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, Lorraine Jones-Brando, David D. Dunigan, Geetha Kannan, Faith Dickerson, Emily Severance, Sarven Sabunciyan, C. Conover Talbot Jr., Emese Prandovszky, James R. Gurnon, Irina V. Agarkova, Flora Leister, Kristin L. Gressitt, Ou Chen, Bryan Deuber, Fangrui Ma, Mikhail V. Pletnikov, and James L. Van Etten
PNAS November 11, 2014 111 (45) 16106-16111; first published October 27, 2014 https://doi.org/10.1073/pnas.1418895111

  1. Contributed by James L. Van Etten, October 3, 2014 (sent for review August 9, 2014; reviewed by Joram Feldon and Allan V. Kalueff)

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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.

Tables

  • Table 1.

    Association between ATCV-1 oropharyngeal DNA and performance on cognitive tests

    Cognitive TestATCV-1 DNA detected, n = 40ATCV-1 DNA not detected, n = 52Overall cohort, n = 93P value
    Trails A, scaled score38.2 (12.4)46.7 (11.7)43.0 (12.7)<0.002
    WAIS III, Information subtest, scaled score10.8 (2.7)10.8 (2.6)10.8 (2.6)NS
    RBANS
    Total Score81.3 (11.9)85.4 (11.5)83.6 (11.8)<0.014
    Attention Index91.4 (17.5)98.5 (14.5)95.4 (16.2)<0.011
    Delayed Memory Index85.2 (11.7)88.3 (9.9)87.0 (10.8)<0.039
    Immediate Memory Index85.8 (15.5)89.3 (14.5)87.8 (14.9)NS
    Visuospatial/Constructional Index72.6 (9.1)74.4 (10.6)73.6 (9.9)NS
    Language Index93.3 (17.0)94.8 (17.0)94.2 (16.9)NS

    • Values listed are means (standard deviations). P values calculated by linear regression adjusted for age, sex, race, educational level, maternal education, cigarette smoking, and place of birth. NS indicates P > 0.1.

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Virus ATCV-1, part of human oropharyngeal virome
Robert H. Yolken, Lorraine Jones-Brando, David D. Dunigan, Geetha Kannan, Faith Dickerson, Emily Severance, Sarven Sabunciyan, C. Conover Talbot, Emese Prandovszky, James R. Gurnon, Irina V. Agarkova, Flora Leister, Kristin L. Gressitt, Ou Chen, Bryan Deuber, Fangrui Ma, Mikhail V. Pletnikov, James L. Van Etten
Proceedings of the National Academy of Sciences Nov 2014, 111 (45) 16106-16111; DOI: 10.1073/pnas.1418895111
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