A placenta as we know now is a relatively new invention in mammals. Data accumulated indicates that a major cell type of the placenta is trophoblast, in which elevated expression of genes derived from various endogenous retroviruses (ERVs) as well as LTR retrotransposons is seen. However, evolutionally significance of ERV expression in placental development has not been well characterized or sorted out. In this review, we describe diversity of placental structures among mammalian species, of which morphological and cells types are far more diverse than those expected from the lines of mammalian orders. We then describe paternally expressed gene 10 (Peg10/Sirh1) and Peg11/Sirh2 as ERVs associated with ancient placenta development, followed by env-related genes such as Syncytin-1, -2, -A, -B, -Rum1, and Fematrin-1 responsible for trophoblast cells fusion, resulting in multinucleate syncytiotrophoblast formation. Because the endogenization of retroviral infections has occurred multiple times in different mammalian lineages, and some of them use similar molecules in their transcriptional activation, we speculate that ERV gene variants integrated into mammalian genomes in a locus specific manner have replaced the genes previously responsible for cell fusion. The role of cell fusion achieved by multiple successive ERV integrations is now called ''baton pass'' hypothesis, possibly resulting in increased trophoblast cell fusion, morphological diversity in placental structures, and survivability of fetuses and/or reproductive advantage in placental mammals.
In the human genome, there are approximately 30 LTR retrotransposon-derived genes, such as the sushi-ichi retrotransposon homologues (SIRH) and the paraneoplastic Ma antigen (PNMA) family genes. They are derivatives from the original LTR retrotransposons and each gene seems to have its own unique function. PEG10/SIRH1 as well as PEG11/RTL1/SIRH2 and SIRH7/LDOC1 play essential roles in placenta formation, maintenance of fetal capillaries and the differentiation/maturation of a variety of placental cells, respectively. All of this evidence provides strong support for their contribution to the evolution of viviparity in mammals via their eutherian-specific functions. SIRH11/ZCCHC16 is an X-linked gene that encodes a CCHC type of zinc-finger protein that exhibits high sequence identity to the LTR retrotransposon Gag protein and its deletion causes abnormal behavior related to cognition, including attention, impulsivity and working memory, possibly via the locus coeruleus noradrenaergic system in mice. Therefore, we have suggested that the acquisition of SIRH11/ZCCHC16 was involved in eutherian brain evolution. Interestingly, SIRH11/ZCCHC16 displays lineage-specific structural and putative species-specific functional variations in eutherians, suggesting that it contributed to the diversification of eutherians via increasing evolutionary fitness by these changes.
RD-114 virus is a feline endogenous retrovirus (ERV) isolated from human rhabdomyosarcoma in 1971 and classified as endogenous gammaretrovirus in domestic cats (Felis catus). Based on the previous reports in 70's, it has been considered that a horizontal, infectious event occurred to transfer the virus from ancient baboon species to ancient cat species, whereupon it became endogenous in the cat species about several million years ago in Mediterranean Basin. Although it has been believed that all domestic cats harbor infectious RD-114 provirus in their genome, we revealed that cats do not have infectious RD-114 viral loci, but infectious RD-114 virus is resurrected by recombination between uninfectious RD-114 virus-related ERVs [here we designated them as RD-114-related sequences (RDRSs)]. Further, we also revealed the RDRSs which would potentially be resurrected as RD-114 virus (here we refer to them as ''new'' RDRSs) had entered the genome of the domestic cat after domestication of the cat around 10 thousand years ago. The fractions and positions of RDRSs in the cat genome differed in Western and Eastern cat populations and cat breeds. Our study revealed that RDRS would be a useful tool for elucidating the world travel routes of domestic cats after domestication.
The first terrestrial vertebrates emerged from water and adapted to living on land approximately 360 million years ago (late Devonian). In particular, amphibians are thought to have surface epithelia that changed from multilayered epithelia into keratinized stratified squamous epithelia by acquiring stratum corneum (SC), which is composed of several dead cell layers that serve as an air liquid interface barrier. Then, reptiles appeared and became a major terrestrial vertebrate group approximately 340 million years ago by forming hard SC. About 220 million years ago, mammals radiated by acquiring soft and moisturized SC, and endogenous retroviruses were thought to be actively integrated into mammalian genomes. Skin ASpartic Protease (SASPase)/ASPRV1 is the mammalian-specific endogenous retroviral-derived protease. SASPase-deficient mice had dry skin and aberrant accumulation of profilaggrin, which is another mammalian-specific gene that regulates SC barrier function and is a major predisposing factor for atopic dermatitis. These findings indicate that the retroviral element SASPase was integrated into the first mammalian species and was involved in the adaptive evolution of mammals, as it facilitates moisturization of skin SC. It is possible that other uncharacterized endogenous retroviruses were also involved in epidermal barrier function.
Endogenous bornavirus-like elements (EBLs) are ancient bornavirus-derived sequence in the genomes of eukaryotes. Expression profile of EBLs suggests that, although most of the EBLs in mammalian genomes have lost their coding potential, many of them are transcribed in a cell-type specific or ubiquitous manner. This observation leads us to speculate that EBLs may have functions in their host cells. Here we describe possible functions of EBLs and their evolutionary significance. Our recent studies revealed that EBLs in some mammals, including humans, play critical roles in viral infection as either RNAs or proteins in previously undescribed mechanisms. Considering that species having EBLs in their genomes appear to be relatively resistance to BDV-mediated pathogenesis, endogenization of RNA viruses might be an evolutionarily inevitable event in the adaptation of hosts to the viruses.
