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NPTEL – Biotechnology – Microbiology Module 10 – Microbial Pathogenicity and Diseases Introduction Although the vast majority of bacteria are harmless or beneficial, quite a few bacteria are pathogenic. Pathogenic bacteria are bacteria that cause bacterial infection. One of the bacterial diseases with highest disease burden is tuberculosis, caused by the bacterium Mycobacterium tuberculosis, which kills about 2 million people a year, mostly in sub-Saharan Africa. Pathogenic bacteria contribute to other globally important diseases, such as pneumonia, which can be caused by bacteria such as Streptococcus and Pseudomonas, and food borne illnesses, which can be caused by bacteria such as Shigella, Campylobacter, and Salmonella. Pathogenic bacteria also cause infections such as tetanus, typhoid fever, diphtheria, syphilis, and leprosy. Koch's postulates are criteria designed to establish a causal relationship between a causative microbe and a disease. Four criteria that were established by Robert Koch to identify the causative agent of a particular disease, these include: 1. The microorganism or other pathogen must be present in all cases of the disease 2. The pathogen can be isolated from the diseased host and grown in pure culture 3. The pathogen from the pure culture must cause the disease when inoculated into a healthy, susceptible laboratory animal 4. The pathogen must be reisolated from the new host and shown to be the same as the originally inoculated pathogen. The changes to the host, manifested as a set of symptoms, may be due to the effect of microbial products such as toxins or the result of the host’s immune reactions to the presence of the bacteria. Pain, fever, redness and swelling are common symptoms of bacterial disease. Joint initiative of IITs and IISc – Funded by MHRD Page 1 of 8 NPTEL – Biotechnology – Microbiology Fig. 1. Different infection stages of disease causing organisms A pathogen is a microorganism that is able to cause disease in a plant, animal or insect. Pathogenicity is the ability to produce disease in a host organism. Microbes express their pathogenicity by means of their virulence, a term which refers to the degree of pathogenicity of the microbe. Hence, the determinants of virulence of a pathogen are any of its genetic or biochemical or structural features that enable it to produce disease in a host. The relationship between a host and a pathogen is dynamic. The outcome of such a relationship depends on the virulence of the pathogen and the degree of resistance and susceptibility of the host, due to the effectiveness of the host defense mechanisms. Two qualities of pathogenic microbes by which they cause disease to the host: 1. Invasiveness is the ability to invade tissues. It consists of colonization, production of extracellular substances which facilitate invasion and ability to bypass or overcome host defense mechanisms. 2. Toxigenesis is the ability to produce toxins. Bacteria may produce two types of toxins called exotoxins and endotoxins. Exotoxins are released from bacterial cells and may act at tissue sites removed from the site of bacterial growth. Endotoxins are cell-associated substance. The bacterial toxins, both soluble and cell-associated, may be transported by blood and lymph and cause cytotoxic effects at tissue sites remote from the original point of invasion or growth. Joint initiative of IITs and IISc – Funded by MHRD Page 2 of 8 NPTEL – Biotechnology – Microbiology The diseases can be caused by: Bacteria: - These one-cell organisms are responsible for illnesses such as strep throat, urinary tract infections and tuberculosis. Viruses:-Even smaller than bacteria, viruses cause a multitude of diseases — ranging from the common cold to AIDS. Fungi: - Many skin diseases, such as ringworm and athlete's foot, are caused by fungi. Other types of fungi can infect your lungs or nervous system. Parasites: - Malaria is caused by a tiny parasite that is transmitted by a mosquito bite. Other parasites may be transmitted to humans from animal feces. MICROBIAL PATHOGENICITY Factors that Influence the degree of Pathogenicity and the Progression of Infection and Disease Host factors: Age, sex, ethnicity, nutrition (diet), hormonal status; personal hygiene and immune status; Underlying disease or medical condition; Antibiotic or drug usage; Presence of foreign object (e.g., splinter, catheter, sutures, etc.); Innate differences between hosts Microbial factors: Bacterial virulence factors; Inoculum size (dosage) External factors (e.g., crowding; seasonal variations; hygiene, sanitation and public health; food processing, storage and preparation; etc. To cause disease a pathogen must: Gain access to the host. Adhere to host tissues. Penetrate or evade host defenses. Damage the host, either directly