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. 2020 Jun 26;12(6):689.
doi: 10.3390/v12060689.

HHV-6 Infection and Chemokine RANTES Signaling Pathway Disturbance in Patients with Autoimmune Thyroiditis

Alina Sultanova  1 , Maksims Cistjakovs  1 , Liba Sokolovska  1 , Katerina Todorova  2 , Egils Cunskis  3 , Modra Murovska  1
Affiliations

HHV-6 Infection and Chemokine RANTES Signaling Pathway Disturbance in Patients with Autoimmune Thyroiditis

Alina Sultanova et al. Viruses. .

Abstract

The aim of this study was to investigate the role of human herpesvirus-6 (HHV-6) in autoimmune thyroiditis (AIT) development. We examined the possible involvement of HHV-6 gene expression encoding immunomodulating proteins U12 and U51 in AIT development and their role in the modulation of chemokine signaling. One hundred patients with autoimmune thyroiditis following thyroidectomy were enrolled in this study. Nested polymerase chain reaction (nPCR) was used to detect the HHV-6 sequence in DNA samples. Reverse transcription PCR (RT-PCR) with three different HHV-6 gene targets (U79/80, U51 and U12) was to detect active infection markers. HHV-6 load was identified using a commercial real-time PCR kit. Immunohistochemistry was performed to investigate the expression of the HHV-6 antigen and RANTES (Regulated upon Activation, Normal T Cell Expressed and Secreted) in thyroid gland tissue. Different commercial immunosorbent assay kits were used for the detection of RANTES, IFNγ, IL-6, and TNFα levels in the AIT patient group and controls. We detected 98% presence of the HHV-6 genomic sequence in AIT patients' thyroid gland tissues. Markers of active HHV-6 infection (HHV-6 U79/80, U12 and/or U51 mRNA) were predominant in AIT patients' thyroid tissue samples in comparison with the control group (56% vs. 6%). Evidence from immunofluorescence microscopy showed that HHV-6 can persist in thyrocytes and can interact with RANTES. Visual confirmation of the intense immunofluorescence signal of RANTES detected in thyroid tissues could indicate high expression of this chemokine in the thyroid gland. On the other hand, immunosorbent assays showed very low RANTES levels in AIT patients' peripheral plasma. These results indicate that RANTES level in AIT patients could be influenced by HHV-6 activation, which in turn may aid AIT development.

Keywords: HHV-6; RANTES; autoimmune thyroiditis; chemokine receptors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Distribution of HHV-6 U79/80 (encoding proteins involved in viral replication), U12 and U51 mRNAs (late and early genes, respectively, encoding viral homologs of cellular G-protein-coupled receptors) in AIT patients’ thyroid gland tissue samples. Results from nPCR investigations of viral gene expression using cDNA as a template.
Figure 2
Figure 2
Median HHV-6 load (error bars indicating IQR) detected in AIT patients’ thyroid gland Table 6. Load was indicated as log HHV-6 copies per 106 cells. HHV-6 U12 and U51 encode viral homologs of cellular G-protein-coupled receptors.
Figure 3
Figure 3
RANTES, IFNγ, IL-6, and TNFα median levels (error bars indicating IQR) in the plasma of AIT patient and blood donor groups. Chemokine (RANTES) and pro-inflammatory cytokine (IFNγ, IL-6 and TNFα) levels from SMIA investigations are expressed as pg/mL. IFNγ, IL-6 and TNFα were chosen as they participate in RANTES induction.
Figure 4
Figure 4
Fluorescent microscopy of thyroid gland tissue. Dyes: DAPI—nucleus; Alexa488—HHV-6 gp82/105 (closed tip arrows (bold)); Alexa647—RANTES (opened tip arrows (sharp)); TD—transmitted light. Channels Alexa488 and Alexa647 are shown in greyscale for better contrast. Row A—part of a thyroid lobule of a patient with Grave’s disease; Row B—limitrophe zone of two separate thyroid follicles of a patient with Grave’s disease; Row C—control patient’s (with adenoma) thyroid lobule; Row D—staining control (secondary antibodies and DAPI only).
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