The Primate Enteric Virome in Health and Disease
Despite significant advances in the diagnosis of infectious diseases, unrecognized or adventitious
agents in nonhuman primates (NHPs) have the potential to confound experimental work and cause
significant morbidity and mortality. One important limitation of current diagnostic endeavors is
that analysis of pathogens is standardly a one-pathogen one-test process for agents that are often
not readily culturable. These tests are expensive and do not reflect the diversity of known or
potential pathogens that are present in primates. Therefore, to perform comprehensive evaluation
of the infections of primates, standard classical methods need to be integrated with front line
genomic approaches. We have developed technologies that can readily, in a single test, detect
multiple novel viruses, other potential pathogens, and the structure of the microbiome in fecal
samples and intestinal tissues. This approach will benefit the management of research primates,
and enhance our basic understanding of how microbial pathogens and ecosystems impact health
and disease in this clinical important research animal.
The microbiome is increasingly accepted as a key determinant of health and disease, but the
concepts that the virome may play a role in normal physiology or in disease via non-standard
pathogenetic mechanisms are newer (1). These concepts are biologically important and may link
metagenomics to classical analysis of pathogenesis and diagnosis of disease. Our studies take
advantage of development of novel methods including a custom informatics pipeline for analyzing
metagenomic data. This pipeline has been refined for several years, optimizing both its sensitivity
and its computational efficiency.
These concepts and techniques have already proven useful for providing insights into novel, virally
induced pathogenic mechanisms during simian immunodeficiency virus (SIV) infection in NHPs
(1). Using sensitive metagenomic techniques and analysis we identified an association between the
enteric virome and disease progression. This association was only observed during progressive
infection in Macaques, but not during infection in African green monkeys. Importantly, no
association with the bacterial members of the microbiome were observable, suggesting this is a
virome dependent phenomenon. These studies have identified a large number of novel viruses in
NHPs and described unexpected adenovirus infection of the intestine as well as parvovirus
viremia.
The approaches used to complete the study described above are currently being adopted to
investigate the microbial associations with disease as SIV infection progresses in a detailed
longitudinal study. In addition, the effect of vaccination on the microbiome and virome is under
investigation. This is just one example of how full microbiome analysis and consideration of the
viral members of a complex microbial ecosystem can be applied. These approaches should be
amenable to the study of a variety of NHP models, particularly those with relevance to enteric
pathology.
(1) Norman JM, Handley SA, Virgin HW. Kingdom-agnostic metagenomics and the importance of
complete characterization of enteric microbial communities. Gastroenterology. 2014 May;
146(6):1459-69
(2) Handley SA, et al. Pathogenic simian immunodeficiency virus infection is associated with
expansion of the enteric virome. Cell. 2012. October 12; 151(2): 253-266.