Biology 216 - Lecture 7 
(Host/Parasite Interactions)
I. Basic perspective of Host/Parasite interactions
   A. Balance:   Host defenses (health) <-----------> 
	Microbe factors (disease)
       Infection is the rule/disease is the exception
       Lives of a cell (Lewis Thomas): Bad business to kill your host; 
	Evolutionary tendency towards attenuation.
	Ex. Myxovirus and Australian rabbits 1950
   B. Terms:
 	1. Disease - alteration of normal body function 
		(inherited; environ; infectious).
	2. Infection - colonization of host by microbe
		 (may or may not lead to disease).
	3. Pathogen - microbe that normally produces disease.
	4. Opportunistic pathogen - disease if host 
		defenses are compromised or impaired.
	5. Intoxication - introduction of preformed toxin 
		which induces disease.
	6. Virulence factor - specific property which 
		contributes to disease (attach, tox, caps)
	7. Pathogenecity - composit of all virulence factors 
		(disease producing ability).
II. Host Defenses
   A. Primary/surface defenses:
	1. Mechanical - skin, tears, saliva, mucus, cough, urine, 
		ciliated expuls(flu after pneumo), desquam...
	2. Chemical - stomach acid (achlorhydria), lysozyme, 
		complement (alternate)
	3. Microbial - competition; AAE.
   B. Non-specific phagocytic system:
	1. Inflammation - vascular response to injury
		 (mobilization of phagocytic cells).
		Also acute phase systemic response - 
			leucocytosis, fever,.....
	    Dilation (from histamine, increased vascular permeability,
		 leakage(edema), PMN stick, diapedesis.
	    Signs - red, swollen, warm, pain ----> pus (pyogenic)
	2. Phagocytosis (cell eating) - PMN early (live days),
		 Mac later (live months)
	 	Macs = tissue, RES.
	    Membrane surrounds (compatible surfaces)
	    Membrane perturbation ->O2 burst (O2 + NADH2) ->
		 H2O2 & O2- (by NADPH oxidase)
	    Microbe internalized in phagosome - not killed.
	 	Lysosome - pH, lactoferrin, lysozyme, etc.
		Degranulation - release into surroundings.
		a. PMN - MPO  (H2O2 + halogen -> 
			halogenation of surface), 3 day life
		    (Chronic granulomatous disease - defective NADPH oxidase 
			or MPO)-> Staph (cat+) infection
		b. Macs - activated by lymphokines -> big macs 
			(angry, incr lysosomes, O2radicals,
			defensins - small peptides which intercalate membranes...)
			Has less active MPO
   C. Specific ir (Humoral vs CMI) - we mount both
	(usually one helps more)
	Affected by age (0 - 2 yr low Ab to CHO); nutrition, 
		stress (decr MHCII decr resist TB).
  	1. Humoral (Ab) - proliferation of T and B clones -> 
		plasma & memory cells -> Ig
	    IgM, IgG, IgA
	    Function of Ab - opsonization, fix C (lysis, chemotax, C3b), 
		toxins, attachment.
	    Generally: Most effective against extracellular parasites.
	2. CMI - proliferation of T clone -> lymphokines, chemotaxis, 
		active mac (TH), 
		granuloma(TDH)(cells immobilized and fuse -> 
			epithelioid/giant cells, fibroblasts surround
		Increased MHC II on surface increase 
			Mac Ag presenting ability.
	    Generally: Most effective against 
		intracellular parasites (ex. TB)
	3. Problems: Autoimmunity (ARF), immune complex 
		(leprosy, AGN), Ag shift
III. Microbial Factors (virulence associated factors) 
   A. Attachment - circumvents clearance (Ex. GC, ETEC, UTI, ...) -
		 mucosal pathogens
   B. Invasion - cytotoxins, hemolysins, proteases (new GpA strept),
		 IgAase (Haemophilus).
   C. Evasion of phagocytosis - capsule; Self Ag coat 
		(E. coli K1; N. meningit B)
   D. Intracellular survival:
	Block phago-lysosomal fusion - TB, leprosy
	Exit phagosome into cytoplasm before fusion - Rickettsia
	Prevent O2 burst - Legionella
	Adapt to phagolysosome - Coxiella best at pH 4.
   E. Elaboration of Exotoxins
	1. Exotoxins - Protein toxin secreted (most enzymatic) -
			 many mechanisms known.
		Formed outside host (intoxications) - 
			botulism, staph food poisoning
		Formed on surface - cholera, diphtheria
		Formed inside host - tetanus
	    ADP-ribosylating toxins (about 1/2 of known exotoxins)
	    NAD + X (cell target) --> 
		ADP-ribose-X (inactive) + nicotinamide
	    Ex. Diphtheria (EFII); Ps toxin A (EFII); 
		cholera (GTP-BP regulator of ad cyc)
	2. Endotoxin - Lipid A of LPS of Gm- only (often UTI -> systemic, 
		70 % fatal once organ failure.)
	    Sets off general alarm - symptoms result from host response.
	    Injection of IL-1, TNFalpha -> shock symptoms
	    General mechanism:
		LPS + LPSBP -> CD14 receptor of monocytes and 
			Macs and endothelial cells
		1. Cytokine release (IL-1, IL-8, TNF, platelet activating factor)
			-> endothelial damage, clotting
		2. DIC - Coagulation system -> clots and 
			decrease blood flow
			Blood in periphery rather than organs.
			Acute Resp Distress Syndrome (ARDS) - 
				fluid and PMN in lung
	    a. Petechiae - peripheral vascular damage - ret blotches 
		(blood in tissues)
	    b. Leukocytosis - marrow releases WBC in
		 response to IL-1
	    c. Fever - PMN release endogenous pyrogen (IL-1) -> 
		hypothalamus
	    d. DIC - Activation of intrinsic pathway 
		(factor XII released by platelets)
		-> clots,slow blood,decrease pressure.
		Clotting consumes platelets and 
			clotting factors.
		Secondary - fibrinolysis -> bleeding into tissues 
			(primarily gut)
	    e. Septic shock - Vascular changes (peripheral dilation) -> 
			decrease blood pressure.
		Decrease blood flow -> blood pools -> 
			organs starve -> circulatory collapse.
	    f. Treatment - heparin, SAIDs (steroidal antiinflammatory drugs)

3. Comparison of Exotoxin vs Endotoxins

Property	Exotoxin	Endotoxin
Chemical	Protein	Lipid A of LPS
Action	Enzyme	Host inflammatory response
Subunits	A (active) & B (binding)	O-Ag, Core, Lipid A
Toxoid	yes	no
Heat sensitivity	yes	no
Examples	Tetanus, botulism, diptheria	plague, Neisseria meningitidis

IV. Summary - Not all microbes have all these factors.
	Importance of identifying factors which are
		 important so vaccines can neutralize
	Outcome of infection is balance between host and microbe