PHA112 Micro 8 (Disease) 2020 PDF

MPharm Programme Disease and Pathogenesis Dr Callum Cooper [email protected] Learning Objectives Sources of disease Look at different stages of disease process Pathogenic virulence factors Examples of toxin producers Examples of biofilms How did this person get infected? How can we stop...

MPharm Programme Disease and Pathogenesis Dr Callum Cooper [email protected] Learning Objectives Sources of disease Look at different stages of disease process Pathogenic virulence factors Examples of toxin producers Examples of biofilms How did this person get infected? How can we stop this disease spreading? Clincal Microbial infections are a major public health problem Infectious disease is still a major killer of people globally; Lower respiratory diseases killed 3 million in 2016 Diarrhoeal disease killed 1.4 million in 2016 In developed countries, 5-12% of hospital patients encounter nosocomial infection i.e. one they were not admitted with In EU each year, ca.400,000 nosocomial infections are resistant to antimicrobial agents; ca. 25,000 of these patients die as a result1 Risk is determined by individual susceptibility and is multifactorial; Chronic illness Genes Previous exposure Age 1 WHO Medicines Surgery Malnourishment data: http://www.euro.who.int/en/health-topics/disease-prevention/antimicrobial-resistance Scale of Disease Endemic: an infection present in a population which is maintained constantly with no external input E.g. Chickenpox Epidemic: An infection which rapidly spreads in a short time period (usually ≤2 weeks or less) E.g. Ebola outbreaks from 2014 Pandemic: An epidemic which has spread across a large region (e.g. multiple continents/globally etc) Historically very important e.g. Black death or Spanish Flu E.g. 2009 H1N1 Influenza pandemic Terminology Pathogenicity: Ability of a pathogen to produce an infectious disease in an organism Virulence:Relative degree of damage done by a pathogen, or the degree of pathology caused by a pathogen Virulence / pathogenicity factor: Microbial product or strategy that contributes to virulence or pathogenicity Colonization of a niche in the host (this includes attachment to cells) Immunoevasion, evasion of the host's immune response Immunosuppression, inhibition of the host's immune response Entry into and exit out of cells (if the pathogen is an intracellular one) Obtain nutrition from the host Sources of Disease People – Major source, particularly of highly infectious disease: HIV, smallpox, diphtheria etc. Obligate pathogen: A microorganism that has to cause disease to be passed between hosts and must also infect a host in order to survive e.g. Mycobacterium tuberculosis WHAT ABOUT COMMENSAL ORGANISMS? Opportunistic pathogen: Normally a commensal or non harmful microorganism that can cause disease when the host's resistance is low e.g. Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa. Commensal microorganisms in disease Commensal microorgansims are part of the normal flora Usually non-pathogenic Some may be pathogenic but unable to enter disease process Lack ability to attach to suitable surface Held in check by other organisms Prevent disease by; Blocking attachment sites Producing antimicrobial products as part of normal metabolism Can cause disease in humans when; Microbial balance is upset (e.g. following antibiotic treatment) Microbes get places where they shouldn’t (e.g. blood stream infections) Host immunity is compromised Sources of Disease Environment – – – – Waterborne: cholera, typhoid, Legionella Food borne: Salmonella, Campylobacter, E. coli Surfaces: Soil: Clostridium botulinum and C. tetani Animals (Zoonoses) – Major source of disease with most new human diseases are believed to have an animal origin; – Bacterial: anthrax, E. coli, plague – Parasites: Toxoplasmosis – Viruses: avian influenza, CCHF, Ebola and Rift Valley fever – Other: BSE The role of animals in infectious disease Zoonoses are infectious diseases that can be naturally transmitted between non-humans (usually vertebrates) and humans Animals can act as a reservoir (place where agents normally reside) Contribute to development of pandemics Exposure to infected animals or contaminated environments is a major risk factor The role of occupation in infectious disease exposure Traditionally occupations which come in close contact with animals or animal products Farmers, tanners, slaughterhouse workers etc Rules implemented to reduce risk These days some occupations at higher risk of exposure to infectious agents; Laboratory Healthcare Still occasionally get cases https://www.theguardian.com/p olitics/2019/jun/14/call-fortattooists-and-body-piercers-toqualify-in-infection-control The role of animals in infectious disease Humans can contract animal viruses “Bird Flu” H5N1 & "swine flu” H1N1 Viruses can recombine to increase pathogenicity Antigenic shift: Combination of two or more different strains Produces new form of virus which shows a mixture of surface antigens Antigenic drift: Accumulation of mutations within antibody binding regions Reduces the effectiveness of the immune system Koch’s postulates 1st described in 1890 Proof available for: Plague, anthrax, diphtheria, cholera, typhoid etc. But less evident when… Condition is chronic or minor Condition has multiple causes or pathogen is non-culturable No suitable animal model of infection Agents causing pneumonia, wound infection, UTIs, septicaemia Updated Koch: Molecular Postulates Identify gene (or gene product) responsible Show that gene is present in disease causing strains of bacteria Not present in avirulent strains Show that disrupting the gene reduces virulence Introduce a cloned gene into avirulent strain Should confer virulence The gene is expressed in vivo Specific immune response to gene protects The Disease Process Disease can be broadly split into 3 stages; Transmission & exposure Pathogen Exposure Skin/mucosa adherence Further exposure Epithelia invasion Attachment and Invasion Colonisation and Damage Further exposure at local