Cellular culprit suspected of pushing dengue fever from bad to worse is cleared by transcripts

LA JOLLA, CA–No one knows what makes a mild dengue viral infection morph into a severe and sometimes deadly dengue hemorrhagic fever/dengue shock syndrome. Experts previously believed the likely cause was ramped up activity of T cells, which can massively boost an immune response to a virus. Now, however, researchers at the La Jolla Institute for Immunology (LJI), have found definitive evidence that CD4 T cells, one of two main subtypes of T cells, are not to blame.

The finding, reported in the December 24, 2019, issue of Cell Reports, is important to both the basic understanding of this disease–the world’s most common mosquito-borne illness–and to the hunt for an effective vaccine for dengue.

“We found no evidence to support the common dogma that these T cells are responsible for turning a mild infection to a severe one. This will help us narrow the search for the true culprit,” says the study’s lead investigator Yuan Tian, Ph.D., an AAI Intersect Fellow and a Bioinformatics Student at LJI. He is also a postdoctoral fellow in the lab of Alessandro Sette, Dr. Sci. Biol, a co-author of the study.

These issues are serious. Dengue fever is spreading. Infected mosquitos have expanded beyond their established tropical and subtropical territories in South East Asia and Latin America to new continents, including Europe and the United States. More than half of the world’s population is now at risk; already, 390 million infections occur annually, according to public health experts.

The goal of the LJI study was to define the molecular pattern of dengue-specific CD4 T cells and to investigate whether there is a difference in the T cell response between patients with mild dengue fever or with severe dengue hemorrhagic fever.

When analyzing dengue-specific CD4 T cells, the researchers realized that the responding CD4 T cells, have both a pro-inflammatory function (regulated by the cytokine interferon gamma, or IFN-?) and an anti-inflammatory function (regulated by the cytokine interleukin 10, or IL-10) which is typically not seen in acute viral infections. To comprehensively define these dengue-virus specific T cells in hospitalized patients, researchers used whole transcriptome analysis to determine if there was a difference in the quality of the increased response.

This approach allows to identify all RNA transcripts–produced when a gene’s DNA sequence is copied, or transcribed–within the transcriptome of dengue-specific CD4 T cells in hospitalized patients being treated for either mild or for severe dengue infection. These patients were being treated in Sri Lanka, where dengue fever is endemic.

“This is a very powerful approach to detect gene expression activity because all genes upregulated in response to the virus can be identified. It is completely unbiased and does not rely on pre-selected genes,” says the study’s senior investigator, Daniela Weiskopf, Ph.D., an instructor at LJI.

The research team, to their surprise, detected no difference in the genomic profile of dengue-virus specific CD4 T cells regardless if they isolated them form patients with mild or severe dengue infection.

“The CD4 T cell response in the severe disease does not look different so that cannot be the switch we are all looking for,” Tian says. “In fact, based on some intriguing preliminary findings, we speculate that to counteract the severe immune response occurring in acute cases, these dengue-specific CD4 cells may have gradually acquired the ability to produce more IL-10 by converting IFN?. It is as if they are trying to calm themselves, calm the inflammation. The double positive CD4 T cells could actually be helping, rather than hurting.”

Tian adds that he hopes these findings will serve to “help guide efforts to develop effective dengue vaccines by improving our understanding of this novel T cell response.”

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This work was performed as a project of the Human Immunology Project Consortium (HIPC) and supported by National Institute of Allergy and Infectious Diseases grants U19 AI118626 and P01 AI106695 and NIH contracts HHSN272200900042C and HHSN27220140045C. It was also supported Shared Instrumentation Grants S10 RR027366, S10 OD018499, and S10 OD016262, from the National Institutes of Health.

Yuan Tian, Grégory Seumois, Luzia M. De-Oliveira-Pinto, Jose Mateus, Sara Herrera-de la Mata, Cheryl Kim, Denise Hinz, N.D. Suraj Goonawardhana, Aruna D. de Silva, Sunil Premawansa, Gayani Premawansa, Ananda Wijewickrama, Angel Balmaseda, Alba Grifoni, Pandurangan Vijayanand, Eva Harris, Bjoern Peters, Alessandro Sette, and Daniela Weiskopf. “Molecular Signatures of Dengue Virus-Specific IL-10/IFN-? Co-producing CD4 T Cells and their Association with Dengue Disease.” Cell Reports, 2019.

DOI: 10.1016/j.celrep.2019.11.098

The La Jolla Institute for Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading toward its goal: life without disease.