Week 2 Flashcards
Innate immune response
- tissue resident white blood cells (leukocytes) at site of infection
• recognise invading pathogen
• release chemical messenger proteins (chemokines recruit more WBC; cytokines activate more WBC -
phagocytic cells engulf invading pathogens and destroy them in large numbers
• Tissue resident macrophages – first responders
• Recruited neutrophils – professional killers
Phagocytes and pattern recognition
Phagocytes recognise microbes through pattern recognition
- Shared structures unique to subsets of microbes =
Pathogen Associated Molecular Patterns (PAMPs) eg:
• LPS of Gram-negative bacteria
• flagellin of bacteria
• Viral RNA or viral DNA
- Toll-like receptors (TLRs) are Pattern Recognition Receptors (PRRs)
- Recognition sends danger signal
- Stimulates production and secretion of cytokines
Inflammation
• Cytokines induce inflammation
• Series of events in reaction to tissue damage – injury and/or infection
• Site becomes swollen, red, hot and painful – part of normal healing process
• Underlying mechanisms explain the symptoms
- Vasodilation – increase in blood vessel diameter and permeability
- Brings more WBCs to site of infection
Fever
• Cytokines, interleukin-1 (IL-1) induces fever
• Phagocytic cells more efficient at elevated body temperature
• Some pathogens unable to reproduce at higher temperatures, e.g. influenza virus
• If fever gets too high – dangerous and life threatening
Interferons
Cytokines that interfere with viral replication and spread
• IFNs made by infected cell in response to viral replication
• Act on neighbour to induce an antiviral state
• Cell in antiviral state do not allow viral replication
• Contribute to flu-like symptoms of aches, headache, chill
Antigen presenting cells (APCs)
• Macrophages and dendritic cells are antigen presenting cells (APCs)
• At sites of infection, APCs use TLRs to recognise a pathogen and then send signals for immune activation
• They ingest and digest pathogens
• Initiate adaptive immune response
Dendritic cells
• DCs that have picked up antigen at the site of infection migrate to nearby (local, draining) lymph nodes
• Activate adaptive immune cells responsible for microbial clearance – T and B cells
• Strategically located where they concentrate
components for adaptive immune responses
- Lymphatic system = network of vessels returning fluid that has leaked out of blood back to circulation
- Lymph = fluid
• Blood is filtered through the spleen
• Like a lymph node for blood-borne pathogens
• Other specialised lymphatic structures exists in areas of high pathogen exposure e.g. gut and respiratory tract
Lymphocytes
• WBCs of adaptive immune response
• T cells and B cells
• Initially formed in bone marrow
• Circulate through blood
• Can leave blood and enter lymph nodes looking for antigen presented by DCs
• If they find DCs presenting foreign antigen that they are specific for, they will become activated
• If they don’t, they keep moving
• Activated lymphocytes undergo rapid proliferation and lymph nodes swell
T cells
• T cells migrate from bone marrow to the thymus
• Complete development and maturation in thymus
• MATURE (but NAÏVE) T cells that have not seen foreign antigen before leave the thymus and begin to circulate
• Upon activation by DC + antigen, they become EFFECTOR T cells:
• Helper CD4+ T cells (Th) coordinate entire adaptive response – activate CTLs and B cells
• Cytotoxic/killer CD8+ T cells (Tc cells or CTLs) are professional killing cells – viruses and tumours
• During activation, some Th cells and Tc cells develop into relatively inactive = long-lived MEMORY T cells
T cell receptors
• **TCRs* recognise foreign antigen presented MHCs by APCs
• Each naïve CD4+ T cell has lots of identical TCRs (same specificity)
- Different CD4+ T cells have different TCRs and antigen specificities
• APC (DCS) release cytokines that attract and activate **naïve CD4+ T **
antigen presented on
• Naïve CD4+ T cells specific for presented activated and begins to divide antigen (C in this case) is activated and begins to divide
• Results in activated effector CD4+ T helper (Th) cells, all bearing TCRs specific for the activating antigen
• Process takes several days to complete = clonal expansion (lymph node swelling)
Microbial clearance
•DCS present antigen to CD4+ and CD8+ T cells activating them > effector Th cells and Tc cells
• Th cell specific for the same antigen secrete cytokines that further stimulate/help Tc cells
• Tc cells can then go looking for host cells infected with virus, displaying viral antigen on MHC
• Tc cells proliferate and leave lymph node in search of infected host cells
