ILK is an enhancing factor for HSV-1 infection.

Front. Cell. Infect. Microbiol. (2022) 12:814307. https://doi.org/10.3389/fcimb.2022.814307

Integrin-linked kinase (ILK) has been shown to facilitate several virus infections, although the mechanism remains to be elucidated. Our current study showed that ILK knockdown increased the binding of TRIM28 and SUV39H1 on HSV-1 DNA, resulting in augmented H3K9 trimethylation on HSV-1 promoters and reduced HSV-1 replication. TRIM28 is known to act as a transcriptional repressor, and its phosphorylation has been linked to transcriptional activation. Interestingly, we observed that HSV-1 infection leads to phosphorylation of TRIM28 at serine positions 473 and 824, which was repressed by treatment with the ILK inhibitor. Our study provides the first evidence of the pro-viral role of ILK in HSV-1 infection, highlighting the potential of ILK as a target for the development of novel anti-viral therapies.  (Image created with BioRender.com)

Microglial phagocytic activity is critical to protect mice from HSV-1 infection.

1. Int. J. Mol. Sci. (2021) 22:12457. https://doi.org/10.3390/ijms222212457

2. J. Neuroinflammation (2022) 19:66. https://doi.org/10.1186/s12974-022-02426-w

Viral infections can induce inflammation and lead to irreversible neural damage in encephalitis patients. Microglia are believed to have a dual role in the process. Due to the lack of an efficient way to deplete microglia, the issue remains unresolved. We employed the CSF-1R inhibitor PLX5622 to deplete more than 95% of microglia in mice and showed that microglia played a crucial role in protecting mice from lethal HSV-1 infection (1). Interestingly, the protective function of microglia was independent of their role in type I IFN responses and antigen presentation. Additionally, we found microglia increased thrombomodulin (TM) expression in response to HSV-1 infection (2). By deleting the lectin-like domain (LeD) in TM, the phagocytic activity of primary mouse microglia and a human microglia cell line were significantly enhanced, even without HSV-1 infection. These suggest that microglial phagocytic activity is critical to control HSV-1 infection in cells and mice. Future studies into how LeD modulates microglial phagocytosis are needed. (Image created with BioRender.com)

*PLoS Pathog. (2022) 18:e1010692. https://doi.org/10.1371/journal.ppat.1010692

It is estimated that up to 50-90% of adults are latently infected with HSV-1, but only a small fraction of them develop encephalitis upon HSV-1 reactivation. Host-enhancing factors could be the disease-determining factor yet to be identified. In the study, we revealed that the expression of Anx-A1, a cellular protein, determined mouse susceptibility to HSV-1-induced encephalitis. Anx-A1, which was present on virus envelopes, provided a versatile way for HSV-1 to attach to the cell surface. Notably, Anx-A1 is a non-essential gene, and Anx-A1-deficient mice show no evident abnormalities, suggesting it is a safe antiviral target. Indeed, by targeting Anx-A1, we were able to reduce the severity of HSV-1-induced diseases in mice, even in those that are immunocompromised and persistently infected with drug-resistant HSV-1. Future studies regarding Anx-A1 levels correlating with human susceptibility or severity to HSV-1-induced encephalitis would be interesting.  (Image created with BioRender.com)