The intestinal microbial metabolite nicotinamide n-oxide prevents herpes simplex encephalitis via activating mitophagy in microglia.

Herpes simplex encephalitis (HSE), a complication of herpes simplex virus type I (HSV-1) infection causes neurological disorder or even death in immunocompromised adults and newborns. However, the intrinsic factors controlling the HSE outcome remain unclear. Here, we show that HSE mice exhibit gut microbiota dysbiosis and altered metabolite configuration and tryptophan-nicotinamide metabolism. HSV-1 neurotropic infection activated microglia, with changed immune properties and cell numbers, to stimulate antiviral immune response and contribute substantially to HSE. In addition, depletion of gut microbiota by oral antibiotics (ABX)-treatment triggered the hyper-activation of microglia, which in turn enhanced inflammatory immune response, and cytokine production, resulting in aggregated viral burden and HSE pathology. Furthermore, exogenous administration of nicotinamide n-oxide (NAMO), an oxidative product of nicotinamide derived from gut microbiota, to ABX-treated or untreated HSE mice significantly diminished microglia-mediated proinflammatory response and limited HSV-1 infection in CNS. Mechanistic study revealed that HSV-1 activates microglia by increasing mitochondrial damage via defective mitophagy, whereas microbial metabolite NAMO restores NAD+-dependent mitophagy to inhibit microglia activation and HSE progression. NAMO also prevented neuronal cell death triggered by HSV-1 infection or microglia-mediated microenvironmental toxicity. Finally, we show that NAMO is mainly generated by neomycin-sensitive bacteria, especially Lactobacillus_gasseri and Lactobacillus_reuteri. Together, these data demonstrate that gut microbial metabolites act as intrinsic restrictive factors against HSE progression via regulating mitophagy in microglia, implying further exploration of bacterial or nutritional approaches for treating neurotropic virus-related neurodegenerative diseases.

Amentoflavone Inhibits HSV-1 and ACV-Resistant Strain Infection by Suppressing Viral Early Infection.

Infection of Herpes simplex virus 1 (HSV-1) induces severe clinical disorders, such as herpes simplex encephalitis and keratitis. Acyclovir (ACV) is the current therapeutic drug against viral infection and ACV-resistant strains have gradually emerged, leading to the requirement for novel antiviral agents. In this study, we exhibited the antiviral activity of amentoflavone, a naturally occurring biflavonoid, toward HSV-1 and ACV-resistant strains. Amentoflavone significantly inhibited infection of HSV-1 (F strain), as well as several ACV-resistant strains including HSV-1/106, HSV-1/153 and HSV-1/Blue at high concentrations. Time-of-drug-addition assay further revealed that amentoflavone mainly impaired HSV-1 early infection. More detailed study demonstrated that amentoflavone affected cofilin-mediated F-actin reorganization and reduced the intracellular transportation of HSV-1 from the cell membrane to the nucleus. In addition, amentoflavone substantially decreased transcription of viral immediate early genes. Collectively, amentoflavone showed strong antiviral activity against HSV-1 and ACV-resistant strains, and amentoflavone could be a promising therapeutic candidate for HSV-1 pathogenesis.

AT-533, a Hsp90 inhibitor, attenuates HSV-1-induced inflammation.

Inflammatory events are tightly associated with the death caused by Herpes simplex virus 1 (HSV-1) infection of the brain. Heat shock protein 90 (Hsp90) is a molecular chaperone that is stimulated in response to many stressful conditions (e.g., inflammation and hypoxia) and Hsp90 inhibitors are suggested to be potent inhibitors of the inflammatory response. The aim of this study was to investigate the effect of Hsp90 inhibitor AT-533 on HSV-1-induced inflammation. AT-533 at a non-antiviral concentration was found to show a prominent inhibitory effect on the production of cytokines induced by HSV-1 infection, such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and interleukin 1ß (IL-1ß). Mechanically, HSV-1 early infection induced inflammation through NF-κB signaling and NLRP3 inflammasome activation, as illustrated by the nuclear translocation of NF-κB and the enhanced cleavage of caspase-1. Besides, HSV-1 enhanced the interaction between NLRP3 and Hsp90. Moreover, AT-533 reduced the nuclear translocation of NF-κB and inflammasome activation via inhibiting the chaperone function of Hsp90. Furthermore, AT-533 inhibited the cleavage of pro-IL-1ß to mature IL-1ß in a NLRP3-independent manner. In summary, AT-533 may be a promising therapeutic strategy in HSV-1-infected inflammation management.