Module 9 Pathogenicity

Module 9

Pathogenicity

Microbial Mechanisms of Pathogenicity

§ Pathogenicity: the ability of a pathogen to cause a disease by overcoming the defenses of the host § Virulence: the degree or extent of pathogenicity

§ A pathogenic organism is able to cause a disease § A pathogen that is highly virulent causes damaging disease

§ Portals of entry: avenues that pathogens can use to gain entry into the human body § Mucous membranes § Skin § Parenteral route

§ Respiratory tract, gastrointestinal (GI) tract, genitourinary (GU) tract, conjunctiva § Most common portals are respiratory, GI tracts § Inhaled through mouth, nose § Eaten - most killed by acid, bile § GU tract is portal for pathogens that cause STDs

§ Largest organ, first line of defense § Unbroken skin is impenetrable to most microbes § Some gain access through openings in skin § Some fungi can infect skin directly

§ Access through breaks in skin § From cuts, bites, drying

§ All microbes have preferred portal of entry § Some microbes have multiple portals of entry

§ Likelihood of disease increases as number of pathogens increase § Too few can be overwhelmed by immune system

§ Virulence of a disease expressed as ID50: infectious dose for 50% of the test population § Expression of relative virulence under experimental conditions – can be different for different portals § Bacillus anthracis has 3 portals of entry

Portal of Entry ID50 Parenteral Route 10-50 endospores Inhalation 10,000-20,000 endospores Ingestion 250,000-1,000,000 endospores

§ Potency of toxin expressed as LD50: lethal dose for 50% of the test population

Toxin LD50 in mice Botulinum toxin 0.03 ng/kg Shiga toxin 250 ng/kg Staphylococcal enterotoxin 1350 ng/kg

§ Structures of molecules that a pathogen uses to cause disease § Many different virulence factors exist

§ Means of attachment § Necessary for pathogenicity in most pathogens § Interfere with binding, interfere with infection § Adhesins (ligands) bind to complementary receptors § Adhesins may be located on glycocalyx, surface structures § Adhesins usually glycoproteins, lipoproteins § Binding is specific for certain host tissues, receptors

Adhesin (ligand)

Pathogen

Host cell surface

Receptor

Surface molecules on a pathogen, called adhesins or ligands, bind specifically to complementary surface receptors on cells of certain host tissues. © 2013 Pearson Education, Inc. How Pathogens Penetrate Host Defenses

§ Pathogens must penetrate tissue to cause disease § Several factors contribute to the ability of pathogens to invade a host

§ Capsules impair phagocytosis (being eaten) § Prevents binding to pathogen § Capsules do not mean a bacterium is virulent

§ Some cell walls contain chemicals that contribute to virulence § M protein resists phagocytosis § Streptococcus pyogenes § Opa protein inhibits T helper cells § Neisseria gonorrhoeae § Mycolic acid (waxy lipid) resists digestion § Mycobacterium tuberculosis

§ Coagulase: coagulates fibrinogen § Kinases: digest fibrin clots § Hyaluronidase: hydrolyzes hyaluronic acid § Collagenase: hydrolyzes collagen § IgA proteases: destroy IgA antibodies

§ During pathogenesis, body produces antibodies to fight infection § Bind to antigens on surface of bacteria § Antigenic variation: ability to alter surface antigen § Changes slowly over time § By the time body produces antibodies, surface antigen has changed § Influenzavirus, N. gonorrhoeae, Trypanosoma brucei (African sleeping sickness)

§ Bacteria can damage host by: § Using host’s nutrients § Direct damage § The production of toxins

§ Siderophores: proteins that tightly bind iron § Iron is required for growth § Iron in human body is tightly bound § Some pathogens release siderophores to take away iron

§ A number of ways that microbes can damage cells § Grow within cells, multiply and rupture cell § Attach to host cell and cause damage as pathogen uses host for nutrients § Penetrate hosts by secreting enzymes

§ Toxins: poisonous substances that are produced by some microbes § Toxigenicity: ability of microbes to produce toxins § Two types of toxins § Endotoxins § Exotoxins

§ Exotoxins: protein toxins made inside bacterium and secreted to its surroundings § Many are enzymes, so small amounts harmful § Can act over and over again

§ Soluble in body fluids, can be transported all over body § Diseases caused by bacteria that produce toxins are a direct result of toxin § Staphylococcal food poisoning is an intoxication § Antitoxins: antibodies produced by the body that provide immunity to toxins

§ A-B toxins: consist of two parts, “A” and “B” § A part is active (enzyme) component § B part is the binding component § Diptheria toxin is A-B toxin

