The 81st Annual Meeting of the American Association of Physical Anthropologists (2012)

Divergence of catarrhine toll–like receptor 4 predicted shape and electrostatics and the evolution of LPS–mediated sepsis resistance in old world monkeys


Department of Anthropology, Graduate Center, City University of New York, NYCEP, (New York Consortium in Evolutionary Primatology)

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Sepsis is a deleterious, systemic innate immune response to immune insult (i.e. pathogens, pathogen components). Despite high genetic similarity, some hominoids and cercopithecoids differ in susceptibility to gram-negative bacterial sepsis (i.e. Escherichia coli). Humans and chimpanzees are highly sensitive to E. coli and its cell wall component Lipopolysaccharride (LPS), requiring only small doses to initiate a severe acute inflammatory response. Baboons and macaques, however, are E.coli/LPS insensitive and require high doses to establish minimal symptoms. The Toll-like receptor-4/Lymphocyte antigen-96 (TLR4/LY96) complex detects LPS and can initiate profound cell activation associated with sepsis. To test if TLR4/LY96 structure and electrostatic potential has diverged in humans, chimpanzees, baboons and macaques, these proteins were comparatively modeled. Best models and known human and mouse structures were examined for charge, sidechain orientation, and shape differences. While LY96 shape and charge were conserved across species, the TLR4 LPS binding region showed significant inter-family differences in electrostatic potential. Baboon and macaque LPS-binding regions are strongly negatively charged, while human, chimpanzee and mouse LPS binding regions show a complex topography of uncharged and charged residues. These results suggest that baboon/macaque TLR4 evolved a weaker binding affinity to the negatively charged LPS than humans, chimpanzees and mouse. Additionally, an 11 amino acid deletion in the TLR4 intracellular signaling domain in baboon/macaques truncates the modeled domain and may affect cell activation. These results suggest that cercopithecoid TLR4 structure and charge have significantly diverged from that of other mammals and may affect LPS binding, cell activation and susceptibility to sepsis.

Supported by NSF 0333415 (NYCEP IGERT), NSF # 0752297

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