e Emergence of viruses into the human population by transmission from nonhuman primates (NHPs) represents a serious potential threat to human health that is primarily associated with the increased bushmeat trade. Transmission of RNA viruses across primate species appears to be relatively frequent. In contrast, DNA viruses appear to be largely host specific, suggesting low transmission potential. Herein, we use a primate predator-prey system to study the risk of herpesvirus transmission between different primate species in the wild. The system was comprised of western chimpanzees (Pan troglodytes verus) and their primary (western red colobus, Piliocolobus badius badius) and secondary (black-and-white colobus, Colobus polykomos) prey monkey species. NHP species were frequently observed to be coinfected with multiple beta-and gammaherpesviruses (including new cytomegalo-and rhadinoviruses). However, despite frequent exposure of chimpanzees to blood, organs, and bones of their herpesvirus-infected monkey prey, there was no evidence for cross-species herpesvirus transmission. These findings suggest that interspecies transmission of NHP beta-and gammaherpesviruses is, at most, a rare event in the wild. Z oonotic transmission of animal pathogens into the human population is regarded as the major source of new human infectious disease (1-3). Such zoonoses have profoundly altered the course of human history, as reflected by the impact of the bubonic plague, Spanish flu, and HIV/AIDS on human society (4-6). Zoonoses are frequently transmitted to humans following an initial cross-species transmission into an intermediate animal host. Mechanisms underlying cross-species transmission and adaptation to new host species are far from clear but appear to be influenced by multiple factors, including the level and mode of interaction between animal reservoir/transmission source and humans, the phylogenetic relationship of these species, and the nature of the zoonotic pathogen (2,7,8). Zoonotic/enzootic cross-species transmission appears to be a relatively common characteristic of RNA viruses (8). In contrast, the efficiency of cross-species transmission for DNA viruses is unclear. For the Herpesviridae family, transmission appears to be a relatively rare event. In the few instances where virus transmission has been observed, the lack of onward transmission and the uncharacteristically highly pathogenic presentation of overt disease in the new species (e.g., ovine/caprine herpesvirus infection in free-ranging cervids and herpesvirus B in humans) suggest that herpesviruses poorly adapt to their new host environment (9-11).To date, most studies examining cross-species transmission of herpesviruses have been based on phylogenetic analysis of genomic sequences. These studies reveal well-defined genotypic groupings of alpha-, beta-, and gammaherpesviruses within the respective herpesvirus subfamilies Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae (12). This phylogenetic distribution has been interpreted as coevolution (co...
Conflict of interest: MAN is an employee of Akari Therapeutics, which currently develops Coversin as novel therapeutic. MAN and CDS are both listed as inventors on a patent application for the use of Coversin in bullous pemphigoid (patent application number 1706404.9, United Kingdom).
Herpesviruses are thought to have evolved in very close association with their hosts. This is notably the case for cytomegaloviruses (CMVs; genus Cytomegalovirus) infecting primates, which exhibit a strong signal of co-divergence with their hosts. Some herpesviruses are however known to have crossed species barriers. Based on a limited sampling of CMV diversity in the hominine (African great ape and human) lineage, we hypothesized that chimpanzees and gorillas might have mutually exchanged CMVs in the past. Here, we performed a comprehensive molecular screening of all 9 African great ape species/subspecies, using 675 fecal samples collected from wild animals. We identified CMVs in eight species/subspecies, notably generating the first CMV sequences from bonobos. We used this extended dataset to test competing hypotheses with various degrees of co-divergence/number of host switches while simultaneously estimating the dates of these events in a Bayesian framework. The model best supported by the data involved the transmission of a gorilla CMV to the panine (chimpanzee and bonobo) lineage and the transmission of a panine CMV to the gorilla lineage prior to the divergence of chimpanzees and bonobos, more than 800,000 years ago. Panine CMVs then co-diverged with their hosts. These results add to a growing body of evidence suggesting that viruses with a double-stranded DNA genome (including other herpesviruses, adenoviruses, and papillomaviruses) often jumped between hominine lineages over the last few million years.
Cytomegaloviruses (CMVs) are known to infect many mammals, including a number of nonhuman primates (NHPs). However, most data available arose from studies led on captive individuals and little is known about CMV diversity in wild NHPs. Here, we analyzed a community of wild nonhuman primates (seven species) in Taï National Park (TNP), Côte d’Ivoire, with two PCR systems targeting betaherpesviruses. CMV DNA was detected in 17/87 primates (4/7 species). Six novel CMVs were identified in sooty mangabeys, Campbell’s monkeys and Diana monkeys, respectively. In 3/17 positive individuals (from three NHP species), different CMVs were co-detected. A major part of the glycoprotein B coding sequences of the novel viruses was amplified and sequenced, and phylogenetic analyses were performed that included three previously discovered CMVs of western red colobus from TNP and published CMVs from other NHP species and geographic locations. We find that, despite this locally intensified sampling, NHP CMVs from TNP are completely host-specific, pinpointing the absence or rarity of cross-species transmission. We also show that on longer timescales the evolution of CMVs is characterized by frequent co-divergence with their hosts, although other processes, including lineage duplication and host switching, also have to be invoked to fully explain their evolutionary relationships.
Murine gammaherpesvirus 68 (MHV68) is a small-animal model suitable for study of the human pathogens Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus. Here, we have characterized the roles of the endosomal Toll-like receptor (TLR) escort protein UNC93B, endosomal TLR7, -9, and -13, and cell surface TLR2 in MHV68 detection. We found that the alpha interferon (IFN-α) response of plasmacytoid dendritic cells (pDC) to MHV68 was reduced in Tlr9−/− cells compared to levels in wild type (WT) cells but not completely lost. Tlr7−/− pDC responded similarly to WT. However, we found that in Unc93b−/− pDC, as well as in Tlr7−/− Tlr9−/− double-knockout pDC, the IFN-α response to MHV68 was completely abolished. Thus, the only pattern recognition receptors contributing to the IFN-α response to MHV68 in pDC are TLR7 and TLR9, but the contribution of TLR7 is masked by the presence of TLR9. To address the role of UNC93B and TLR for MHV68 infection in vivo, we infected mice with MHV68. Lytic replication of MHV68 after intravenous infection was enhanced in the lungs, spleen, and liver of UNC93B-deficient mice, in the spleen of TLR9-deficient mice, and in the liver and spleen of Tlr7−/− Tlr9−/− mice. The absence of TLR2 or TLR13 did not affect lytic viral titers. We then compared reactivation of MHV68 from latently infected WT, Unc93b−/−, Tlr7−/− Tlr9−/−, Tlr7−/−, and Tlr9−/− splenocytes. We observed enhanced reactivation and latent viral loads, particularly from Tlr7−/− Tlr9−/− splenocytes compared to levels in the WT. Our data show that UNC93B-dependent TLR7 and TLR9 cooperate in and contribute to detection and control of MHV68 infection. IMPORTANCE The two human gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), can cause aggressive forms of cancer. These herpesviruses are strictly host specific, and therefore the homolog murine gammaherpesvirus 68 (MHV68) is a widely used model to obtain in vivo insights into the interaction between these two gammaherpesviruses and their host. Like EBV and KSHV, MHV68 establishes lifelong latency in B cells. The innate immune system serves as one of the first lines of host defense, with pattern recognition receptors such as the Toll-like receptors playing a crucial role in mounting a potent antiviral immune response to various pathogens. Here, we shed light on a yet unanticipated role of Toll-like receptor 7 in the recognition of MHV68 in a subset of immune cells called plasmacytoid dendritic cells, as well as on the control of this virus in its host.
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