Bacterial Virulence Mechanisms PDF

Mechanisms of bacterial virulence Prof. Nick Waterfield November 2024 / MD2B3  By the end of this session, you should: Understand what a bacterial pathogen is and how we define it Understand terms such as pathogenicity, virulence and virulence-factors Understand the step...

Mechanisms of bacterial virulence Prof. Nick Waterfield November 2024 / MD2B3  By the end of this session, you should: Understand what a bacterial pathogen is and how we define it Understand terms such as pathogenicity, virulence and virulence-factors Understand the steps involved in bacterial infection and types and roles of different virulence factors  What is a pathogen? A pathogen is an organism that causes disease to its host. Pathogenicity is the capacity to initiate an infectious disease. Virulence: The capacity to cause disease & the severity of the disease. Transmissibility: The ability to transmit from human-to-human or reservoir-to-human. Survival: To not be killed by host immunity and be able to“feed” and reproduce in the host. Infectivity: The ability to breach host defenses in the first place. Virulence factors are proteins or other molecules produced by an organism essential for its pathogenicity.  Virulence Factors Cytosolic Adaptive metabolic, physiological and morphological shifts. Membrane-associated Used to aid in adhesion to host tissues/cells and evasion of the host immunity. Secretory Used to invade tissues and/or to evade the innate and adaptive immune response mounted by the host.  Steps to infection Survival Transmissi Adheren Tissue Invasion in the on ce damage host Exposure to Binding to Breaking Growth at Toxicity and pathogens the skin or through original and disease mucosa barriers distal sites, production of virulence factors  Transmission: Reservoirs Transmission starts with exposure to pathogens which reside in reservoirs, the natural site of a pathogen. Human reservoirs Person to person transmission without intermediaries. It can occur even if a person is just a carrier of the disease and is unaware (ie asymptomatic carriage). Examples: COVID, HIV, measles, mumps, streptococcal infection, and many respiratory pathogens. Animal reservoirs Transmitted from animal to animal, with humans as incidental hosts. A Zoonosis refers to transmission from animal to human. Examples: Brucellosis (cows and pigs), Anthrax (sheep), Plague (rodents), Trichinellosis (swine) and rabies (bats, dogs, other mammals and sometimes humans).  Transmission: Reservoirs Environmental reservoirs Plants, soil, and water in the environment. Examples: Vibrio Cholera in contaminated water leading to Cholera outbreaks (A very bad outbreak of Cholera in London in 1854 was caused by contaminated water from a public water pump on Broad Street as eventually proved by Dr John Snow). Outbreaks of Legionnaires disease are often traced to water supplies in cooling towers and evaporative condensers, reservoirs for the causative organism. Cholera and Salmonella are also often spread by contaminated water.  Transmission: mechanisms Direct Contact Direct body surface to body surface contact and the physical transfer of microorganism between an infected or colonized person to another person by touch. Skin-to-skin contact, kissing, sexual intercourse, vertical transmission (mother > neonate). Eg. HIV, Staph aureus infections, infectious mononucleosis, and Gonorrhoea. Indirect Contact Involves contact between a person and a contaminated object. The microorganism remains on this surface to be picked up by the next person who touches it. Fomites: objects or materials such as clothes, utensils and furniture. Eg. Cholera, Salmonellosis, Listeriosis, viral hepatitis.  Transmission: mechanisms Droplets Droplets containing microorganisms are generated during coughing, sneezing and talking are propelled through the air. They land on another person, entering that new person’s system through contact with his/her conjunctivae, nasal mucosa or mouth. Microorganisms remain suspended in the air for long periods of time and can be dispersed widely by air currents. In addition to droplets, dust particles can carry infectious agents. Examples : Influenza, Pneumonia, Meningococcal infections and Pertussis (whooping cough), anthrax spores, M. tuberculosis, rubeola, SARS-CoV-2, varicella and hantaviruses.  Transmission: mechanisms Zoonosis from mammals Animal bites such as Rabies virus or Hepatitis from primates. Animal food products such as contaminated meat (E. coli in beef or Salmonella from chicken). Animal hide products. An example is anthrax contracted off contaminated drum skins. Invertebrate vector borne Ticks, mosquitos and fleas. Examples; Lyme's disease, Malaria, Yellow and Typhus fever, bubonic plague. Biological products Including vaccines and blood products. Examples include Hepatitis, HIV and Fungal Transmissi on Transmissi on  Transmissi on However! To successfully transmit by any of these routes a pathogen must be able to adapt and survive in the changing environmental conditions it experiences. pH Temperature Oxygen levels Salt levels Host cell immune responses Nutrient availability How do pathogens achieve all this?  