Herpes Simplex Virus 1 Suppresses the Function of Lung Dendritic Cells via Caveolin-1

Abstract

Caveolin-1 (Cav-1), the principal structural protein of caveolae, has been implicated as a regulator of virus-host interactions. Several viruses exploit caveolae to facilitate viral infections. However, the roles of Cav-1 in herpes simplex virus 1 (HSV-1) infection have not fully been elucidated. Here, we report that Cav-1 downregulates the expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) in dendritic cells (DCs) during HSV-1 infection. As a result, Cav-1 deficiency led to an accelerated elimination of virus and less lung pathological change following HSV-1 infection. This protection was dependent on iNOS and NO production in DCs. Adoptive transfer of DCs with Cav-1 knockdown was sufficient to confer the protection to wild-type (WT) mice. In addition, Cav-1 knockout (KO) (Cav-1 ؊/؊ ) mice treated with an iNOS inhibitor exhibited significantly reduced survival compared to that of the nontreated controls. We found that Cav-1 colocalized with iNOS and HSV-1 in caveolae in HSV-1-infected DCs, suggesting their interaction. Taken together, our results identified Cav-1 as a novel regulator utilized by HSV-1 to evade the host antiviral response mediated by NO production. Therefore, Cav-1 might be a valuable target for therapeutic approaches against herpesvirus infections. Herpes simplex virus 1 (HSV-1) is a double-stranded DNA (dsDNA) virus belonging to the Alphaherpesvirus family, which causes oral herpes, encephalitis, keratitis, neonatal herpes, and pneumonia disease, establishing latency in the neurons after acute infection of mucosal tissues (1-3). Notably, HSV-1 can be isolated from the respiratory tract of immunosuppressed patients and newborn infants, where it induces pneumonitis, resulting in remarkable morbidity and mortality (4). Recent studies have suggested that HSV-1-induced bronchopneumonitis is common in nonimmunocompromised persons who are undergoing continuous mechanical ventilation (5). Currently, the mechanisms of HSV-1-induced pneumonia and obstructive pulmonary disease are not fully understood, although intranasal (i.n.) infection with HSV-1 in mice can be used as a model to investigate these mechanisms (4, 6, 7). Such investigations might reveal a valuable therapeutic approach for HSV-1-induced pneumonia.Innate defense cells and inflammatory factors serve as the firstline of host defense against viral infections. DCs can be recruited to the lungs and in the cornea of the eye, where they contribute to host defense (8, 9). Studies have shown that diphtheria toxin (DT)-induced depletion of DCs in CD11c-DTR mice (in which the DT receptor [DTR] is expressed under the control of the CD11c promoter) inhibited the migration of natural killer cells and neutrophils to locally infected cornea, resulting in severe pathology (10, 11). Moreover, involvement of the free radical nitric oxide (NO) has been indicated. This is a powerful vasodilator factor and cell signaling molecule, with a short half-life of 3 to ϳ4 s in the blood, and it is synthesized by nitric oxide s...

A Herpes Simplex Virus Type 2 Deleted for Glycoprotein D Enables Dendritic Cells to Activate CD4+ and CD8+ T Cells

“…Furthermore, HSV-2 can limit DC presentation of viral antigens on MHC-I molecules by interfering with the transport of antigenic peptides from the cytoplasm to the endoplasmic reticulum and decrease the expression of T cell costimulatory molecules on the DC surface, thus impeding effective T cell activation (Figure 1 ) ( 74 , 75 , 77 , 78 ). HSV can also block the activity of inducible nitric oxide synthase (iNOS) and NO production, by interacting with caveolin-1 (Cav-1) in DCs (Figure 1 ) ( 79 ). Additionally, and most importantly, HSV-2 elicits DC apoptosis early after infection, further limiting the chances of the host to establish an optimal antiviral T cell response (Figure 1 ) ( 17 , 78 , 80 ).…”

Unraveling the role of membrane microdomains during microbial infections

“…This is important because Src-mediated signaling induced by JEV is known to play a critical role in neuronal cell death. Earlier studies revealed the role of lipid rafts in the activation of Src, Ras, Raf, ERK, and NF-кB, which all contribute to JEV-induced TNF-α and IL-1β production (McCubrey et al 2007;Wu et al 2015). Furthermore, involvement of lipid rafts in Src-mediated signaling pathways upstream of the activation of Raf/ ERK/NF-кB has been reported in response to several stimuli (Roux and Blenis 2004).…”

Characteristics of herpes simplex virus infection and pathogenesis suggest a strategy for vaccine development

“…Further study of infected DCs has revealed that the transfer of antigen from the cytosol to the endoplasmic reticulum is blocked by HSV infection, which could downregulate antigen presentation to T cells by DCs through restricting the binding of antigen to the major histocompatibility complex 1 (MHC‐1) molecule in cells . The data have also suggested that HSV is capable of interacting with caveolin‐1 to alter the activity of nitric oxide synthase and limit the production of NO and that the migration rate of infected DCs moving from the local tissue to the lymph nodes was decreased because of an increased death rate . All of these data suggest the hypothesis that by interfering with DCs, a major antigen‐presenting cell in the immune system, HSV infection might lead to abnormal immune signaling in T cells and induce weakened adaptive immunity.…”