Phylogenetic Distribution of CMP-Neu5Ac Hydroxylase (CMAH), the Enzyme Synthetizing the Proinflammatory Human Xenoantigen Neu5Gc

Peri, Sateesh; Kulkarni, Asmita; Feyertag, Felix; Berninsone, Patricia M; Alvarez-Ponce, David

Loss of Neu5Gc triggered a cascade of changes in the sialic acid biology of humans, with several evolutionary and biomedical consequences (for review, see Okerblom and Varki 2017) . The animals lacking a functional CMAH gene identified in this study may have undergone similar changes, making them ideal model organisms for the study of human sialic acid biology and its related diseases. For instance, the altered sialic acid profile of humans makes us susceptible to pathogens using Neu5Ac for binding and recognition of the host, including P. falciparum (Martin et al. 2005) , S. pneumoniae (Hentrich et al. 2016) , and Influenza type A virus (Rogers and Paulson 1983) . Ferrets, which lack a functional CMAH gene (Ng et al. 2014) , are used as model organisms to study the transmission mechanisms of human-adapted influenza-A virus strains (Ng et al. 2014) . Likewise, New World monkeys, which also lack a functional CMAH gene, have been proposed as model organisms for the study of the effects of anti-Neu5Gc antibodies in xenotransplantation (Salama et al. 2015) . In addition, species lacking a functional CMAH gene are potential reservoirs for Neu5Ac-binding human pathogens (Chothe et al. 2017) . For instance, bats are asymptomatic hosts to viruses like Hantaviruses (Guo et al. 2013) , which might lack the antigenic Neu5Gc on their viral envelopes. Our study very significantly expands the list of animals with these characteristics.