How do pathogens achieve all this? Adhesion The process by which organisms attach themselves to tissues or cells. It is necessary for successful colonization within host. Pathogens use adhesion factors which may be; Attachment proteins (pili, fimbriae, flagella) Specialized surface structures (EPS, CPS)  Adhesion proteins Adhesion structures Initial attachment often mediated by protein appendages such as: Fimbriae/pili. Short fibers made up of proteins that enable bacteria to stick to the surface of host cells. Flagella. Long filaments (primary role in motility). Type IV Pili are used to transfer DNA, such as antibiotic resistance plasmids, between bacteria. Others for so called “twitching motility”  Surface structure Attachment can also be mediated through more generic surface structures such as exopolysaccharides (EPS). EPSs typically consist of monosaccharide- polymers that are secreted by bacteria into their environment. They are often hydrophobic and can displace water between the bacterium and the host cell surface promoting closer contact. They can also form a protective shield around a bacterium in what is known as a capsule, preventing ingress of harmful chemicals (immune molecules or antibiotics). These CPS can also prevent phagocytosis.  Biofilms After initial attachment many bacteria form ”biofilms” to enhance survival. This can be inside host tissues or on abiotic surfaces. Examples include, dental plaque, the intestines and medical devices such as catheters. Biofilms contain many biological polymers, mainly exocellular polysaccharides but also DNA and proteins. They provide a barrier to harmful factors in the environment. Antibiotics and immune factors are often unable to penetrate them.  Biofilms Biofilms “grow” in a complex architecture that allow fluid flow between the regions. This allows nutrients in and removes waste products. In the natural environment biofilms are normally “mixed”, containing sometimes hundreds of different species of bacteria and sometimes yeasts. For example, dental plaque. https://youtu.be /Aa8WE2LOOcQ How do pathogens achieve this? Active combat Eg. The amino acid Serine is often scavenged by pathogens as it deprives the host of an important energy source. Especially immune cells. Active combat: Toxins Active combat: LPS “endotoxin” LPS triggers the Toll Like Receptor TLR4. This initiates an inflammatory response and causes a powerful fever. Active combat: exotoxins Active combat: Single chain protein toxins Active combat: Single chain “superantigens” Superantigens directly target a central aspect of the immune system. They trigger non-specific activation of T-cells by Antigen Presenting cells leading to an uncontrolled release of cytokines, a “cytokine storm”. They bridge the Class II MHC on an APCs with the TCR on T-cells. Symptoms are fever, nausea, vomiting, diarrhea, shock and death. Example: Toxic shock syndrome toxin-1 (TSST-1) which is produced by some strains of Staphylococcus aureus that causes toxic shock syndrome (TSS). Active combat: Multiple subunit protein toxins Active combat: Multiple subunit protein toxins The “Toxin Complex” is a multi-protein injection machine deployed to deliver toxic payload proteins directly across host cell membrane. First discovered in insect pathogens but now in pathogens of mammals, fish etc… https://www.mgc.ac.cn/ dbTC/ Injector Toxin “adaptor" Toxin https://youtu.be /Y1dMsNyW5Zo Active combat: Non-protein small drug like toxins  Multi-enzyme ”factories” produce these Such molecules include: Toxins Polyketi Immune inhibitors de Antibiotics synthesi Siderophores (Fe2+ scavenging) s Non-Ribosomal peptide synthases Active combat: Specialized toxin delivery systems  Active combat: Specialized toxin delivery systems Many such systems are key to pathogenicity and virulence activities of bacterial pathogens Some secrete proteins that are freely released and gain entry to the host cell by themselves. Some can secret molecules and virulence factors out of the bacterial cell directly into a host cell upon contact. PVCs In both Gram-positive Only in Gram positive Mainly Gram and Gram-negative bacteria negative bacteria bacteria  Active combat: Specialized toxin delivery systems Many such systems are key to pathogenicity and virulence activities of bacterial pathogens Some secrete proteins that are freely released and gain entry to the host cell by themselves. Some can secret molecules and virulence factors out of the bacterial cell directly into a host cell upon contact. PVCs Only in Gram-negative bacteria