• Tc cells recognises infected cell displaying same foreign antigen bound to MHC on surface that was used to activate them from naive cells
• Releases toxic chemicals to cause infected cell to die = targeted cell killing; uninfected cells not displaying antigen are not affected
Antibody functions
a) Coat surface of viral particles preventing them from
attaching to host cell receptors = neutralisation
b) Each antibody has two antigen binding sites - large agglutinated clumps of antigen and antibody may form. Complexes are readily available to phagocytic cells = agglutination
c) Enhances phagocytosis by acting as opsonin for phagocytic cells which have receptors for antibody tail = opsonisation
Vaccines
Vaccines induce immune memory without causing disease
• Ability to mount ever stronger immune response with each antigen exposure is basis of vaccination
• Primary immune response stimulated by exposure to dead / inactivated, weakened / attenuated, or component of pathogen
• Subsequent exposure to live pathogen immediately triggers secondary adaptive response
Nosocomial infection
Defined as a hospital acquired infection
- “hot beds” for infection
• sick people - damaged barriers, weakened immunity
• Medical staff movement
- Preventable with basic control measures
• Hand washing
• Instrument sterilisation
- Antimicrobial resistance (AMR)
• Once curable infection no longer respond
Physical control: Manipulation of environment
- Microbes have optimal growth temperature (range)
- Direct and inexpensive
-
Heat is effective means of killing = ”cidal”
• can penetrate an object and kill organisms throughout
• denatures proteins (not suitable for all substances) -
Cold generally doesn’t kill, it inhibits growth = ”static”
• inhibits microbial replication -
Heat to sterilise = complete elimination of all organisms
• Dry heat (flame or hot oven) - requires considerable time and higher temps
• Moist heat (for autoclaves add pressure) - penetrates more quickly at lower temps - Pasteurisation = temporary heating of liquids/ foods sensitive to prolonged heat (lose flavour)
- Liquids that can’t tolerate high temps may be filtered through membrane with pores of size to exclude microbes
- Radiation can be used to kill microorganisms in some situations
-
UV rarely sterilises, but can significantly reduce numbers on surfaces
• Inhibits microbial DNA replication - Gamma radiation used for some food products
-
Drying is an “age-old” way of preserving fish and meat products
• Coupled with water removal by salt/sugar
Chemical control on living and non-living materials
- For non-living materials = disinfectants
• Bleach (chlorine) – forms an acid when added to water
• Alcohol – kills by denaturing proteins and disrupting microbial cell membranes - For living tissue = antiseptics
• Iodine – binds enzymes to inhibit activity, also affects microbial cell membranes
• Alcohol – good for skin, but not open wounds
• Soaps, detergents disrupt microbial adherence, can kill through disruption of microbial cell membrane
Antibiotics
Antibiotics are anti-bacterial agents
- Either Bactericidal or Bacteriostatic
- Initially produced by microorganisms
- Ideally inhibits microorganism without harming host = selective toxicity
- Selection of most appropriate antibiotic depends on:
• Known drug allergies
• Identification of infecting organism and antibiotic sensitivity
• Site of infection
• Cost
• Speed of infection progression and/or antibiotic effectiveness
- Some combat a wide variety of microorganisms = broad spectrum
• Used prophylactically – for immunocompromised patients – or if pathogen is not known
• Most likely to have off-target effects – disrupt normal microbiota
- Narrow spectrum = highly targeted to specific types of infection/bacterial pathogens
Bactericidal Antibiotics
-
Bactericidal antibiotics KILL – e.g. Penicillin prevents bacterial cell wall synthesis causing rupture
• More direct effect; essential in immunocompromised patients
Bacteriostatic Antibiotics
-
Bacteriostatic antibiotics INHIBIT REPLICATION - hold numbers in check allowing the immune response a greater chance of clearance
• Effect relies on continual presence of the drug until infection is cleared
Why is selective toxicity harder to achieve against eukaryotic pathogens?
- Limited drug options against protozoa and fungi
• Similar to human cells – far fewer unique drug targets - Side effects common
- Quinine - plant extract effective against malaria parasites
- Chloroquine, synthetic analogue, produced after
global (WWII) shortage
• Today, resistance is spreading…new drugs are needed!
