • PARASITE RECEPTOR & HOST LIGAND DENSITY MUST BE HIGH FOR ATTACHMENT TO OCCUR
         • Glycosaminoglycans = GAGs
           • Host receptors for variety of microbes
             • Cell surface carbohydrates mediate interactions between cell and another cells, antibodies, viruses etc Envelpoed viruses such as HIV can evade immune recognition by exploiting host glycosylation machinery to protect potential antigenic epitopes
           • Proteoglycans = extreme form of protein glycosylation
             • Carbohydrates are polysaccharides that contain amino surges (GAGs)
             • repeating disaccharide units
               • Chondritin sulfate/dermatan sulfate
               • heparin sulfate/heparin
               • keratin sulfate
           • Heterogeneous structure
             • N-linked glycol subject to extensive modification while traversing the Golgi by mannosidases, glycosyltransferases and glucosidases Most secreted proteins are modified by carbohydrate attachment
       • Pathogenesis of P. falciparum malaria due to cytoadherence
         • Infected RBCs adhere to endothelium and each other, causing clogging and haemorrhaging
           • In the node, VSRs bind different GAGs
             • VSR expressed by parasite determines endothelial cell interactions
               • Different parasites may express differ surface antigens, so interact with different endothelial cells Some recognise endothelial cells in the brains, so more likely to adhere there and cause cerebral malaria Others more likely to bind to endothelium of lung and cause respiratory failure.
         • PfEMP1 found in knobs, responsible for cytoadherence
           • PfEMP = Plasmodium falciparum Erythrocyte Membrane Protein
           • Large membrane protein anchored in RBC membrane, bulk extends into blood stream
           • Various domains bind to ligands on endothelia of vasculature and placenta
     • Colonisation
       • e.g. bacterium that use pili to bind to microvilli then secrete digestive enzymes to get closer to the host cell so that it can multiply
       • Pathogen must multiply and utilize host substrates as source of nutrients
     • Tissue damage
       • Produces enzymes to destroy cell membrane/connective matrix etc
       • To release nutrients
   • Adapting to new environments
     • Random mutation - v slow
     • Horizontal gene transfer - v rapid
       • New environments already colonised by bacteria adapted to specific conditions serve as a source of genetic material to pathogens and allow rapid adaptation to new environments 
       • Transformation - uptake of DNA from environment
       • transduction - transfer of genetic material by phage
         • Occurs between closely related organisms only
       • Conjugation - direct transfer of DNA between bacteria, usually plasmids/transposons
         • Can occur between distantly related bacteria
     • Natural selection
       • Maximises pathogen transmission as mutation generates different strains of pathogen.  Strains with highest transmission rates spread through host population