§ Lyse host cells by making protein channels in the plasma membrane – Leukocidins – Hemolysins – Streptolysins § Disrupts phospholipid bilayer

§ Provoke very intense immune response § Stimulate proliferation (division) of T cells § Release chemicals, cytokines, that regulate immune response § Too many cytokines in blood à fever, shock, death

§ Part of cell wall of gram-negative bacteria § LPS portion of outer membrane § Endotoxin is the lipid portion, called Lipid A

§ Endotoxins are released when Gram-negative bacteria die and cells lyse § Liberates endotoxins § Antibiotics can cause lysis à release LPS

Endotoxins: toxins composed of lipids Intact cell that are part of the Dead cell cell membrane

§ All endotoxins produce the same signs and symptoms § Chills, fever, weakness, aches, shock, death § Disseminated intravascular clotting § Shock: life threatening drop in blood pressure § Endotoxic shock: shock produced by Gram- negative bacterial endotoxin

Endotoxins cause fever (by inducing the release of cytokines) and shock

§ R factors carry antibiotic resistance genes § Others can carry virulence factors § Toxins – tetanus neurotoxin, staphylococcal enterotoxin § Fimbriae, adhesins, enzymes (coagulase)

§ Prophage: phage DNA incorporated into bacterial chromosome § Prophage can provide new properties to bacteria § Lysogenic conversion: change in characteristics due to a prophage § Diptheria toxin, staphylococcal toxin, capsule of S. pneumoniae are encoded by prophages § Can transfer virulence genes to nonpathogenic strains

1 Phage attaches 5 Occasionally, the prophage may excise Phage DNA to host cell and from the bacterial chromosome by another (double-stranded) injects DNA. recombination event, initiating a lytic cycle. Bacterial chromosome Many cell divisions

Lytic Lysogenic cycle cycle 4A Cell lyses, releasing 2 Phage DNA circularizes and enters 4B Lysogenic bacterium phage virions. lytic cycle or lysogenic cycle. reproduces normally. Prophage OR

3A New phage DNA and 3B Phage DNA integrates within the proteins are synthesized bacterial chromosome by and assembled into virions. recombination, becoming a prophage.

§ Viruses have a number of mechanisms to evade immune system § Can grow inside of host cells § Some can “hide” attachment sites - HIV has attachment sites too small for antibodies to bind § Some attack immune cells - HIV

§ Cytopathic effects (CPE): visible effects of viral infection § CPE used to diagnose many viral infections

Inclusion body

Cytoplasmic mass

Nuclei

§ Fungal waste products may cause symptoms § Chronic infections provoke an allergic response § Tichothecene: toxins that inhibit protein synthesis § Fusarium, Stachybotrys § Proteases that modify host membranes, allow attachment § Candida, Trichophyton § Capsule prevents phagocytosis. § Cryptococcus

§ Presence of protozoa and their waste products often produce symptoms § Some (Plasmodium) invade host cells (red blood cells) § Others (Giardia lamblia) attach to host cells by a “sucking disc” and digest cells and tissue § Some undergo antigenic variation (Giardia, Trypanosomas)

§ Presence of helminths causes disease § Interferes with host function § Some (Wuchereria bancrofti) use host tissues for growth, reproduction (elephantitis) § Block lymphatic circulation, leads to accumulation of lymph, grotesque swelling

§ Some produce neurotoxins § Paralytic shellfish poisoning § Alexandrium, a dinoflagellate

§ Specific route that microbes use to leave the body § In secretions, excretions, discharges, tissue that’s been shed § In general, portals of exit are related to infected tissue

§ Respiratory tract § Coughing and sneezing § Gastrointestinal tract § Feces and saliva § Genitourinary tract § Urine and vaginal secretions § Skin § Blood § Arthropods that bite; needles or syringes

When the balance between host and microbe is tipped in favor of the microbe, an infection or disease results. Learning these mechanisms of microbial pathogenicity is fundamental to understanding how pathogens are able to overcome the host’s defenses.

H1N1 flu virus

penetration or evasion of Number of damage to portals of entry invading host defenses host cells portals of exit Mucous membranes microbes Capsules Siderophores Generally the same as • Respiratory tract Cell wall components Direct damage the portals of entry for a • Gastrointestinal tract Enzymes Toxins given microbe: • Genitourinary tract Antigenic variation • Exotoxins • Mucous membranes • Conjunctiva Invasins • Endotoxins • Skin Skin Intracellular growth Lysogenic conversion • Parenteral route Parenteral route Adherence Cytopathic effects

Mycobacterium intracellulare

Clostridium tetani Micrographs are not shown to scale.