Loss of cell surface alphaGal during catarrhine evolution: Possible implications for the evolution of resistance to viral infections and for Oligocene lineage divergence

摘要: FEBRUARY 2014 IDALIA ARACELY RODRIGUEZ, B.A., VIRGINIA COMMONWEALTH UNIVERSITY M.A., OF MASSACHUSETTS AMHERST Ph.D., Directed by: Professor Laurie R. Godfrey and Raymond M. Welsh The divergence of the two superfamilies belonging to Infraorder Catarrhini – Cercopithecoidea (Old World monkeys) Hominoidea (apes, including humans) is generally assumed have occurred during Oligocene, between 38 20 million years ago. Genetic studies indicate that this time period was one active genetic evolution under strong purifying selection for catarrhine primates. This includes selective pressures on glycoprotein galactosyltransferase 1 (GGTA1) gene subsequent inactivation “clocked” at approximately 28 ma, possibly prior Cercopithecoidea/Hominoidea split. GGTA1 codes an α1,3 (GT) enzyme synthesizes a terminal disaccharide, αgalactosyl (αGal), found glycoproteins glycolipids surface cells in tissues most mammals. Currently, catarrhines are only mammals studied αGal residue do not express sugar their cell surfaces. proposed advantage mutation ability produce anti-Gal antibodies, which may be effective immune component neutralizing αGal-expressing pathogens, as certain helminthes, many bacteria, those primate guts, some viruses derived from positive species However, known utilize host carbohydrates various ways such binding receptors or attachment proteins, making these moieties “hot spots” evolution. Cell predisposed ancestral pathogens toxins could sites other capacities infection. I that, fact, presence absence affects course viral infections. Infections paired lines with differential expression GT showed Sindbis (SINV) preferentially replicate αGal-positive cells, whereas herpes simplex type 2 (HSV-1 HSV-2) grow lacking αGal. In both cases, differences infection levels resulted virus successfully initiate points role early stages also knockout mice infected HSV-2 had higher load greater pathology compared WT B6 naturally increased susceptibility KO due were even more evident immunocompromised mice. clearly indicates animal hosts can affect able further confirm HSV using mouse backcrosses (KO x WT). Unknown factors, independent expression, introduced crosses need investigated. did yield definitive data require suitable reagents. mechanism by GT-dependent operates still remains deciphered. it clear infections tied cells. Overall, results implications resistance catarrhines. Pathogens exert great pressure hosts, possible pathogen, exploit αGal, helped shape lineage Oligocene. TABLE CONTENTS Page ACKNOWLEDGEMENTS v ABSTRACT viii LIST TABLES xv FIGURES xvi