Special Issue: Summary of Battle against Ebola Hemorrhagic Fever
While ebola virus disease (EVD) outbreak in West Africa seemed to be subsided, there are still some sporadic cases reported from the field. Many studies were conducted during the outbreak. It was identified that the virus can survive for a long period in certain areas of the survivors and they can be a reservoir. But the mechanism is still unknown. Currently no specific drug for EVD is established and classic supportive therapy was the mainstay of the treatment. A new ebola vaccine candidates appear to be highly effective for post-exposure prophylaxis. Rapid diagnostic tests are under development. In West Africa, Ebola response and recovery efforts to achieve and to sustain a "resilient zero" are ongoing. The situation in the communities is stabilized but ebola survivors are still suffering both from stigma and sequelae. EVD outbreak damaged affected countries' health, economic and education systems. The risk of re-outbreak is still remained. It is important to strengthen comprehensive public health system to prevent the future emerging disease outbreaks.
Since December 2013, West Africa has experienced the worst Ebola virus outbreak in recorded history. Of the 28,639 cases reported to the World Health Organization as of March 2016, nearly half (14,124) occurred in Sierra Leone. With a case fatality rate of approximately 40%, this outbreak has claimed the lives of 11,316 individuals. No FDA-approved vaccines or drugs are available to prevent or treat Ebola virus infection. Experimental vaccines and therapies are being developed; however, their safety and efficacy are still being evaluated. Therefore, there is an urgent need to develop control measures to prevent or limit future Ebola virus outbreaks. Previously, we developed a replication-defective Ebola virus that lacks the coding region for the essential viral transcription activator VP30 (Ebola ΔVP30 virus). Here, we evaluated the vaccine efficacy of Ebola ΔVP30 virus in a non-human primate model and describe our collaborative Ebola project in Sierra Leone.
Ebolaviruses, members of the family Filoviridae, cause severe hemorrhagic fever in humans and nonhuman primates, with human case fatality rates of up to 90%. No effective prophylaxis or treatment for Ebola virus disease (EVD) is yet commercially available. During the latest outbreak of EVD in West Africa, several unapproved drugs were used for the treatment of patients. This outbreak has indeed accelerated efforts to develop antiviral strategies and some of the vaccine and drug candidates have undergone clinical trials. This article reviews previous researches and recent advances on the development of vaccine, therapeutics, and diagnostics for EVD.
Herpes simplex virus type-1 (HSV-1) causes a range of human diseases, from mild uncomplicated mucocutaneous infection to life-threatening ones. The Us3 gene of HSV-1 encodes a serine/threonine protein kinase that is highly conserved among alphaherpesviruses. Accumulating evidence suggests that Us3 is a critical regulator of HSV-1 infection; however, the molecular mechanism by which Us3 regulates HSV-1 pathogenicity remains to be elucidated. This article presents a brief summary of the present knowledge on the roles of HSV-1 Us3, with a special focus on its relevancy in vivo.
Human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS, is a human-speci珣 virus. Because HIV-1 cannot infect and cause disorders in other animals, it has been an arduous struggle to investigate the dynamics of HIV-1 infection in vivo. In order to understand and elucidate HIV-1 pathogenesis in vivo, we have established a human hematopoietic stem cell-transplanted "humanized" mouse model, which has the potential to maintain human hematopoiesis including human CD4-positive leukocytes under a physiological condition. In HIV-1-infected humanized mice, we reproduced HIV-1 pathogenesis including the gradual decline of peripheral CD4-positive T cells and immune activation. HIV-1 encodes four "accessory" genes, Vif, Vpu, Vpr, and Nef. It is known that these accessory genes are occasionally crucial for viral replication in in vitro cell culture system. However, since there were no adequate animal models for HIV-1 infection, the roles of these HIV-1 accessory genes in viral infection, replication, and pathogenesis in vivo remain unclear. By utilizing humanized mouse model and a series of mutated HIV-1, we have revealed that these viral accessory proteins potently promote viral replication by antagonizing/degrading anti-viral cellular proteins or exploiting a unique subset of human CD4-positive T cells. In this paper, I introduce the findings in HIV-1-infected humanized mouse model particularly focusing on the roles of HIV-1 accessory proteins in viral replication in vivo.
Influenza A virus (IAV) recognizes terminal sialic acid of sialoglyco-conjugates on host cells through the viral envelope glycoprotein hemagglutinin (HA), followed by initiation of entry into the cells. Molecular species of sialic acid are largely divided into two moieties: N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc). A receptor for IAV infection generally means Neu5Ac. Almost all equine IAVs and some human, swine, and duck IAVs bind not only to Neu5Ac but also to Neu5Gc. In nonhuman animals, Neu5Gc has been detected in swine and equine tracheas and the duck colon, which are the main replication sites of mammalian and avian IAVs. Therefore, Neu5Gc in these sites has been suggested to be a functional receptor for IAV infection. Humans cannot synthesize Neu5Gc due to a genetic defect of the Neu5Gc-synthesizing enzyme. We evaluated the receptor function of Neu5Gc in IAV infection in human cells. Our results indicated that Neu5Gc expression on the surface of human cells is not a functional receptor for IAV infection and that it has a negative effect on infectivity of IAV possessing Neu5Gc binding ability. IAV also binds to non-sialo 3-O-sulfated galactosylceramide (sulfatide). Sulfatide has been suggested to be a functional receptor for IAV infection. However, we have shown that sulfatide is not a functional receptor for IAV infection and that the binding of HA with sulfatide enhances progeny virus production. It is expected that functions of these glyco-molecules can be used in prevention and development of new drugs against IAV.
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