Dengue’s Progression to a Severe Case Found Not Related to T Cells

Double positive CD4 T cells could actually be helping prevent severe dengue fever

scientist working with blood

Researchers at the La Jolla Institute for Immunology (LJI), have found definitive evidence that CD4 T cells are not to blame when a mild dengue viral infection morphs into a severe and sometimes deadly dengue hemorrhagic fever/dengue shock syndrome.

This finding 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, in the December 24, 2019, issue of Cell Reports.

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 and an anti-inflammatory function 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 identifying 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, in a related press release.

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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 from 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."

Dr. Tian concluded saying 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.”

This work was performed as a project of the Human Immunology Project Consortium (HIPC) and supported by the 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.

No conflicts of interest were disclosed.

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.

Dengue News is published by Precision Vaccinations