Lecture 7

• Define a Pathogen

  A microbe or parasite that can cause disease
• Pathogenicity


  The ability of a pathogen to cause disease in a host, it is a qualitative trait - an organism is either pathogenic or not to a particular individual host, but not all hosts are the same
• Virulence


  A term used to quantify the effect of a pathogen on its host, it is a quantitative trait, so a highly virulent organism will cause a lot of damage to its host
• What dictates the immune response elicited by a pathogen

  • Its location= different defence mechanism
• Examples of different microbes, location, innate immunity and adaptive immunity response

  • Intracellular viruses - Innate = IFNs, Macrophages. Adaptive = cytotoxic T cells
  • Extracellular bacteria - Innate = complement. Adaptive = B cells, Antibodies
  • Extracellular helminths - Innate = Mast cells, eosinophils. Adaptive = B cells, IgE
  • Extracellular fungi = Innate = Complement and macrophages
• Viruses consist of an RNA genome (e.g. SARS-CoV-2, Influenza A) or a DNA genome (e.g. Vaccinia virus) surrounded by a protein coat, and sometimes a membrane envelope
• All viruses are INTRACELLULAR
• Viruses rely on host cell for replication .... therefore they are obligate intracellular pathogens
• PAMPs


  DNA and/or RNA from genomes or replication intermediated are detected as PAMPs
• Immune response to viruses

  1. Type I interferons (IFN-alpha, and beta) are produced

  2. Natural killer cells and cytotoxic T lymphocytes (CTLs) can kill virus-infected cells

  3. Activate DCs and macrophages = increased APC
• Where can bacteria be found

  • Extracellular
  • Intracellular
• Immune response to intracellular bacteria

  Eliminated through the killing of infected cells by NK cells and cytotoxic T cells, some interferon mechanism here but generally interferons don't help much for bacteria
• Immune response to extracellular bacteria

  Involved antibodies, which can neutralise bacterial toxins, activate complement and promote phagocytosis by macrophages and neutrophils
• Antibiotic resistance


  When bacteria develop the ability to defeat the drugs designed to kill them. Antibiotic resistance genes often located on plasmids that can be shared between bacteria
• Antibiotic resistance examples


  • Staphylococcus aureus has acquired methicillin resistance (MRSA) and causes hospital-acquired infections
  • Mycobacetrium tuberculosis - causes tuberculosis, multidrug-resistant TB (MDR-TB) occurs
• Antibody mediated mechanisms against extracellular bacteria


  • Antibodies can bind to and neutralise toxins
  • Complement activation and lysis
  • Antibodies and C3b opsonise bacteria for phagocytosis
  • C3a and C5a anaphylotoxins stimulate mast cell degranulation, and the released mediators cause vasodilation and attract neutrophils
  • Macrophages (engulf bacteria and try clear site of infection) are attracted by C3a and C5a
• Parasites


  They are eukaryotic pathogens (excluding fungi)
• Main classes of parasites

  • Protozoa = single cell which live extracellularly (e.g. Plasmodium, Trypanosoma brucei)
  • Helminths = multicellular worms (e.g. Schistosoma, Ascaris, tapeworms)
• Phagocytes cannot work against helminths
• Immunity to protozoa

  Species-specific, stage-specific and largely strain-specific- many different strains circulate, so re-infection is common. Antibodies against one life cycle stage or strain are not effective against others due to continuous variation
• Immunity to helminths

  1. Involves T-helper 2 (Th2) response, with IgE antibodies and activation of granulocytes (mast cells and eosinophils)

  2. Release of histamine and leukotrienes from granulocytes causes smooth muscle contraction and mucus production, with the aim to expel the parasite
• Innate cells involved in immune responses to fungi

  • Macrophages can detect fungal cell wall components (e.g. chitin and beta-glucans) using Toll-like receptors and the Dectin-1 receptor
  • Antibodies and complement enhance phagocytosis of fungal cells by neutrophils and macrophages
• When do fungi cause problems

  In immunocompromised patients (e.g. HIV), or if the normal microbiota are disrupted DYSBIOSIS (e.g. following antibiotic treatment)
• Examples of fungal pathogens

  • Candida albicans (oral/vaginal thrush)
  • Cryptococcus neoformans, Coccidioides immitis and Histplsma capsulatum can affect immunocompromised individuals, systemic infections are diagnostic of AIDS
• define Immune evasion

  Where all pathogens evade their host's immune defences, to establish an infection
• Example of a virus that uses immune evasion

  • Influenza A
• Protein important for immune evasion

  Non-structural protein NS1 is a multifunctional immune evasion protein. It binds viral RNA to prevent recognition by pattern recognition receptors and (binds and) inhibits the RNA receptor RIG-I, inhibits gene expression by the cell (host cell shut-off), promotes transcription of viral genes
• Antigenic drift


  Point mutations due to error-prone polymerase (viral polymerase= poor proof reading) gradually yield a protein not recognised as efficiently by original antibodies
• Examples of antigenic drift

  • Common seasonal flu is H3N2 which changes a little every year through antigenic drift
  • SARS-CoV-2 -> spike protein
• Antigenic shift


  Co-infection with different strains in an animal host creates a new virus with different HA and N proteins. They require different vaccines
• Example of antigenic shift


  • Influenza A fragments of RNA can be swapped between viruses, in 2009 H1N1 'swine flu' originated from antigenic shift by reassortment of genome fragments from swine
• Variolation


  Ancient Chinese practice of intentional inoculation with small amounts of dried smallpox pustules
• First vaccine


  1800, Edward Jenner inoculated children with pus containing cowpox (vacca=cow) to protect against smallpox- example of a live vaccine. Smallpox was the first disease to be eradicated in 1979
• Immunisation


  The process of generating long-lived immune protection against a pathogen, either by recovering form disease or by vaccination
• Vaccination


  The intentional exposure to components of pathogen that do not cause disease
• Effective vaccine


  Causes the development of memory B and T cells that recognise antigens on the target pathogen
• Herd immunity


  If many individuals in a population are immune, there will be less spread of the infection to other vulnerable people
• Eradication


  The pathogen dies out when there are no susceptible individuals left
• How vaccines work


  1. First exposure = infection --> transport of antigen to lymphoid organs --> naive T-cell recognition --> clonal expansion and differentiation into effector cells --> removal of infection

  2. Subsequent exposure = re-infection --> recognition by antibodies and effector T-cells --> rapid expansion and differentiation to effector cells --> removal of infection
• Components needed for activation/ stimulation of vaccines

  • Antigens= (usually proteins) from the pathogen that can be recognised by T cells, B cells and antibodies
  • Adjuvants= molecules that help activate the innate immune system (e.g. pathogen components, synthetic formulations like alum slats or isolated PAMPs e.g. dsRNA) needed for the development of effective adaptive immunity