What is a pathogen?
organism that has the capacity to cause disease:
What are opportunistic pathogens?
-rarely cause disease in healthy hosts regularly cause disease in compromised hosts:
-burn victims susceptible to infection with pseudomonas aeruginosa
-HIV patients more susceptible to intracellular bacteria (mycobacteria)
-hospitalized patients on broad spectrum antibiotics (clostridium difficile)
What are primary pathogens?
cause disease in healthy individuals
-have virulent mechanisms to overcome, mechanical, innate and adaptive immune responses rarely associate with their host except in the case of disease
-damage or loss of tissue or organ function due to infection or host inflammatory response
-symptoms of infections are caused by the microorganism or by the immune response of the host
Contact with organism does not always lead to disease, what could it lead to?
-elimination by host defense
-part of normal flora
Whether or not disease results depends on what?
-virulence of pathogen
What is virulence determinate?
properties that enable an organism to enter, replicate and persist in a host:
-expression of capsule, LPS, or pili
-elaboration of exotoxins that kill WBCs, proteases, siderophores
-generation of DNA inversions that lead to antigenic and phase variation
How do we determine what properties of an organism are necessary or involved in the disease process?
there are scientific processes that we can go through to determine whether or not a virulence factor is required for that organism to cause disease or whether it facilitates ability to cause disease -some have several factors
Stages of infection?
transmission from mother to child
-the ability to resist physical removal during infection
-establishment at site of infection can be mediated by specific receptor mediated interactions or biofilm formation
Receptor mediate adhesion?
-adhesion: macromolecules on the surface of bacteria (pili, MSCRAMMs)
-receptor: specific carb or peptide on the surface of host cell that is bound by the adhesion
-bacterial adhesions mediate host specific adherence (E coli 987P only cause diarrhea in young pigs) and tissue specific adherence (E coliP pili mediate adherence to urinary tract)- gram -
Microbial surface components recognizing adhesive matrix molecules?
-superfamily of surface adhesions that target host extracellular matrix proteins such as fibrinogen, fibronectin, collagen for adhesion
-only been studied in Gram + bacteria (lipoteichoic acid binds fibronectin)
-aggregate of bacteria that bind to each other on a surface within a slime layer
-many difficult to treat infections are caused by bacteria in biofilms
-bacteria can communicate with other bacterial species in biofilms
-within biofilms bacteria resist:
-being flushed away
-phagocytosis and complement attack
How can bacteria acquire iron?
-secrete chelator called siderophore that bind ferric ions for transport into cell, can steal iron
-some bacteria have membrane proteins that have more affinity for iron than lactoferrin or transferrin, they take the iron
-multiplication: acquisition of iron
What bacteria invade cells?
-facultative intracellular bacteria- invasion of cells is part to pathogenesis (bloody diarrhea instead of watery)
-obligate intracellular bacteria- invasion of cells required for growth or survival (can't make their own ATP), chlamdyia trachomatis
What are exoenzymes?
-allow organisms to degrade certain structures in the body, such as DNA
-Hyaluronidase- breaks down hyaluronic acid the ground substance of connective tissue
-Deoxyribonuclease (DNase)- thin pus made viscous by DNA released by dead WBC
-Streptokinase- activates plasminogen and converts it to plasmin which attacks fibrin clots allowing spread
What can direct damage due to infection be the result of?
-by products of bacteria growth (acids, gas)
-secretion of exoenzymes that break down cells intracellular matrixes of host tissues
-secretion or elaboration of bacterial toxins (endo and exotoxins)
-damage by the immune response (host mediated pathogenesis)
-alter metabolism of host cells
-exaggerate normal physiological functions
-stop cell growth
-some cause disease by themselves (purified toxin)
-LPS, lipid A-moiety toxic
-chromosomal, necessary gene
-weakly antigenic- cannot purify lipid A to immunize someone
-no toxoid, no vaccine
-weakly neutral by antibodies
-stable at high temps
-effect of LPS is the same regardless of bacterial origin
-immune response is responsible for disease
-liberated when bacteria lyse and/or released as part of membrane fractions
-Gram negative and Gram +
-extracellular- excretes it
-frequent phage or plasmid- acquired from
-can make toxoid vaccines
-neutralized by antibodies (IgG)
-unstable by high temperatures
-effects vary depending on bacterial origin
-different specificities, different diseases
What is lipid A part of?
LPS- this is the toxic portion
-liberated when bacteria lyse and released as part of membrane fractions
Lipid A is what?
PAMP- pathogen associated molecular pattern
-bind to and are recognized by PRR of the innate immune system
Examples of PAMPs?
-LPS, lipoteichoic acid, lipoproteins, mycobacterial lipoarabinomannan
-DNA (unmethylated CpG motifs not in mammalian DNA), toxins
What are toll like receptors?
-pattern recognition receptors (PRR)
-many that bind extracellular bacteria (TLR-4 for LPS)
Mechanism that LPS stimulates immune system (lipid A induces cytokines)?
-different than with super antigens
1. lipid A binds to LBP
2. binds to CD14 and TLR-4
3. signal is sent inside cell to stimulate NF-kappaB to release TNF-alpha (coagulation) and IL-1 (fever)
4. could cause septic shock
TNF and IL-1?
-primary mediators of endotoxemia
-produced by macrophages when stimulated by endotoxin
-endotoxin shock is usually associated with systemic spread of organisms:
local release -> containment and removal of infection
systemic release -> hypotension, DIC, systemic shock (septic)
Characteristics of exotoxins?
-secreted or membrane bound and released upon lysis, not integral part of structure of organism
-specifically destroy or inhibit cell functions or tissue components
-vary in specificity (neuro, cyto, entero- gut)
-many, but not all, possess enzymatic activity
routes of entry of exotoxins?
-food poisoning (intoxication)
Exotoxin structures and mechanism of action?
A is the active unit responsible for specific action in the cell that interferes with cell
B- specific binding unit to receptor pore forming
-bind to surface, cause pores, water leaves cell, lyses superantigens
-inappropriate association with TCR and MHC molecule so response is polyclonal and large number of T cells and cytokines respond, toxic shock
What is diphtheria toxin?
-blocks protein synthesis
-A is the active unit, B is binding unit
-only cells with a receptor B, will be affected by A
-toxin expressed on a prophage, only diphtheria strains with phage are pathogenic
-toxin converted to toxoid -part of DTap vaccine
What does cholera toxin result in?
-massive loss of water from intestinal epithelial cells
-get it through drinking water, bacteria gets into gut -enterotoxin
-causes increased adenylate cyclase, increased cAMP
-watery diarrhea, rice water stools (vibrio cholera)
What are hemolysins?
-bind to surface of cells and cause holes in cells
-toxins that damage cell membranes enzymatically or by the insertion of pore forming molecules
-clostridium perfringens (gas gangrene)
What are super antigens?
-powerful polyclonal T cell mitogens, get more activation, more aggravation, more cytokines
-stimulates nonspecific T cell responses
-binds to MHC class 2 molecule and T cell receptor outside of antigen binding sites (outside of cleft)
-leads to improper immune response and a toxic cascade of cytokines (toxic shock syndrome)
Evasion of antibody?
-antigenic and phase variation
-bind antibody inappropriately (S Aureus)
-elaboration of Ig A protease
-bacteria must overcome/survive constitutive and induced defenses to successfully cause infection
Mechanisms microbes use to prevent harmful effects of complement?