Functional Comparison of Innate Immune Signaling Pathways in Primates

Luis B Barreiro,Yoav Gilad,Matthew Stephens,Ran Blekhman,John C Marioni,Greg Gibson

doi:10.1371/journal.pgen.1001249

Abstract

Humans respond differently than other primates to a large number of infections. Differences in susceptibility to infectious agents between humans and other primates are probably due to inter-species differences in immune response to infection. Consistent with that notion, genes involved in immunity-related processes are strongly enriched among recent targets of positive selection in primates, suggesting that immune responses evolve rapidly, yet providing only indirect evidence for possible inter-species functional differences. To directly compare immune responses among primates, we stimulated primary monocytes from humans, chimpanzees, and rhesus macaques with lipopolysaccharide (LPS) and studied the ensuing time-course regulatory responses. We find that, while the universal Toll-like receptor response is mostly conserved across primates, the regulatory response associated with viral infections is often lineage-specific, probably reflecting rapid host–virus mutual adaptation cycles. Additionally, human-specific immune responses are enriched for genes involved in apoptosis, as well as for genes associated with cancer and with susceptibility to infectious diseases or immune-related disorders. Finally, we find that chimpanzee-specific immune signaling pathways are enriched for HIV–interacting genes. Put together, our observations lend strong support to the notion that lineage-specific immune responses may help explain known inter-species differences in susceptibility to infectious diseases.

Highlights

Due to our natural focus on humans, we know of a large number of diseases or medical conditions that affect humans more severely than non-human primates
We know of a large number of diseases or medical conditions that affect humans more severely than nonhuman primates, such as AIDS, malaria, hepatitis B, and cancer
We present the first genome-wide characterization of functional differences in innate immune responses between humans and our closest evolutionary relatives

Summary

Introduction

Due to our natural focus on humans, we know of a large number of diseases or medical conditions that affect humans more severely than non-human primates. While very little comparative functional data in primates has been collected, recent genomic scans for signatures of natural selection have reported that genes involved in immunity processes are strongly enriched among targets of positive section in human and chimpanzee [3,4,5,6,7,8,9,10,11]. Immune responses are typically classified as either ‘innate’ or ‘adaptive.’ Historically, the focus of most immunological studies has been on the adaptive response and its hallmarks, namely the generation of a large repertoire of antigen-recognizing receptors and immunological memory. Innate immune responses were shown to play a pivotal role in the development of pathogen-specific humoral and cellular adaptive immune responses, which are mediated by B and T cells [16,17,18]

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