Torre and colleagues used a

Torre and colleagues used a planarian experimental infection with as a model to study the properties of innate immune memory, with relevance for vertebrate immunity as well. In this model, infection of planarians with changes innate immune responses in an adaptive manner, resulting in an improved rate of pathogen clearance upon subsequent reinfection. Indeed planarians are renowned for their capacity to fight infection and remarkable regenerative abilities. In the pursuit of a mechanistic link between these processes, Torre et al. identified two important novel mechanisms central to the induction of trained immunity (or , as defined by the authors). First, the authors demonstrate the importance of a specific population of pluripotent stem nebivolol hcl cost called neoblasts for innate immune memory. Second, through a series of experiments using RNA interference, the researchers revealed that genes important for innate immunity confer sustained resistance to via a signaling cascade that is contingent on the Smed-setd8–1 lysine methyltransferase. These observations are significant for understanding responses during infection and vaccination in humans. One important aspect for which the study of Torre and colleagues is significant is for providing important clues on the physiological mechanisms mediating trained immunity in humans at the level of immune progenitor cells. The long-term protection conferred by vaccination with Bacillus Calmette–Guérin (BCG) far exceeds the lifespan of innate immune cells in the circulation (). The capacity to induce innate immune memory in pluripotent neoblasts in planarians advocates the possibility that innate immune cell precursors in vertebrates can also mount epigenetic and functional reprogramming and thus mediate innate immune memory. Indeed, myeloid cell progenitors have been demonstrated to mediate long-term TLR2-induced tolerance (), and a similar role may be expected for trained immunity. An important observation is also that Smed-setd8–1 in planarians is homologous to human SET8 (also known as KMT5A), indicating potential for a similar regulatory function in vertebrates. Studies exploring epigenetic changes associated with innate immune memory have focused predominantly on post-translational modifications of H3 histones. Torre et al. now provide the impetus to expand this search to the tails of H4 histones, which are methylated only at lysine 20. Methylation of H4 histones has previously been associated with transcriptional memory in diabetic rodents (), although the precise regulatory function of this modification remains controversial (). Importantly the addition of a single methyl group to H4 histones is associated with transcriptional activation (), and SET8 is the only enzyme known to write this modification (). To conclude, the elegant study by Torre et al. describes a system of acquired resistance in planarians that shares several important features with trained immunity in vertebrates. Infection with initiates a program of heightened defense against the same pathogen. It remains to be seen how closely this system mirrors the broad non-specific memory of trained immunity. Nevertheless, the central role of neoblasts and Smed-setd8–1 informs about potential new research paths in the search for epigenetic regulators of innate immune memory in vertebrates. Identification of these key factors will greatly accelerate the realization of novel therapeutic approaches to the treatment of infectious and auto-inflammatory diseases, as well as the improvement of vaccination programs (). Disclosure
Acknowledgements MGN was supported by an ERC Consolidator Grant (#310372) and a Spinoza grant of the Netherlands Organization for Scientific Research. NPR and MGN received funding from the European Union Horizon 2020 research and innovation program under grant agreement No 667837.
Zika virus (ZIKV) is a mosquito-borne flavivirus that was originally identified in 1947 from a sentinel Rhesus monkey in the Zika forest in Uganda (). Prior to 2007, ZIKV infections occurred periodically in Africa and Asia with mild, self-limiting febrile illnesses such as rash, headache, conjunctivitis, myalgia, and arthralgia. However, in the past decade, ZIKV became explosive in causing outbreaks and epidemics, first on Yap Island in the Federated States of Micronesia in 2007, second in French Polynesia in 2013, third in northeastern Brazil in late 2014, followed by a rapid spread to other countries in the Americas in 2015–2016, including autochthonous transmissions in Florida and Texas in the United States (). During the recent outbreaks and epidemics in Asian and the Americas, ZIKV infection has caused devastating severe diseases, particularly Guillain-Barre syndrome in adults and congenital malformations in fetus, among which congenital malformation is unique to ZIKV infection when compared with diseases caused by other flavivirus infections. Guillain-Barre syndrome is an autoimmune disease characterized by ascending paralysis and polyneuropathy that could occur during the acute or convalescent phases of ZIKV infection (). During pregnancy (especially in the first trimester), ZIKV infections of fetus have been associated with a variety of clinical manifestations, now collectively known as congenital Zika syndrome, including microcephaly, craniofacial disproportion, spasticity, seizures, ocular abnormalities, cerebral calcification, and miscarriage (). Moreover, the disease spectrum of congenital Zika syndrome is expected to grow as some of the infected babies with a normal head circumference may manifest new disease symptoms as they develop; clinical and epidemiological studies are ongoing to uncover the prognosis of these congenitally infected baby patients (). The molecular mechanisms of ZIKV-mediated Guillain-Barre syndrome and congenital malformations remain to be determined. One of the notable driving forces for the congenital Zika syndrome could be the neurotropic nature of ZIKV infection that preferentially targets cortical neural progenitor cells and, to a lesser extent, neuronal cells in other stages of maturity ().