Antiviral Drugs
Antiviral drugs interfere with viral replication
- viral replication inside host cells
- viruses have some unique features - selective toxicity possible
- Newer, innovative anti-viral drugs on horizon
Drug resistance
- Antibiotic Misuse has led to drug resistance
• when antibiotics used inappropriately to treat non-bacterial infections (no effect on viruses!!) - Antibiotic resistance is not new, but is now a major public health threat
- Mechanisms of antibiotic resistance (R) are well understood
Antibiotics and selection pressure
- Resistance is genetically determined
- Evolves through natural selection
- After each dose, increasingly more resistant bacteria are left behind
- If halted early, more resistant bacteria may reproduce
Epidemiology
- The study of disease in population and factors that influence a disease’s frequency and distribution
- Aim to predict future problems and make recommendations that might prevent disease or limit spread
Prevalence
Total number of individuals in a population who have a disease or health condition at a specific period of time = usually expressed as a percentage of the population
Incidence
Number of individuals who develop (new cases) a specific disease or experience a specific health-related event during a particular time period (such as a month or year)
Rates
Mortality rate– number/percentage of deaths in a given population
Morbidity rate – number/percentage of people who have complications/illness
Outbreak
Occurrence of cases of disease in excess of that normally expected in a defined community, geographical area or season
Epidemic
A sudden increase in the number of cases of a specific disease, beyond what is considered to be a normal number of cases; rapid spread
Common source epidemic
A single contaminated site gives rise to a common source epidemic
•e.g. cholera contaminated water supply in London
• Rapid rise in cases with all affected individuals becoming ill in a short time
• Once source is eliminated, cases will continue to be reported for a time period approx. equal to one incubation
period (time between exposure to organisms and first sign of symptoms)
• Usually occur because of a breakdown in sanitation
Host-to-Host epidemics
Host-to-host epidemics spread from infected to uninfected individuals
• No single source; multiple new sources are made
• e.g. flu epidemic
• Start slowly, picks up speed until number of cases reaches a peak, slowly wanes for as long as some susceptible individuals remain with chance of exposure
• Multiple factors that often interact e.g. weather and immune status of population
Immunity
- When immunity is sufficiently high, an epidemic becomes unlikely or impossible (to few susceptible people)
- Host-to-host epidemics often occur in cycles associated with cyclic population immunity
Herd immunity
Immunity is so high that possible routes of transmission are reduced
• Provides protection for susceptible people who can’t achieve their own protection e.g. immunocompromised
Epidemic threshold
Minimum proportion of population that must be immune to specific pathogen to prevent an epidemic
(vaccination aims to achieve coverage above this threshold)
Antigenic drift
A minor genetic change in antigenic make up of virus due to random mutations (errors)
- Immune memory against an original antigen may no longer confer protection
Antigenic shift
A major change when gene segments form different strains of virus, infecting a cell at same time =, recombine to create a new strain
- facilitated by animal reservoirs
- population immunity to these new strains is generally very low or non-existent
Case definition
Helps authorities determine if unusual cases are related
- is a list of common symptoms for a particular medical condition
- is a standard criteria for categorising an individual as a case, or probable case
- helps local doctors identify patients with similar symptoms
- time, place and personal characteristics of a new disease provides clues to disease’s identity
Case-control studies
- Once time, place and personal charecteristics are defined, next step is to develop a case-control study
- used to determine what factor(s) link affected individuals and distinguish them from uninfected individuals - often provide the missing clues
- Affected people = cases
- Each matched to uninfected individual = control
• Should be as similar as possible to each other (sex, age, place of residence, etc)
Emerging and Re-emerging diseases
Emerging and Re-emerging diseases are new or changing diseases that are increasing in importance
• A new or changing disease that is increasing in importance = emerging
• A disease that was considered to be under control but is now causing
increasingly serious problems = re-emerging
• Changes in pathogen, environment, and human behaviour can all contribute to emergence and reemergence
- Increasing human population and urbanisation
- Increasing global travel and trade
Categorisation of emerging diseases
- Invasion of a new host population by a known pathogen
• Commonly zoonoses (animal reservoirs), e.g. Zika virus - Appearance of a completely new, previously undescribed disease
• e.g. AIDS and Ebola - Association of a well known disease with a new pathogen
• e.g. Helicobacter pylori as cause of gastric ulcers; HIV as cause of Kaposi’s sarcoma - Increased virulence or a renewed problem with a well-known but previously less virulent or well-controlled pathogen = re-emerging
• e.g. multi-drug resistant Staphylococcus aureus and Mycobacterium tuberculosis
