Herpes Simplex Virus Type 1 Engages Toll Like Receptor 2 to Recruit Macrophages During Infection of Enteric Neurons

Abstract

Herpes simplex virus type 1 (HSV-1) is a widespread neurotropic pathogen responsible for a range of clinical manifestations. Inflammatory cell infiltrate is a common feature of HSV-1 infections and has been implicated in neurodegeneration. Therefore, viral recognition by innate immune receptors (i.e., TLR2) and the subsequent inflammatory response are now deemed key players in HSV-1 pathogenesis. In this study we infected with HSV-1 the enteric nervous system (ENS) of wild-type (WT) and TLR2 knock-out (TLR2ko) mice to investigate whether and how TLR2 participates in HSV-1 induced neuromuscular dysfunction. Our findings demonstrated viral specific transcripts suggestive of abortive replication in the ENS of both WT and TLR2ko mice. Moreover, HSV-1 triggered TLR2-MyD88 depend signaling in myenteric neurons and induced structural and functional alterations of the ENS. Gastrointestinal dysmotility was, however, less pronounced in TLR2ko as compared with WT mice. Interesting, HSV-1 caused up-regulation of monocyte chemoattractant protein-1 (CCL2) and recruitment of CD11b+ macrophages in the myenteric ganglia of WT but not TLR2ko mice. At the opposite, the myenteric plexuses of TLR2ko mice were surrounded by a dense infiltration of HSV-1 reactive CD3+CD8+INFγ+ lymphocytes. Indeed, depletion CD3+CD8+ cells by means of administration of anti-CD8 monoclonal antibody reduced neuromuscular dysfunction in TLR2ko mice infected with HSV-1. During HSV-1 infection, the engagement of TLR2 mediates production of CCL2 in infected neurons and coordinates macrophage recruitment. Bearing in mind these observations, blockage of TLR2 signaling could provide novel therapeutic strategies to support protective and specific T-cell responses and to improve neuromuscular dysfunction in pathogen-mediated alterations of the ENS.

Herpes Simplex Virus 1 Infection of Neuronal and Non-Neuronal Cells Elicits Specific Innate Immune Responses and Immune Evasion Mechanisms

“…TLR2 activation is also required to reduce the viral load in trigeminal ganglia and the brain during HSV–1 infection ( 122 , 123 ). In TLR2 knockout mice, neuronal CCL2 levels were decreased, in association with reduced macrophage recruitment into the enteric nervous system after intragastric HSV–1 infection ( 124 ). TLR2’s role in the production of cytokines results in viral containment in response to HSV–1 infection.…”

Herpes Simplex Virus Type 1 Interactions with the Interferon System

“…Interestingly, TLR2 knockout mouse models infected with HSV-1 have a higher survival rate and fewer complications compared to wild type mice [ 42 ]. TLR2 deficient mice also have fewer infiltrating macrophages following HSV-1 neuronal infection [ 50 ]. This suggests that TLR2 activation and the subsequent immune response generated may be detrimental to the host.…”

Role of Herpes Simplex Virus Type 1 (HSV-1) Glycoprotein K (gK) Pathogenic CD8+ T Cells in Exacerbation of Eye Disease

“…Current therapies for treatment of ocular HSV-1 infection include the use of antiviral drugs and corticosteroids which can minimize the lesions but often lead to certain side effects (34); therefore, new measures need to be adopted. Studies on mouse models of ocular HSV-1 infection have unraveled many insights into the disease pathogenesis paving ways to future innovative therapies (35, 36). It is well-documented that HSV-1 pathology is a consequence of the immune response mounted by the host after virus infection and therefore, it is considered an immunopathological disease (37).…”