or accumulation of microbial wastes. Progression of Infection and Disease Entrance (Portal of entry). Joint initiative of IITs and IISc – Funded by MHRD Page 3 of 8 NPTEL – Biotechnology – Microbiology Mucous membrane: - is most common route for most pathogens. The mucous membranes are respiratory tract, gastrointestinal tract, urinary/genital tracts and conjunctiva. Skin (keratinized cutaneous membrane):- Some pathogens infect hair follicles, sweat glands and colonize surface. But unless broken, skin is usually an impermeable barrier to microbes. Parenteral route: - penetrate skin, punctures, injections, bites, cuts, surgery and deposit organisms directly into deeper tissues. The microbes must enter through preferred portal of entry in order to cause disease. But some can cause disease from many routes of entry Colonization (Adherence; Adhesion; Attachment) Attachment/Adherence: Close association of bacterial cells and host cells generally characterized by receptors and target sites. Surface Receptors/Target Sites: Receptor sites present on both hosts (Receptor) and bacterial surfaces (Adhesins). Adhesins: Bind Specific Host Receptors often involve fimbriae as structural cell component; Host cell receptors are often sugar moieties. The lectins are adhesin specific for polysaccharide target receptor (sugar residues). Fimbriae (plural): Short hair-like protein (pilin) appendages extending outward from the surface of certain bacteria. Pili (plural); Pilus (singular): Short hair-like protein (pilin) appendages extending outward from the surface of certain bacteria and responsible for bacterial conjugation. Numbers of Invading Microbes: - The chances of causing diseases increase as the numbers of invading pathogens increases. This expressed by infectious dose (ID50) and lethal dose (LD50). The ID50 (Infectious Dose) is the number of microbes required to produce infection in 50% of the population. The ID50 is different for different pathogens i.e. different ID50 for different portals of entry for the same pathogen. The LD50 (Lethal Dose) amount of toxin or pathogen necessary to kill 50% of the population in a particular time frame. Joint initiative of IITs and IISc – Funded by MHRD Page 4 of 8 NPTEL – Biotechnology – Microbiology Biofilms: - are formed when microbes adhere to a surface which usually moist and contains organic matter. The microbe secretes glycocalyx allowing other microbes to adhere a large mass is formed. The biofilms are resistant to disinfectants and antibiotics. Prevention of Host Defenses:Some pathogenic bacteria are inherently able to resist the bactericidal components of host tissues. For example, the poly-D-glutamate capsule of Bacillus anthracis protects the organisms against cell lysis by cationic proteins in sera or in phagocytes. The outer membrane of Gram-negative bacteria is a formidable permeability barrier that is not easily penetrated by hydrophobic compounds such as bile salts which are harmful to the bacteria. Pathogenic mycobacteria have a waxy cell wall that resists attack or digestion by most tissue bactericides. And intact lipopolysaccharides (LPS) of Gram-negative pathogens may protect the cells from complement-mediated lysis or the action of lysozyme. Enzymes (exoenzymes):- The microbes produce many enzymes to prevent host defenses areCoagulases: clot fibrin in blood to create protective barrier against host defenses. Kinases: dissolve clots (fibrinolysis) to allow escape from isolated wounds e.g.Streptokinase (Streptococcus pyogenes) Staphylokinase (Staphylococcus aureus) Hyaluronidase: Hydrolyzes hyaluronic acid (‘glue’ that holds together connective tissues and epithelium barriers) allowing deeper invasion e.g. Clostridium species: allows them to cause gangrene (tissue necrosis). Collagenase: breaks down collagen (fibrous part of connective tissue) for invasion into muscles and organs e.g. Clostridium species IgA proteases: destroy host IgA antibodies found in mucous secretions to allow adherence and passage at mucus membranes e.g. Neisseria species that infect CNS. Joint initiative of IITs and IISc – Funded by MHRD Page 5 of 8 NPTEL – Biotechnology – Microbiology Antigenic Variation There are many pathogens which alter its surface antigens to escape attack by antibodies and immune cells e.g. Neisseria gonorrhoeae has many variety of Opa gene, which can alter one is being expressed e.g. influenza virus constant genetic recombination between flu viruses always new spike proteins. Penetration into Host Cytoskeleton Many a time the pathogen penetrates into host cytoskeleton and use actin of host cell to penetrate and move within the cells of host. The invasins a surface proteins produced by bacteria to control actin e.g. Salmonella rearrange actin to cause the cell membrane to wrap around the microbe and take it into the cell (endocytosis) allows