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Innate Immunity I know pornography when I see it. I know a pathogen when I see it. Definition • Natural ability to fight pathogens. • Acts rapidly. • Does not depend upon previous contact with the pathogen. Don’t let your competition define you • Textbook definition of innate immunity: non-clonal immune defenses. • It is the adaptive immune response that needs a special definition as it is the most recent addition to our repertoire. Adaptive immunity is a recent arrival from an evolutionary point of view Organisms do well without an adaptive immune response Oldest Largest Diverse http://BeeLab.cas.psu.edu Genetic resistance to disease • Malaria: sickle cell anemia, thalesemia, duffy coat, G6PDH • Cholera: cystic fibrosis • AIDS: CCR5 Glucose 6-phosphate dehydrogenase (G6PDH) • Most polymorphic human gene. • Principal source of reducing power. Glucose-6-phosphate NADP 6-phosphogluconate NADPH Malaria and polymorphisms coincide G6PDH protects against severe malaria infections • Severe malaria sufferers are less likely than control groups to be heterozygous or hemizygous for G6PDH. • Female heterozygotes odds ratio: 0.54 • Male hemizygous odds ratio: 0.42 The deficiency has some costs • Severe jaundice at birth • Hemolytic anemia • Severe sensitivity to free radical production Pythagoras: “avoid the bean” Fava beans and favism • Fava beans can cause hemolytic anemia in G6PDH deficient patients • Meals, mothers milk, pollen • Staple food in areas where • G6PDH is prevelant Fava bean active ingredients • Two pro-oxidants: vicine and convicine • Glycosidase releases active compounds which can react to produce H2O2. • Normally these are reduced by glutathione which is reduced by NADPH • All of this happens at a slower rate in G6PDH deficiency patients Results • Normal RBC + vicine: • Hemizygous G6PDH • Homozyogous G6PDH 1 +/- 0.053 0.76 +/- 0.043 0.33 +/- 0.103 Equilibrium is shifted reduction oxidation G6PDH Fava beans Plasmodium does poorly under oxidizing conditions Main points • Genetics of host is critical in defining the disease. • Behavior can modify natural susceptibility. Flora and Disease • Body ecology can prevent disease • Microorganisms occupy and defend their niche. • This can be use in an applied manner. Chagas Disease: Trypanosoma cruzi How do you know it is a symbiont? • Grow the bugs axenically - fail to thrive • Add back bacteria to their food. What antimicrobial do you use • • • • Antimicrobial peptide Ecoli 23 uM Rodococcus rhodnii 500 uM Trypanosoma cruzi 150 uM Transform gut bacteria with cecropin • • • • • Create a shuttle vector Clone in cecropin Transform bacteria Introduce to insect Stability is an expected problem. Paratransgenic triatomines cannot vector T.cruzi T.cruzi In hindgut Triatomines are caprophagic Cruzigard; seeded mock bug frass Other applications of this model • BT corn: proteinaceous toxin cloned into corn to kill insect pests. • Mosquito expressing single chain antibody against Plasmodium. • Mosquito expressing peptide blocking Plasmodium binding. Main points • Flora is an important part of an immune system. • Flora can be manipulated. Parasite defense Parsitoid wasps lay eggs in insect hosts Process reconstructed in vitro • Cells purified based upon size and adhesive properties • Plastic bead used as surrogate egg • Monoclonal antibodies raised against different cell types • Factors affecting cell behavior purified Bead encapsulation Wasp carries a provirus • • • • • Polydna virus Poly disperse DNA virus Made only in calyx Injected into larva with egg and toxin Induces apoptosis of granular cells only How don you demonstrate viral activity • Apoptosis seen in blood cells in natural infection • Add calyx extracts to purified cells and perform tunel assays Main points • Complex cellular interactions are used to destroy parasites • Apoptosis can be used by the host to prevent the spread of infection. • Apoptosis can also be used by the parasite to destroy the immune system.