Characteristic Of The Immune Response And The Effects On ILCs Induced By HSV-1 Infecting Epithelium

Herpes simplex virus type 1(HSV-1)infection is an critical human health issue.According to World Health Organization,67%of people under the age of 50 are currently infected with the HSV-1.HSV-1 infection causes cold sores and herpes encephalitis,and morbidity and mortality increase in neonates and immunodeficient patients.Currently,several anti-HSV-1 drugs have been approved for clinical treatment,such as cidofovir,valaciclovir,penciclovir,and famciclovir.These drugs can alleviate symptoms,relieve pain,however,cannot eliminate latent virus or prevent disease recurrence,and studies have shown that the use of these antiviral drugs leads to drug resistance.At the same time,clinical studies of multiple HSV-1 vaccines have not provided meaningful results.Therefore,in order to provide more theoretical basis for the development of HSV-1 vaccine and more highly effective therapeutic drugs,we need to further explore the HSV-1 infection mechanism.HSV-1 first enters the body by infecting human epithelial cells,but the mechanism of immune response to HSV-1 at the site of initial infection is not fully understood.Previous studies have shown that there are a group of Innate lymphoid cells(ILCs)in the epithelial and mucosal tissues,which can be activated by pathogenic epithelial cells to produce some natural immune signal molecules and participate in the natural immune response and the formation of adaptive immune responses.This article focus on the characteristics of the immune response of infecting epithelial tissues with HSV-1 and the mechanism for natural immune cells activation in skin and mucous membranes to gain insight into the interaction between HSV-1 and the immune system.We first analyzed the infection characteristics of HSV-1 on respiratory epithelial cells and found that after HSV-1 infect human bronchial epithelial cells 16HBE,the non-canonical NF-kB pathway associated with the innate immune response was activated,and expression of signaling molecules,such as IL-33,IL-25,which activate natural lymphocytes(ILCs),were activated.Further studies using mouse models showed that,compared to the control group and the muscular infection group,mice in the mucocutaneous infection group had higher viral loads in various tissues,especially nervous system tissues.And the virus infection leads to epithelial tissue damage.And the signalling molecules which recruite and activate ILCs were upregulated in epithelial tissues.HSV-1 enters the submucosa and co-localized with ILCs after breakthrough the respiratory mucosal epithelial barrier.These results indicate that HSV-1 infection of epithelial tissue leads to tissue damage and induces cytokine production of epithelial cells which recruit and activate ILCs.And HSV-1 shows signs to infect ILCs in vivo.Further we infected the ILCs and KMB17 cells with HSV-1 and found that HSV-1 can proliferate in ILCs,but the proliferation rate was lower than that in KMB17 cells.At the same time,gene expression profile of infected ILCs was changed,for example,the expression of HVEM was upregulated.We further analyzed the regulation of ILCs to T cells specific responses,We found that ILCs have the ability to non-specifically stimulate the proliferation of T cells.The effect of HSV-1 on ILCs can in turn inhibit the ability of ILCs themselves to stimulate nonspecific proliferation of T cells.We propose the binding of HSV-1 gD protein to HVEM may block the binding of HVEM to LIGHT on the surface of T lymphocytes,thereby inhibiting T lymphocytes from exerting specific immune responses,Thus inhibiting the activation and proliferation of T lymphocytes.The above results indicate that the infection of epithelial tissues with HSV-1 can induce the activation of ILCs,and ILCs can be infected with HSV-1 and this may inhibit T lymphocytes from exerting immune responses.