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Primate-associated phage communities

By Jan F. Gogarten, Image of grooming chimpanzees in Taï National Park by Roman Wittig and the Taï Chimpanzee Project

We live in a world dominated by viruses; those causing disease in humans are painfully familiar to us, but little is known about most viruses harbored within a person, what scientists refer to as ‘viral dark matter’. The majority of these human-associated viruses are actually phages that infect bacteria in the gut. To determine the origins of the phage communities in the human gut, we set out to describe the phages of our closest living relatives, non-human primates. This comparative study published in PNAS examined the gut phages in 23 wild primate species living in very different ecosystems across the globe, as well as from humans living in Europe and Africa.

Figure 1: Map indicating locations where samples from superhost taxa included in the current study originated. Black circles indicate samples that were collected and sequenced as part of the current study, while white circles indicate superhost samples that were sequenced by others previously.

Surprisingly, we found relatives of most human associated phages in wild primates! When we then looked at the evolutionary relationships of these phage lineages, they found that for many, the relationships of phages were a near mirror image of the evolutionary history of the primates. This pattern of co-divergence suggests that some phages maintained an association with specific primate lineages over millions of years. We sometimes observe patterns of co-divergence between primates and the viruses that infect them, demonstrating that some viruses maintain a close relationship with their hosts over evolutionary timescales. But phages infect bacteria, not primate cells, and we were rather surprised to find that some phages also showed such a pattern.

Figure 2: Wild non-human primate and human phageomes. A) A phylogeny of the wild primate taxa examined in this study. Scale in millions of years. B) An ordination of phage community composition for these species (non-metric multidimensional scaling: NMDS, Sørensen’s dissimilarity, stress=0.182), with each point representing the phage community detected in an individual; colors correspond to the primate superhost species in A. C) The same NMDS plot of phage community composition, now colored by the superhost's family, as indicated in A. D) A phage phylogeny demonstrating evidence for host-specificity (i.e., within superhost species distances were significantly lower than between superhost species distances; categorical Mantel: P=0.001). This phage phylogeny also shows evidence consistent with co-divergence between superhosts and the phage (i.e., all of the 1000 ParaFit tests after downsampling to one representative sequence per superhost taxa were significant). The * indicates the reference HHAP sequence generated in: (16). Branches supported by Shimodaira-Hasegawa-like approximate likelihood ratio test values <0.95 are dashed.

We then set out to determine how such long-term associations between primates and their phages are maintained. We found that neighboring social groups of baboons harbored unique phage communities, with close grooming partners having more similar phage communities, even after controlling for similarities in the baboon’s bacterial communities and the genetic relationship of the baboons. This study really highlights the importance of long-term observational studies of wild primates, like the Amboseli Baboon Research Project, to answer questions that are actually quite difficult to address in humans. These baboon groups have been followed for decades and we know their genealogy and their grooming partners, with scientists frequently collecting fecal samples. Such a resolution of data simply does not exist for human populations. These findings certainly suggest that human social relationships might also influence phage transmission, but proving this will require more research.

Figure 3: Within-species phage ecology and evolution. A) The social networks of two neighboring social groups of baboons (orange = Mica, purple = Viola). Circles represent individuals (individual ID shown within circle) and thickness and color of lines indicate the strength of the grooming relationships between individuals. B) An ordination of phage community composition (NMDS, Sørensen’s dissimilarity, stress=0.153), with each point representing the phage community from a fecal sample (colors correspond to groups as shown in A). C) Box plots showing the relationship between pairwise grooming bond strength and pairwise Sørensen’s dissimilarity in phage community composition in the social groups. Raw data are plotted to aid in interpretation. D) Baboon phage phylogenies; the left is an example where pairwise distance between phages from group members is lower than between non-group members (categorical Mantel: P=0.001). On the right, an example where there is no difference between the pairwise distances of phages from groupmates and non-groupmates (categorical Mantel: P=0.456). Branches supported by Shimodaira-Hasegawa-like approximate likelihood ratio test values <0.95 are dashed. E) The relationship between phageome community composition and bacterial community composition in these social groups. The dashed lines show the line of equality and the solid colored line represents the fit of a linear model to aid in interpretation of the relationship; significance was assessed with Mantel tests, not these linear models (Mica's group: Z=33.15, P=0.003; Viola’s group, Z=62.86, P=0.001).

The team set out to understand how flexible the association of primates and their phages are by studying the phages of primates in zoos, as well as the phages of their zookeepers. Captive primates lost the phages they normally harbor in the wild, with those phages all replaced by human-associated ones. Considering that wild primates seem to have maintained their phages over millions of years of evolutionary history, we were really surprised to find that great apes that have only lived in captivity for a generation or two, have completely lost these phage lineages via replaced by human-associated ones.

Figure 4: Captive primate phageomes. A) An ordination of great ape phage community composition (NMDS, Sørensen’s dissimilarity, stress=0.195) colored by their origin. B) Box plots showing the dissimilarity of great ape phageome community composition to that of zookeepers. The phageomes of wild and captive samples from a species are compared separately, following the coloring scheme in A. C) The percent identity of phages from wild great apes, captive great ape, and humans, compared to the HHAP, following the coloring scheme in A. D) An example phage phylogeny suggestive of human to captive great ape phage transmission (captive great apes are nested within the branch containing all humans instead of the branch containing all wild great apes): colors are indicative of the categories indicated in A, the * indicates the reference HHAP, and branches supported by SH-like aLRT values <0.95 are dashed. E) The relationship between bacterial community composition and phage community composition for the location categories indicated in A. The dashed lines show the lines of equality. The solid colored lines represents the fit of linear models to aid in interpretation of the relationship; significance was assessed with Mantel tests not these linear models (African humans, Z=132.06, P=0.001; captive great apes, Z=488.74, P=0.001; European humans, Z=105.66, P=0.001; wild great apes, Z=2774.68, P=0.001). For zookeepers, we did not detect a significant relationship (Z=2.29, P=0.135), though the relationship was in the expected direction and sample size was small (N=4).

This study provides insights into the evolutionary and ecological origins of our associated ‘viral dark matter’ and opens up exciting avenues of research. It suggests phages can serve as a marker of microbial transmission at the human wildlife interface, providing a much-needed tool to identify high-risk areas for pathogen transmission. The part of this study focusing on captive great apes highlights that between species transmission of phages is feasible – now we need to understand whether and where it occurs in the wild and what impact these phages have on primate and human health.

This study was an international collaborative effort with scientists in Germany working at the Robert Koch Institute, Christian-Albrecht-University of Kiel, the Max Planck Institute for Evolutionary Biology, and the Max Planck Institute for Evolutionary Anthropology, as well as colleagues from the University of Neuchatel in Switzerland, the Université Alassane Ouattara de Bouake in the Côte d’Ivoire, the National Institute for Biomedical Research in the Democratic Republic of the Congo, and the University of Notre Dame, Duke University, and Harvard University in the USA, and many organizations working with long-term primates in the field. Thanks to all these wonderful collaborators.

Original publication: Gogarten, J. F., Rühlemann, M., Archie, E., Tung, J., Akoua-Koffi, C., Bang, C., Deschner, T., Muyembe-Tamfun, J.-J., Robbins, M. M., Schubert, G., Surbeck, M., Wittig, R. M., Zuberbühler, K., Baines, J. F., Franke, A., Leendertz, F. H., and Calvignac-Spencer, S., Primate phageomes are structured by superhost phylogeny and environment. Proceedings of the National Academy of Sciences of the United States of America. doi: 10.1073/pnas.2013535118/

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