sites Colonisation and growth Invasiveness – further growth at Original/othersites Tissue damage and disease Local/systemic toxicity Transmission and Exposure Transmission is the passing of a communicable disease from an infected host to a particular individual or group, regardless of whether the other individual was previously infected. Vertical transmission: Mother to child e.g. HIV Horizontal transmission: Person to person transmission e.g. Chlamydia Vehicle borne transmission: Transmission through an inanimate object. Vector borne transmission: Transmission through another organism e.g. Malaria Diseases can be transmitted via different routes HIV can be vertical, horizontal or vehicle borne Transmission and Exposure Horizontal exposure to disease tends to be one of three routes; Inhalation Ingestion Contact Successful exposure depends on multiple factors Microbe count: more = better Airborne: size, density, surface features. Waterborne: density, surface features, hydrophobicity Contact: environmental persistence. Particularly important in hospital acquired infections Distribution on host: into cuts, digestive system, GU system, lungs etc. Vectors Transmission and Exposure Utilities Facilities Process Contaminated Product Materials Equipment Personnel Transmission and Exposure Attachment & Invasion Bind to receptors on host cells to stick to cells and avoid host defenses Depends on surface break or on active microbial procedures Virulence factors play an important role; Pili or adhesins (aid attachment to cells) Capsules (resist phagocytosis) Enzyme production Biofilms A biofilm comprises any group of microorganisms in which cells stick to each other and often also to a surface Naturally occurring, but clinically important Estimated 80% of infections involve biofilms Increases average hospital stay Increases resistance to treatment Especially important in Cystic fibrosis sufferers Biofilms form within lung Ref: D. Monroe. "Looking for Chinks in the Armor of Bacterial Biofilms". PLoS Biology 5 (11, e307) Colonisation and Damage: Consequences Growth in tissues requires cells to resist host responses Potentially neutralise – e.g. enzymes, capsules etc. Growth also requires appropriate nutrients Some tissues have limited (e.g. iron) or specific nutrients which slow or enhance microbial growth Host cell death as a result of; Damage Toxin accumulation Enzymatic digestion Pathogenicity factors play an important role; Bacterial toxins Exotoxins Endotoxins (LPS) Capsule Bacterial enzymes Microbial toxins Microbial toxins promote infection by damaging tissue Endotoxin (LPS) Exotoxin (secreted toxin) Endotoxins part of the bacterial cell membrane Can lead to septic shock Highly controlled in sterile pharmaceutical products Clostridium difficile produces two main toxins; Toxin A (enterotoxin) & Toxin B (cytotoxin) Play important role in disrupting gut epithelia Some toxins have found other uses; Botulinum toxin among the most powerful Estimated LD50 of 1.3–2.1 ng/kg IV or IM Microbial Exotoxins Three general types of microbial exotoxin based on effect; Cytotoxin (kills cells) Neurotoxins (interfere with normal nerve impulses) Enterotoxins (affects cells lining the GI tract) Can be further divided; Type I Superantigens; Cause intense immune response due to nonspecific cytokine release from host cells Produced by some S. aureus strains Type II Membrane disrupting toxins; Disrupt phospholipid bilayer or make protein channels in PM e.g Cholera toxin Type III Protein modification; e.g Diphtheria and Shiga toxin inhibit synthesis Tetanus toxin cleaves protein involved neurotransmitter release Microbial Endotoxins LPS (Lipopolysaccharides) O Antigen Lipid A Heat Stable (c.f. exotoxins – typically heat liable [proteins / peptides]) Quite difficult to remove from pharmaceutical preparations Lipid A - Toxin portion of the LPS Responsible for fever that is associated with many G- bacterial infections When G- cells are ‘digested’, endotoxins are released: causes fever If immune system acting on high G- bacterial load, large release of endotoxins can trigger septic shock Antibiotics can initially cause fever / shock due to release of endotoxins Haemolysins Heamolysins cause red blood cell lysis by forming pores in the plasma membranes Most are proteins but some are lipid biosurfactants Not to be confused with haemolysis Bacteria can be classified on basis of haemolysis Alpha (Oxidises iron) S. pneumoniae Beta (ruptures RBC) S. pyogenes Gamma (non-haemolytic) Can lead to haemolytic anaemia Bone marrow cant produce RBC fast enough to replace loss By Y tambe - Y tambe's file, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=860707 Non-bacterial disease: Mycoses Mycoses are diseases caused by fungi Can be persistent (chronic) Can be localised or systemic Often from inhalation of fungal spores Most common in immunocompromised patients or those who have taken antibiotics Fungal diseases commonly include; Athletes foot (irritation, dry and inflamed skin with localised pain) Caused by species of Trichophyton, Epidermophyton, and Microsporum Thrush By James Heilman, MD - Own work, CC BY Caused by Candida albicans (most SA 3.0, https://commons.wikimedia.org/w/index.p hp?curid=17770316 common) Aspergillosis Generally caused by Aspergillus fumigatus Can be invasive in immune compromised patients Non-bacterial disease: Viral Viral diseases can cause both communicable and noncommunicable diseases Communicable: Herpes HIV Influenza AND MANY MANY MORE Non-communicable: HPV → Cervical cancer1 Human adenovirus Ad-36 → Obesity2 Mouse mammary tumor virus → human breast cancer3 1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC145302/ 2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517116/ 3: https://www.ncbi.nlm.nih.gov/pubmed/16061645 Extra reading Prescotts Microbiology:Part VIII; section 35, 36, 38 Brock Microbiology: Part VI Percival, S.L et al. 2015. Healthcare-associated infections, medical devices and biofilms: risk, tolerance and control. J Med Microbiol, 64(4), pp.323-334.