Introduction: Herpes simplex virus type 1 (HSV-1) causes recurrent infections of skin and mucosal tissues with high global prevalence. HSV-1 also invades the nervous system where it establishes a lifelong latency-making infection poorly treatable We previously showed that both tannic acid-modified silver and gold nanoparticles (TA-Ag/AuNPs) inhibit HSV-1 infection in vitro. Methods: We used an in vitro and in vivo model of HSV-1 infection to study how metal type, size and tannic acid modification of nanoparticles can influence development of the early innate response and the mounting of specific anti-HSV-1 response upon treatment of the nasal mucosa. Results: We found that tannic acid is necessary for binding with HSV-1, with smaller sizes independent of the NPs composition, whereas for larger NPs, only TA-AgNPs can inhibit HSV-1 infection. Intranasal treatment of HSV-1 infection with TA-Ag/AuNPs results in lower viral titers and a better antiviral response, followed by increased IFN-α, CXCL9, and CXCL10 levels as well as infiltration of T cells and NK cells in the infected sites. We also found that the application of TA-NPs to the nasal cavities of infected mice induced infiltration of both monocytes and Langerhans cells (LCs), which lasted longer compared to the application of unmodified NPs. Furthermore, TA-NPs activated monocytes and microglia to produce antiviral cytokines and chemokines better than unmodified NPs, except for the large TA-AuNPs. Discussion: Treatment of the mucosal tissues at the early stage of HSV-1 infection helps to modulate specific and effective antiviral immune response by attracting cytotoxic lymphocytes and inducing the production of antiviral cytokines and chemokines. Furthermore, tannic acid modification is helpful for the removal of nanoparticles from the respiratory tract, which increases the safety of nanoparticle applications to treat infections.

Herpes simplex virus-1 (HSV-1) is a neurotropic virus that can infect the brain, and an uncontrolled infection can lead to severe encephalitis. NO can exert both antiviral as well as cytotoxic effects in the central nervous system (CNS) depending on its concentration and site of infection. In this study, we report that treatment of an intranasal murine HSV-1 infection with aminoguanidine (AMG) decreases both neuroinflammation and neurodegeneration markers, but its positive effect depends on the time of treatment. Specifically, early treatment with AMG impaired the activation of microglia/monocytes, leading to decreased virus-specific antiviral response and higher viral titers in the brain. However, AMG treatment during the peak of brain infection significantly improved antiviral response, reduced inflammation and improved general clinical score. We also found that treatment with AMG decreased beta amyloid levels during both primary and latent infections and protected from the accumulation of phosphorylated Tau protein during early infection. Our findings position inducible nitric oxide synthetase (iNOS) as a potential therapeutic target for mitigating virus-induced neuroinflammation and neurodegeneration.

Many studies have shown an association between herpes simplex virus type 1 (HSV-1) infection and the development of neurodegeneration processes later in life, such as Alzheimer’s disease. The Fas/FasL death pathway plays an important role in the complex regulation of the local inflammatory response and mounting of the specific antiviral response in HSV-1 infection. Here, we applied a mouse model of latent HSV-1 neuroinfection to Fas- and FasL-deficient mice (lpr and gld) to explore whether the lack of functional Fas/FasL pathway protects from inflammation-related neurodegeneration. The latently infected Fas- and FasL-deficient mice (lpr and gld) were not protected from virus replication despite the accumulation of virus-specific cytotoxic T cells. However, the lack of Fas/FasL pathway decreased neuroinflammation- and neurodegeneration-related markers, including cognitive impairment, amyloid-β protein, and tau hyperphosphorylation. The use of a glucocorticoid, dexamethasone, to decrease neuroinflammation in wild-type mice did not protect from cognitive impairment, despite the improved antiviral response. Our data indicate that excessive neuroinflammation via the Fas/FasL pathway during HSV-1 infection is associated with neurodegeneration. Furthermore, the administration of immunomodulatory agents to ameliorate the outcome of HSV-1 latent infection should be restricted to the peak of neuroinflammation.