Chapter 18-Microbial Pathogenesis.pdf

Chapter 18: Microbial Pathogenesis Examples of Virulence Factors and how they work: • • • Effector proteins: enzymes that harm the host by disruption normal cellular functions Secretion systems o Allow bacteria to move compounds from the cytosol to the periplasm, extracellular environment and host...

Chapter 18: Microbial Pathogenesis Examples of Virulence Factors and how they work: • • • Effector proteins: enzymes that harm the host by disruption normal cellular functions Secretion systems o Allow bacteria to move compounds from the cytosol to the periplasm, extracellular environment and host cells Cellular structures that assist with persistence (capsules) and adhesion(pilus and fimbrae) Ability to distinguish between Typhoidal and Non-Typhoidal Salmonella • • • • Healthy Salmonella Enterica o Found in plants, animals, and hospitals (reservoirs) o Are part of microbiota in humans and play a comensalist role aiding in metabolism and homeostasis by outcompeting other pathogens Salmonellosis o Food poisoning/stomach flu o Illness that causes gastric and water/nutrient loss due to accumulation of water in the colon o Bacteria may penetrate crypts and adhere to host cells but does not attack the epithelium o Uses an effector protein SopB (SPI-5) released via type 3 secretion and goes into the host cell causing osmotic imbalance due to activation of chloride channels Typhoid Fever o Serious and possibly fatal o Leads to bacterial proliferation in the bloodstream and organs → causing sepsis o Bacteria invades the cells of the host that are lining the epithelium (SPI-1) causing immune cell activation Effector mechanisms of Salmonella that lead to Typhoid fever o Macrophages and other immune cells attempt to kill the bacteria by engulfing it (phagocytosis) and fusion to a lysosome for breakdown but the salmonella escapes the phagocyte (SPI-2) o Salmonella then form a Salmonella Containing Vacuole (SCV) which serves as the internal reservoir and is the inactive form o SCVs can become SIFs which are large branched complex structures (Salmonella Induced Filament) o SIF can then penetrate tissue and enter the blood stream and it allows for further salmonella replication and proliferation Mechanisms by which Salmonella evade the immune system • • Salmonella evade destruction through the immune system by escaping the phagocyte (SPI-2) They also may inhibit the fusion of the lysosome to the macrophage Defining Pathogenicity Islands • Pathogenicity islands are genomic islands with multiple virulence factors o o o Genomic island: genetic loci with one or more coding genes and different GC content than the rest of the genome indicating horizontal gene transfer. Gene expression is regulated by one master regulator Virulence factors are the molecules that assist the bacteria in colonizing the host cell at the cellular level Distinguish between SPI 1, SPI2 and SPI5 via effector mechanisms, component genes, and context in which they are used by Salmonella SPI: SALMONELLA PATHOGENICITY ISLAND • SPI-1 o o o o o • SPI-2 o o o o o o o Associated with the invasion of host cells Loci contains all of the genes required to form functional type 3 secretory systems AvrA: induces expression of cytokines Sip protein family ▪ SipC: binds to actin and initiates membrane ruffling ▪ SipA: enhances ruffling Master regulator: HilA which is activated in response to environmental cues Associated with survival within host cells and maintaining the salmonella containing vacuoles (SCV) Loci also contains all the genes to form functional type 3 secretion systems SPI-2 is able to fill the role of SPI-1 when SPI-1 is unavailable SseF: structures and localizes SCV (salmonella containing vacuoles) SifA: Forms and maintains the SIF networks SSpH1: inhibits host apoptosis pathways via down regulation of JNK pathway ( pathway for programmed cell death) Master regulator: SsrAB a two component system ▪ SSrA a large trans membrane protein : likely a kinase ▪ SsrB a transcriptional regulator which becomes phosphorylated by SsrA and promotes the transcription of SPI-2 genes • SPI-5 o o o o Function is still debated but plays a role in both intra and extracellular survival Does not contain a type 3 secretion system (T3SS), relies on SPI-1 and SPI-2 T3SS for translocation of effector proteins SopB which causes water loss from host tissue by activating chloride channels using SPIT3SS PipD a cysteine protease that seems to be associated with long term systemic infections using SPI-2 T3SS Understand