Research Topic

Local Immune Responses to Herpes Simplex Virus

About this Research Topic

Herpes simplex viruses (HSV) are highly prevalent human pathogens that establish latent infections and cause a significant amount of morbidity worldwide. HSV typically targets squamous epithelial barriers and disseminates into the peripheral nervous system (PNS). Depending on the tissue involved, HSV can cause diseases such as genital herpes, herpes labialis and herpes keratitis. While partially effective antiviral therapy is available, thus far there is no cure or vaccine for HSV infection.

A wealth of evidence indicates that optimal control of HSV infection is mediated by local innate and adaptive immune responses that are activated hours following viral exposure or reactivation. These responses can be highly influenced by the surrounding microenvironment, which at barrier tissues includes the local microbiome. Many clinical and preclinical studies on HSV have focused on the role of tissue-resident memory T cells (TRM) due to their importance in conferring both vaccine-mediated protection as well as control of reactivating virus through rapid production of IFNg. Despite this, open questions remain about the mechanism(s) by which TRM and IFNg restrict HSV infection, and the influence of the local microenvironment on their function. Aside from TRM, the role of other resident immune cells in controlling HSV infection is less well understood. Peripheral barrier sites targeted by HSV can undergo immunosurveillance by cells such as granulocytes, dendritic cells, macrophages and innate lymphoid cells (ILCs), while nervous tissues are populated by glial cells, astrocytes and other tissue-specific immune cells. The contribution of these resident immune cells to the anti-HSV immune response is, in general, poorly defined, and in some cases, the immune cell populations themselves are not well-characterized.

Deeper understanding of tissue-specific immune responses and antiviral pathways that restrict HSV could reveal novel targets for therapeutics as well as improved vaccine design. Moreover, studies of tissue resident immunity for HSV in animal models and humans reveal that acquired cellular immune responses in tissue are often highly discordant from those in blood. Therefore, assessments of only circulating immune responses, especially against other important viral pathogens such as SARS-CoV-2 and HIV that replicate in less accessible tissue, may provide misleading information about crucial host-pathogen interactions that take place at the actual site of infection.

The goal of this research topic is to increase understanding of the mechanisms by which antiviral TRM restrict infection, highlight the involvement of resident immune cells in enhancing HSV clearance, and reveal how the local microenvironment shapes immune responses against HSV in all tissues that support productive viral replication or latency. We welcome the submission of Original Research articles, Reviews, Mini-reviews, Hypothesis and Theory as well as Perspective articles that address but are not limited to:

1. Role of resident immune cell populations other than T cells on antiviral immunity against HSV
2. Profiling of resident immune cells in understudied tissues that are targets of HSV infection
3. Regulation of local anti-HSV immune responses by tissue-specific factors such as the local microbiome
4. Generation of HSV-specific memory in situ
5. Role of bystander T cells in containing infection
6. Vaccine design that incorporates resident immune cell populations


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

Herpes simplex viruses (HSV) are highly prevalent human pathogens that establish latent infections and cause a significant amount of morbidity worldwide. HSV typically targets squamous epithelial barriers and disseminates into the peripheral nervous system (PNS). Depending on the tissue involved, HSV can cause diseases such as genital herpes, herpes labialis and herpes keratitis. While partially effective antiviral therapy is available, thus far there is no cure or vaccine for HSV infection.

A wealth of evidence indicates that optimal control of HSV infection is mediated by local innate and adaptive immune responses that are activated hours following viral exposure or reactivation. These responses can be highly influenced by the surrounding microenvironment, which at barrier tissues includes the local microbiome. Many clinical and preclinical studies on HSV have focused on the role of tissue-resident memory T cells (TRM) due to their importance in conferring both vaccine-mediated protection as well as control of reactivating virus through rapid production of IFNg. Despite this, open questions remain about the mechanism(s) by which TRM and IFNg restrict HSV infection, and the influence of the local microenvironment on their function. Aside from TRM, the role of other resident immune cells in controlling HSV infection is less well understood. Peripheral barrier sites targeted by HSV can undergo immunosurveillance by cells such as granulocytes, dendritic cells, macrophages and innate lymphoid cells (ILCs), while nervous tissues are populated by glial cells, astrocytes and other tissue-specific immune cells. The contribution of these resident immune cells to the anti-HSV immune response is, in general, poorly defined, and in some cases, the immune cell populations themselves are not well-characterized.

Deeper understanding of tissue-specific immune responses and antiviral pathways that restrict HSV could reveal novel targets for therapeutics as well as improved vaccine design. Moreover, studies of tissue resident immunity for HSV in animal models and humans reveal that acquired cellular immune responses in tissue are often highly discordant from those in blood. Therefore, assessments of only circulating immune responses, especially against other important viral pathogens such as SARS-CoV-2 and HIV that replicate in less accessible tissue, may provide misleading information about crucial host-pathogen interactions that take place at the actual site of infection.

The goal of this research topic is to increase understanding of the mechanisms by which antiviral TRM restrict infection, highlight the involvement of resident immune cells in enhancing HSV clearance, and reveal how the local microenvironment shapes immune responses against HSV in all tissues that support productive viral replication or latency. We welcome the submission of Original Research articles, Reviews, Mini-reviews, Hypothesis and Theory as well as Perspective articles that address but are not limited to:

1. Role of resident immune cell populations other than T cells on antiviral immunity against HSV
2. Profiling of resident immune cells in understudied tissues that are targets of HSV infection
3. Regulation of local anti-HSV immune responses by tissue-specific factors such as the local microbiome
4. Generation of HSV-specific memory in situ
5. Role of bystander T cells in containing infection
6. Vaccine design that incorporates resident immune cell populations


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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Submission Deadlines

13 June 2021 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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Topic Editors

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Submission Deadlines

13 June 2021 Manuscript

Participating Journals

Manuscripts can be submitted to this Research Topic via the following journals:

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