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Conference Paper: Host Genetic Susceptibility to Emerging Infectious Diseases

TitleHost Genetic Susceptibility to Emerging Infectious Diseases
Authors
Issue Date2008
PublisherAssociation of Chinese Geneticists in America and the Hong Kong Society of Medical Genetics.
Citation
ACGA-HKSMG International Conference on Genetic & Genomic Medicine, Hong Kong, 8-11 June 2008, p. Abstract no.S17-4 How to Cite?
AbstractIn the face of emerging epidemics, understanding variation in individual responses to pathogens takes on new importance. Two closely related trans-membrane C-type lectins DC-SIGN (dendritic cell-specific ICAM-3 grabbing non-integrin) and L-SIGN (liver/lymph node-specific ICAM-3 grabbing non-integrin) recognize a wide range of micro-organisms. Both genes encode an extended neck-region consisting of tandemrepeats that support the carbohydrate recognition domain which plays a crucial role in influencing the pathogen-binding properties of these receptors. This neck-repeat region remains relatively constant size for DC-SIGN, but has considerable polymorphism for L-SIGN. Homo-oligomerization of this neck-region is important for high-affinity ligand binding. We have shown that heterozygous expression of L-SIGN in which neck lengths differ can affect ligand-binding affinity. By in-situ hybridization, we demonstrated that L-SIGN is expressed in lung in cytokeratin positive alveolar epithelia as well as a subset of cells co-expressing ACE2 but negative for cytokeratin. In-vitro experiments showed that L-SIGN binding to SARS-CoV leads to proteasomedependent viral degradation rather than productive viral replication. Compared with heterozygotes, cells homozygous for L-SIGN show higher binding capacity for SARSCoV, higher proteasome-dependent viral degradation and a lower capacity for trans infection. This was supported by genetic risk association study which showed that individuals homozygous for L-SIGN tandem-repeats are less susceptible to SARS infection. L-SIGN-positive, cytokeratin- and surfactant- negative SARS-infected cells also co-express stem/progenitor cell markers CD34 and Oct-4 which can also be identified in some non-SARS individuals and can be infected ex-vivo by SARS-CoV. Worldwide demographic data of the tandem-neck repeat region showing distinct differences in the neck-region allele and genotype distribution among different ethnic groups which support the neck-region as an excellent candidate acting as a functional target for selective pressures exerted by pathogens will be discussed.
Persistent Identifierhttp://hdl.handle.net/10722/104441

 

DC FieldValueLanguage
dc.contributor.authorKhoo, US-
dc.date.accessioned2010-09-25T21:53:13Z-
dc.date.available2010-09-25T21:53:13Z-
dc.date.issued2008-
dc.identifier.citationACGA-HKSMG International Conference on Genetic & Genomic Medicine, Hong Kong, 8-11 June 2008, p. Abstract no.S17-4-
dc.identifier.urihttp://hdl.handle.net/10722/104441-
dc.description.abstractIn the face of emerging epidemics, understanding variation in individual responses to pathogens takes on new importance. Two closely related trans-membrane C-type lectins DC-SIGN (dendritic cell-specific ICAM-3 grabbing non-integrin) and L-SIGN (liver/lymph node-specific ICAM-3 grabbing non-integrin) recognize a wide range of micro-organisms. Both genes encode an extended neck-region consisting of tandemrepeats that support the carbohydrate recognition domain which plays a crucial role in influencing the pathogen-binding properties of these receptors. This neck-repeat region remains relatively constant size for DC-SIGN, but has considerable polymorphism for L-SIGN. Homo-oligomerization of this neck-region is important for high-affinity ligand binding. We have shown that heterozygous expression of L-SIGN in which neck lengths differ can affect ligand-binding affinity. By in-situ hybridization, we demonstrated that L-SIGN is expressed in lung in cytokeratin positive alveolar epithelia as well as a subset of cells co-expressing ACE2 but negative for cytokeratin. In-vitro experiments showed that L-SIGN binding to SARS-CoV leads to proteasomedependent viral degradation rather than productive viral replication. Compared with heterozygotes, cells homozygous for L-SIGN show higher binding capacity for SARSCoV, higher proteasome-dependent viral degradation and a lower capacity for trans infection. This was supported by genetic risk association study which showed that individuals homozygous for L-SIGN tandem-repeats are less susceptible to SARS infection. L-SIGN-positive, cytokeratin- and surfactant- negative SARS-infected cells also co-express stem/progenitor cell markers CD34 and Oct-4 which can also be identified in some non-SARS individuals and can be infected ex-vivo by SARS-CoV. Worldwide demographic data of the tandem-neck repeat region showing distinct differences in the neck-region allele and genotype distribution among different ethnic groups which support the neck-region as an excellent candidate acting as a functional target for selective pressures exerted by pathogens will be discussed.-
dc.languageeng-
dc.publisherAssociation of Chinese Geneticists in America and the Hong Kong Society of Medical Genetics.-
dc.relation.ispartofACGA-HKSMG International Conference-
dc.titleHost Genetic Susceptibility to Emerging Infectious Diseases-
dc.typeConference_Paper-
dc.identifier.emailKhoo, US: uskhoo@pathology.hku.hk-
dc.identifier.authorityKhoo, US=rp00362-
dc.identifier.hkuros162971-
dc.identifier.spageAbstract no.S17-4-
dc.identifier.epageAbstract no.S17-4-
dc.publisher.placeHong Kong-

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