Host genetic susceptibility to emerging infectious diseases

Abstract

In 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.