Salmonella to penetrate intestinal epithelium e.g. Shigella and Listeria trigger endocytosis. Damage to Host Cells:The damages to the host cell can be direct or indirect. The direct damages are: Tissue damage, cell components and metabolic by-products, toxins and enzymes. Organ necrosis: - Sum of morphological changes indicative of cell death and caused by the progressive degradative action of cellular components, metabolic by-products, enzymes and/or toxins. Metabolic Effects: Pathogenic organisms can affect any of the body systems with disruptions in metabolic processes. Indirect Damage: Damage to host from excessive or chronic immune response (immunopathogenesis). Production of Toxins Toxins are poisonous substance produced by microbes tend to cause widespread damage/disease in host may be necessary for virulence. There are two types of toxins produced by bacteria. Exotoxins: - produced inside the bacteria and either secreted or released following microbe lysis and toxin genes are often found on plasmids or via lysogenic phages. The most exotoxins are enzymes and function to destroy certain host cell parts or inhibit particular metabolic functions or damage from toxin results in the particular signs or symptoms of a disease. Joint initiative of IITs and IISc – Funded by MHRD Page 6 of 8 NPTEL – Biotechnology – Microbiology The named for the disease, type of cell attacked or organism that produces it e.g. tetanus toxin: causes tetanus (contraction) of muscle. Three types of exotoxins: A-B toxins: - have two parts: A is the enzyme that disrupts some cell activity and B binds surface receptors to bring A into the host cell e.g. botulinum & tetanus toxin. Membrane disrupting toxins: - cause lysis of the host cell by disrupting the plasma membrane e.g. leukocidins: make protein channels in phagocytic leukocytes e.g. hemolysins: make protein channels in RBCs (hemolysis: Steptococcus pyogenes). Superantigens:- bacterial proteins that cause proliferation of T cells and release of cytokines and excessive cytokines can cause fever, nausea, vomiting, diarrhea, shock and death (septic shock) e.g. toxic shock syndrome (Staphylococcus) e.g. enterotoxins: Staphylococcal food poisoning. Endotoxins: - is part of the outer membrane portion of the cell wall of gram negative bacteria: Lipopolysaccharide (LPS) released when dead cells lyse in blood, causes macrophages to release high levels of cytokines resulting in chills, fever, weakness, aches, small blood clots, tissue necrosis, shock and death e.g. endotoxic shock: critical loss of blood pressure due to bacterial endotoxins (LPS). Pathogenic Properties of Virus Viruses have mechanisms to evade host defenses viruses grow inside host cells to hide from immune defense. Kill immune cells e.g. HIV – TH Cells. Cytopathic effects: - The visible effects of viral infection on host cell. Some effects will kill the cell and some will just change the cells. Viruses stop DNA, RNA and/or protein synthesis e.g. Herpes virus block mitosis. Lysosomal autolysis of host cells e.g. Influenza: bronchiolar epithelium. Production of inclusion bodies (visible viral parts inside the cell) can identify a particular virus e.g. Rabies virus: Negri bodies. Syncytium formation (neighboring cells fuse together) e.g. Varicella Zoster virus. Change in cell function e.g. Measles, production of interferons by host cell (triggers host immune response), induce antigenic changes on host cell surface (triggers destruction of infected cell by host immune response). Joint initiative of IITs and IISc – Funded by MHRD Page 7 of 8 NPTEL – Biotechnology – Microbiology Induce chromosomal changes, cell transformation: may activate or deliver oncogenes resulting in loss of contact inhibition (cancer) e.g. Papilloma virus. Eukaryotic Pathogens Fungi They produce toxins causing allergies or disease e.g. -chronic sinusitis (black molds). Stachybotrys: headaches, vomiting, mental disturbance. Invasive systemic mycosis in immune compromised patients e.g. Candida. Mushrooms: mycotoxins may be hallucinogenic or deadly. Protozoa: They can grow inside host cells causing lysis e.g. Malaria (Plasmodium) They use host cells as food source and produce wastes that cause disease. Algae: - It produces neurotoxin substances e.g. shellfish poisoning REFERENCES: Text Books: 1. Jeffery C. Pommerville. Alcamo’s Fundamentals of Microbiology (Tenth Edition). Jones and Bartlett Student edition. 2. Gerard J. Tortora, Berdell R. Funke, Christine L. Case. Pearson - Microbiology: An Introduction. Benjamin Cummings. Reference Books: 1. Lansing M. Prescott, John P. Harley and Donald A. Klein. Microbiology. Mc Graw Hill companies. 2. Biology, Raven and Jhonson, 6th edition (2001) 3. Microbiology, Pelczar. M.J , Chan E.C.S, Kreig N.R, 5th edition (2007) Joint initiative of IITs and IISc – Funded by MHRD Page 8 of 8