# Interleukin-36 cytokines in antiviral immune responses

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $390,000

## Abstract

SUMMARY
Frequent and/or prolonged reactivation of herpes simplex virus (HSV) infection is common in human
immunodeficiency virus (HIV) positive patients and causes greatly diminished quality of life due to disfiguring
and painful skin, oral and genital lesions. Antiviral drug resistant HSV strains are on the rise especially in HIV
patients; hence, new and improved treatment and preventive approaches are urgently needed. This project will
identify immune mechanisms that may be harnessed to control HSV reactivation and acute disease in
HIV/AIDS patients. Agents that enhance the immune system are promising as novel antiviral drugs as they: 1)
may overcome immune suppression in HIV/AIDS patients, 2) may have long-term preventive properties, and 3)
represent a greater challenge for the virus in terms of developing new resistance. Imiquimod and polyinosinic-
polycytidylic (poly(I:C)) are two immune response modifies, which have successfully been used in humans
and/or mice to treat acute HSV skin disease; however, their mechanisms of action are incompletely
understood. Furthermore, their immune activating potency limits their prolonged use. Individual down-stream
effectors of imiquimod and poly(I:C) activity, e.g., those studied here, may be better suited as therapeutic and
preventive agents due to their more limited, yet focused, action. The IL-36 system involves three related
cytokines, IL-36α, IL-36β and IL-36γ and a common receptor, IL-36R. The system is predominantly expressed
in epithelial tissues, such as the skin and oral and genital mucosa; tissues which are also the targets of HSV.
The physiological function of the IL-36 system is unknown; however, preliminary, predominantly in vitro,
studies suggest that it activates the immune system through leukocyte recruitment and initiation of the adaptive
immune response. We were the first to demonstrate that poly(I:C), a double stranded RNA analogue often
used to simulate viral infections, induces IL-36γ expression and extracellular release. Recently we published
our further work demonstrating that IL-36α is essential for the inflammatory immune response induced by
imiquimod in the skin. Additional, unpublished data reveal that IL-36β deficient mice develop larger HSV-1 skin
lesions and have a higher mortality rate than wild type mice. This leads us to hypothesize that the IL-36 system
promotes immunity against HSV and the therapeutic effects of imiquimod and poly(I:C) is driven, at least in
part, by the IL-36 system. Hence, in Aim 1 we will define the IL-36 dependent immune mechanisms directed
against HSV. In Aim 2 we will test our hypothesis that the IL-36 system is, at least in part, responsible for the
therapeutic effects of imiquimod and poly(I:C). Finally, in Aim 3 we will test the therapeutic and preventive
activity of IL-36. Correlations to human HSV disease and immune responses will be drawn and the impact of
HIV infection examined. The knowledge gained may underpin the development of novel ap...

## Key facts

- **NIH application ID:** 9962278
- **Project number:** 5R01AI125111-05
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** LISELOTTE E JENSEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2016-07-02 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962278

## Citation

> US National Institutes of Health, RePORTER application 9962278, Interleukin-36 cytokines in antiviral immune responses (5R01AI125111-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9962278. Licensed CC0.

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