how heat shock influences SPI -2 gene expression - Heat stress has been shown to increase the expression of SsrB and SPI-2 genes Therefore, improperly cooked food could contain more virulent populations of Salmonella Many heat shock proteins share homology with SPI-2 effector proteins Distinguish between different types of secretion systems and how they work (Type II, III, IV) - Type II secretion system o Requires inner membrane bound proteins Tat and Sec to move compounds into periplasm similar to type 1 and 5 o Specific: allowing only one compound to pass though the membrane o Allows bacteria to secrete compounds into the extracellular environment o Has a piston which is reversible polymerization that causes compounds to be ejected out of the second membrane/ cell wall o Derived from fimbriae proteins - Type III Secretion system o Non specific allowing a variety of effector proteins and other compounds to be localized o Does not require secondary proteins to secrete compounds o Allows bacteria to secrere compounds directly into host cells o “Needle”: consumption of ATP allows compounds to be moved against their concentration gradient o Deruved from flagella proteins o Involved with virulence - Type IV secretion systems o Non-specific, variety of effector proteins can be localized o Does not require secondary proteins to secrete compounds o Allows bacteria to secrete compounds directly into host cells o “Tube”: Passive diffusion relies on compounds flowing with their concentration gradient o Derived from flagella proteins o Involved with conjugation Understand cellular structures involved with Persistence and Adhesion to cells. - Persistence o Bacterial capsules are composed of dense layers of hydrated glycoproteins o The capsules help them evade immune detection by altering the antigenic epitopes they present to the luminal environment o Capsules also aide in adherence - Adhesion o Assembly of pili starts with the tip protein which bidns carbohydrates on the host cell surface o Pili are made up of identical pilin protein subunits: the tip of the pilus contains adhesion proteins that bind to host cell receptors o PapD a molecular chaperon that plays an essential role in pili synthesis and must be translocated to the periplasm by SecA Differences between endotoxin and exotoxin; Examples of each along with their function - Endotoxin: components of bacterial cells that are released when the cell is destroyed o LPS: lipolysaccharide ▪ Part of the outer membrane of the gram negative cell wall that includes lipopolysaccharide ▪ After lysis LPS fragments may be released in the blood causing an inflammatory response: fever, activation of clotting factors, activation of complement, vasodilation, shock and death by sepsis - Exotoxin is secreted by microbes o Example is the Two-Subunit AB exotoxin called Tetanospasmin released by Clostridium tetani ▪ A subunit is toxic ▪ B binds to host cell receptors; many B subunits are complexes of 5 units arranged as a ring Anthrax toxin (exotoxin) - Has two A subunits called edema factor (EF) and lethal factor (LF) B subunit is called protective antigen (PA) Edema factor causes fluid los to extracellular spaces Lethal factor destroys regulatory cascades and cripples the immune response Toxin is produced by the Bacillus anthracis a soil microbe that has been used in terrorist attacks and exposure to high doses of anthrax can be fatal causing lung necrosis(death of tissue) Prokaryotic immune system evasion strategies Immune avoidance (Eukaryotic immune system evasion - By protozoa Antigenic masking: some protozoans coat themselves in host antigens to avoid detection by the immune system Antigenic variation Ex: A variant surface glycoprotein (VSG) coat covering the membrane of African trypanosomes protects them from lytic factors in human plasma and allows them to escape the host immune reaction. Intracellular location - Immunosuppression: some protozoans induce secretion of anti inflammatory cytokines to reduce the innate immune response The role of viral latency in the pathogenesis of infection. Name an example. - - Human herpesvirus and latency: after a primary infection, herpes becomes latent in host cells (nerve or white blood cells). Latent viruses an reemerge after years of latency to cause a new active infection o DNA circularizes and exists as episome o DNA integrates into host cell genome Varicella-zoster virus: chicken pox at a young age but virus remain latent and can cause shingles later in life (50 years or older but may happen earlier)