Chlorovirus ATCV-1 is part of the human oropharyngeal virome and is associated with changes in cognitive functions in humans and mice - PubMed (original) (raw)

Clinical Trial

. 2014 Nov 11;111(45):16106-11.

doi: 10.1073/pnas.1418895111. Epub 2014 Oct 27.

Lorraine Jones-Brando 2, David D Dunigan 3, Geetha Kannan 4, Faith Dickerson 5, Emily Severance 2, Sarven Sabunciyan 2, C Conover Talbot Jr 6, Emese Prandovszky 2, James R Gurnon 3, Irina V Agarkova 3, Flora Leister 2, Kristin L Gressitt 2, Ou Chen 2, Bryan Deuber 2, Fangrui Ma 3, Mikhail V Pletnikov 4, James L Van Etten 7

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Clinical Trial

Chlorovirus ATCV-1 is part of the human oropharyngeal virome and is associated with changes in cognitive functions in humans and mice

Robert H Yolken et al. Proc Natl Acad Sci U S A. 2014.

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.

Keywords: chlorovirus ATCV-1; cognitive functioning; infection; metagenomic sequencing; oropharyngeal virome.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Chlorovirus ATCV-1 genome showing the gene block distributions [blue arrows, protein coding sequence (CDS); red arrows, tRNAs] on each strand of the genome. Histograms in black indicate the G+C distribution along the genome; colored histograms (green, magenta) indicate the GC skew of the genome. The most inner circle indicates the genome map position with the start position at “12 o’clock.” The viral genome is a linear dsDNA, but is represented here as a circle for convenience of presentation. Control throat swab deep sequencing consensus sequence reads are matched to ATCV-1, and two experiments (17 and 16 individuals per experiment) are represented by the black lines connecting the gene blocks. BLAST hits, 61; Query, ATCV-1; Subject, human throat swab chlorovirus consensus sequence reads (52).

Fig. 2.

Fig. 2.

Odds of detecting ATCV-1 in the pharynx by percentile of score on cognitive testing. Bars represent the mean and 95% confidence interval odds of detecting ATCV-1 DNA in the oropharynx in individuals with the indicated test. The odds ratios are adjusted for the demographic variables of age, sex, race, maternal education, educational status, and place of birth in the United States. Trails A and Information are separate tests and not part of the RBANS. **P < 0.005, *P < 0.01, adjusted for the same covariates.

Fig. 3.

Fig. 3.

Behavioral effects of oral ATCV-1 exposure. Mice were orally infected with C. heliozoae alone (open bars) or with ATCV-1–infected C. heliozoae (solid bars) as described in the text. (A) Spatial recognition memory; the y axis displays the percentage of the previously blocked (i.e., novel) arm entries; *P = 0.015 measured by one-way ANOVA. (B) Novel object recognition; the y axis depicts the percentage of time spent exploring the novel object; *P < 0.001 measured by one-way ANOVA. (C) Place recognition memory recognition; the y axis depicts the percentage of time spent exploring the new location of the familiar object; *P < 0.008 measured by one-way ANOVA. (D) Impaired PPI; mice were exposed to presentation of pulse alone (120 dB) and prepulse–pulse combinations across different prepulse intensities; for example, p4 indicates pairing of the prepulse (4 dB above the background noise of 70 dB) with the pulse alone (120 dB) (see the text for more details); the y axis displays the percentage of PPI. (E) Impaired average PPI; the y axis displays the percentage of PPI; *P < 0.015 measured by post hoc test.

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