In brief

By transferring ZIKV-primed CD8+ T cells into genetically modified mice, researchers discovered that CD8+ T cells can control the viral load effectively, but also cause tissue damage, providing critical insights for the design of future ZIKV vaccines.

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Virus killers get under the skin

10 May 2024

Research suggests monitoring individuals previously infected with Zika virus for chronic skin diseases caused by overactive T cells.

Immune cells are regarded as the body’s antiviral guardians. But some infections by pathogens such as Zika virus (ZIKV) can bring out the ‘dark side’ of CD8+ T cells. In these cases, T cells can also play a pathogenic role, highlighting the complex balance between immunity and inflammation.

Prior reports focused on the dual role of CD8+ T cells in the central nervous system. Lisa Ng, the Executive Director and a Senior Principal Investigator at A*STAR Infectious Diseases Labs (ID Labs) said that a key characteristic of the ZIKV resurgence in 2015 was its preference for neural cells; evidence suggested a correlation with neurological disorders in adults and birth defects in infants.

Ng teamed up with researchers from A*STAR’s Singapore Immunology Network (SIgN) and Institute of Molecular and Cell Biology (IMCB) to study the lesser-known effects that CD8+ T cells might have on non-neural tissues such as the skin. The group hypothesised that CD8+ T cells may have a long-term pathogenic effect on the skin in the aftermath of ZIKV infections, especially in the absence of CD4+ T cells.

To test the theory, the researchers developed a genetically engineered, T-cell-deficient mouse model known as TCR knockouts (TCRKO).

Activated CD8+ T cells, transferred from ZIKV-experienced mice into TCRKO mice, effectively diminished viral loads, achieving clearance within 40 days post-infection. Significant eye and ear tissue damage was also observed in mice receiving activated CD8+ T cells, unlike in wildtype and control animals.

The researchers hypothesised that in the absence of regulatory input from other T cell types like CD4+, ZIKV-primed CD8+ T cells can become self-reactive, mistakenly targeting the body's own tissues. Single-cell RNA sequencing data underpinned this hypothesis, revealing a heightened proinflammatory profile in the CD8+ T cells.

“Our findings indicate the importance of monitoring chronic skin diseases in patients previously exposed to ZIKV, as they may harbour ZIKV-specific or autoreactive memory CD8+ T cells capable of triggering skin conditions,” Ng said.

The team is currently working on identifying and understanding the specific interactions between T cells and ZIKV antigens that result in skin pathologies.

Ng explained that this finding could significantly influence vaccine development, emphasising the need to design vaccines that do not activate T-cell responses against these viral antigens.

The A*STAR-affiliated researchers contributing to this research are from the A*STAR Infectious Diseases Labs (ID Labs), the Singapore Immunology Network (SIgN) and the Institute of Molecular and Cell Biology (IMCB).

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Lee, C.Y.-P., Carissimo, G., Teo, T.-H., Tong, S.J.M., Chang, Z.W., et al. CD8+ T cells trigger auricular dermatitis and blepharitis in mice after Zika virus infection in the absence of CD4+ T cells. Journal of Investigative Dermatology 143 (6), 1031–1041 (2023). | article

About the Researcher

Lisa F.P. Ng obtained her PhD in molecular virology in coronaviruses from the National University of Singapore (NUS) in 2002. After joining A*STAR’s Genome Institute of Singapore (GIS) in 2002 as a Postdoctoral Fellow, she worked on viral diseases such as hepatitis, severe acute respiratory syndrome and influenza. Ng is currently the Executive Director at A*STAR Infectious Diseases Labs (ID Labs) where she focuses on the immune responses to arthritic arboviruses that are epidemic or highly endemic in the tropical region. Ng has won numerous accolades for her research, including the ASEAN ‘International Young Scientist and Technologist Award’ in 2008 and A*STAR’s ‘Most Inspiring Mentor Award’ in March 2013.

This article was made for A*STAR Research by Wildtype Media Group