Abstract
Zoonotic infections are an imminent threat to human health. Pangolins were recently identified as carriers and intermediate hosts of coronaviruses. Previous research has shown that infection with coronaviruses activates an innate immune response upon sensing of viral RNA by interferon-induced with helicase C domain 1 (IFIH1), also known as MDA5. Here, we performed a comparative genomics study of RNA sensor genes in three species of pangolins. DDX58/RIG-I, a sensor of cytoplasmic viral RNA and toll-like receptors (TLR) 3, 7, and 8, which bind RNA in endosomes, are conserved in pangolins. By contrast, IFIH1 a sensor of intracellular double-stranded RNA, has been inactivated by mutations in pangolins. Likewise, Z-DNA-binding protein (ZBP1), which senses both Z-DNA and Z-RNA, has been lost during the evolution of pangolins. These results suggest that the innate immune response to viruses differs significantly between pangolins and other mammals, including humans. We put forward the hypothesis that loss of IFIH1 and ZBP1 provided an evolutionary advantage by reducing inflammation-induced damage to host tissues and thereby contributed to a switch from resistance to tolerance of viral infections in pangolins.
Highlights
Emerging infectious diseases represent a major challenge to public health
ZBP1 binds to left-handed double helix structures of DNA and RNA (Z-DNA and Z-RNA) and thereupon triggers necroptosis and inflammation through interactions with receptor-interacting serine/threonine-protein kinase 3 (RIPK3) [36]
Based on the known target specificities of mammalian RNA sensors (Figure 3B), the loss of ZBP1 and interferon-induced with helicase C domain 1 (IFIH1) suggests that the response to Z-RNA and long double-stranded RNA is diminished in pangolins
Summary
Emerging infectious diseases represent a major challenge to public health. The transmission of pathogens from other vertebrate animals to humans is of particular concern because the resulting diseases, known as zoonoses, have caused major epidemics in the past and continue to pose enormous threats to the human population, as exemplified by the recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak [1, 2]. To cope with viral infections, vertebrate species have evolved response strategies which can be classified into resistance and tolerance [3]. Resistance depends on the efficient sensing of the infection and mounting of antiviral responses that involve programmed death of infected cells, suppression of viral replication, inflammation and the establishment of adaptive immunity. Species that tolerate infections can carry a high burden of infectious agents, and may be important reservoirs for transmissions to other species. This notion is supported by the finding that bats tolerate many viral infections some of which have spread to humans causing zoonoses such as Ebola, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) [7]
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