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Contributed by James L. Van Etten, October 3, 2014 (sent for review August 9, 2014; reviewed by Joram Feldon and Allan V. Kalueff)
Significance
Human mucosal surfaces contain a wide range of microorganisms. The biological effects of these organisms are largely unknown. Large-scale metagenomic sequencing is emerging as a method to identify novel microbes. Unexpectedly, we identified DNA sequences homologous to virus ATCV-1, an algal virus not previously known to infect humans, in oropharyngeal samples obtained from healthy adults. The presence of ATCV-1 was associated with a modest but measurable decrease in cognitive functioning. A relationship between ATCV-1 and cognitive functioning was confirmed in a mouse model, which also indicated that exposure to ATCV-1 resulted in changes in gene expression within the brain. Our study indicates that viruses in the environment not thought to infect humans can have biological effects.
Abstract
Chloroviruses (family Phycodnaviridae) are large DNA viruses known to infect certain eukaryotic green algae and have not been previously shown to infect humans or to be part of the human virome. We unexpectedly found sequences homologous to the chlorovirus Acanthocystis turfacea chlorella virus 1 (ATCV-1) in a metagenomic analysis of DNA extracted from human oropharyngeal samples. These samples were obtained by throat swabs of adults without a psychiatric disorder or serious physical illness who were participating in a study that included measures of cognitive functioning. The presence of ATCV-1 DNA was confirmed by quantitative PCR with ATCV-1 DNA being documented in oropharyngeal samples obtained from 40 (43.5%) of 92 individuals. The presence of ATCV-1 DNA was not associated with demographic variables but was associated with a modest but statistically significant decrease in the performance on cognitive assessments of visual processing and visual motor speed. We further explored the effects of ATCV-1 in a mouse model. The inoculation of ATCV-1 into the intestinal tract of 9–11-wk-old mice resulted in a subsequent decrease in performance in several cognitive domains, including ones involving recognition memory and sensory-motor gating. ATCV-1 exposure in mice also resulted in the altered expression of genes within the hippocampus. These genes comprised pathways related to synaptic plasticity, learning, memory formation, and the immune response to viral exposure.
Footnotes
- ↵1To whom correspondence may be addressed. Email: jvanetten1{at}unl.edu or rhyolken{at}gmail.com.
Author contributions: R.H.Y., L.J.-B., M.V.P., and J.L.V.E. designed research; L.J.-B., G.K., F.D., E.S., S.S., J.R.G., I.V.A., F.L., K.L.G., O.C., B.D., and M.V.P. performed research; R.H.Y. and L.J.-B. supervised the overall performance of the analyses; D.D.D. and F.M. mapped the virus genes; G.K. performed the animal infection and behavior experiments; F.D. supervised the collection of the human samples; E.S. supervised the processing of the human samples and the measurement of the antibodies in the mouse samples; S.S. supervised the experiments related to high throughput sequencing; C.C.T. and E.P. performed the analysis of gene expression; J.R.G. tested for infectious virus and produced the virus; I.V.A. tested for infectious virus; F.L. performed the experiments related to viral DNA detection; K.L.G. performed the antibody measurement studies; O.C. performed the experiments related to high throughput sequencing; B.D. produced the virus; M.V.P. supervised the animal infection and behavior experiments; D.D.D., C.C.T., E.P., and F.M. analyzed data; and R.H.Y., L.J.-B., D.D.D., M.V.P., and J.L.V.E. wrote the paper.
Reviewers: J.F., The Swiss Federal Institute of Technology; and A.V.K., Tulane University.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1418895111/-/DCSupplemental.
Virus ATCV-1, part of human oropharyngeal virome
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