Wild-Type Herpes Simplex Virus (HSV-1, MacIntyre)

Herpetic-related neuralgia (HN) caused by varicella-zoster virus (VZV) infection is one of the most typical and common neuropathic pain in clinic. Here, researchers used a mouse model of HN induced by herpes simplex virus type-1 (HSV-1) infection and screened differentially expressed genes (DEGs) in dorsal root ganglia (DRG) and spinal cord using RNA sequencing technology. After HSV-1 inoculation in mice, both DRG and spinal cord were infected with HSV-1, resulting in mechanical hyperalgesia, heat hyperalgesia, and cold hyperalgesia. HSV-1 inoculation induced upregulation of ATF3, CGRP, and GAL expression in DRG and activated astrocytes and microglia in the spinal cord. GO and KEGG enrichment analysis showed that after HSV-1 infection, DRG and spinal cord neurons of mice were involved in immune response and cytokine-cytokine receptor interaction. In addition, after HSV-1 infection in mice, CCL5 and its receptor CCR5 were significantly upregulated in DRG and spinal cord. Blocking CCR5 exhibited significant analgesic effects and inhibited the upregulation of inflammatory cytokines in the DRG and spinal cord of mice induced by HSV-1 infection. HSV-1 infection caused allodynia and hyperalgesia in mice through immune response dysregulation and cytokine-cytokine receptor interaction mechanisms. Blocking CCR5 may alleviate allodynia and hyperalgesia by inhibiting inflammatory cytokines. Therefore, CCR5 may serve as a therapeutic target for alleviating HN caused by HSV-1 infection.

To simulate human HN, HSV-1 was inoculated subcutaneously into the tibia of the right hind leg of mice using a microsyringe, as shown in Figure 1A. After virus inoculation, the mechanical threshold and paw withdrawal latency of mice in the HSV-1 group, HSV-1 inactivated inoculation group, and naive group were detected to heat and cold stimulation. Behavioral results showed that the mechanical threshold (ipsilateral) of mice to von Frey stimulation was significantly reduced 3 days after HSV-1 inoculation compared with the inactivated HSV-1 inoculation group and the naïve group, and reached the lowest value on the 7th day after inoculation. 7 days after HSV-1 inoculation, the mechanical threshold (ipsilateral) of mice gradually increased until 56 days after inoculation, but it was still significantly lower than that of mice in the HSV-1 inactivated group and the naive group (Figure 1B). In addition, the latency of paw withdrawal reaction was significantly shortened in mice inoculated with HSV-1 virus for 3 days, whether it was heat stimulation or cold stimulation, and reached the most sensitive state on the 7th day after inoculation. After that, the latency of the paw withdrawal reaction gradually returned to the baseline level until day 56 after inoculation (Figure 1C, D). These results suggest that mechanical hyperalgesia, thermal hyperalgesia, and cold hyperalgesia have already occurred in mice after HSV-1 inoculation.

Figure 1. The schematic of the experimental design and behavioral tests in mice after HSV‐1 inoculation. (Wu S, et al., 2023)