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Understanding the Distinct Strategies of Zika and Dengue Viruses
Zika virus and dengue virus share a close genetic relationship as mosquito-borne flaviviruses that primarily infect a host’s dendritic cells. However, a recent study published in Nature Communications by researchers from the La Jolla Institute for Immunology (LJI) and UC San Diego reveals that these viruses utilize markedly different mechanisms to induce illness.
Zika virus employs a stealth approach, effectively infiltrating dendritic cells and preventing these immune cells from alerting T cells to the presence of danger. It is akin to a classic horror scenario where the intruder has already entered the house while communication lines are severed.
Conversely, dengue virus opts for a shock-and-awe strategy, prompting dendritic cells to produce pro-inflammatory cytokines that place the immune system in a heightened state of response. This aggressive immune activation allows dengue virus to spread to additional host cells as the body struggles to cope with the overwhelming immune reaction.
Insights into the disparate infection strategies of these two viruses are crucial for developing effective vaccines, according to LJI Professor Sujan Shresta, Ph.D. Her team is dedicated to creating vaccines that harness T cells to counteract Zika, dengue, and other flaviviruses with the potential to cause widespread outbreaks.
“Our ultimate goal is to devise vaccines against these challenging viruses,” states Shresta, who co-led this research with UC San Diego Professor Aaron Carlin, M.D., Ph.D. “Understanding how these viruses exploit the immune response will inform the development of effective vaccine strategies.”
Exploring Zika’s Intricate Mechanism of Immune Evasion
This collaboration marks a significant advancement in comprehending how Zika virus executes its stealthy invasion. Researchers utilized innovative techniques developed by Carlin during his postdoctoral research to isolate dendritic cells infected with either Zika or dengue from human blood samples. They then scrutinized the gene expression of these cells to assess their response to infection.
The findings revealed that Zika-infected dendritic cells exhibited minimal activity, clarifying the mechanism behind their inactivity. Research indicated that Zika virus suppresses a key cellular molecule known as NF-κB p65. This suppression causes dendritic cells to remain in an immature state, hindering their ability to activate T cells for fighting the infection.
In contrast, dengue virus significantly stimulates dendritic cells to produce abundant pro-inflammatory cytokines, leading to a robust immune response against the virus.
This research elucidates why many individuals show a relatively weaker immune reaction to Zika in comparison to dengue, notes Ying-Ting Wang, Ph.D., a former LJI postdoctoral fellow and the study’s lead author. Additionally, these findings shed light on how Zika virus can evade immune defenses in the placenta, leading to fetal infection.
“Zika virus represses any productive response from dendritic cells,” remarks Carlin. “We believe this is pivotal for its pathogenesis, allowing it to silently spread and persist in infected individuals.”
At present, effective vaccines or treatments for Zika and dengue viruses remain unavailable. These new insights hold promise for scientists seeking to outmaneuver these viral threats.
“Studying human cell cultures provides valuable information about the mechanisms at work in the human body,” explains Shresta. “Our discoveries could pave the way for developing vaccines and antiviral therapies that target these cellular pathways.”
The Urgency of Developing Zika and Dengue Vaccines
Shresta and Carlin are keen to advance their flavivirus research, recognizing the urgency of their work.
Many mosquito-borne viruses are rapidly spreading as disease-carrying Aedes mosquitoes extend their reach to new environments. The prior year reported the highest number of dengue cases on record, infecting between 100 million and 400 million individuals globally in 2024, according to the World Health Organization (WHO). This surge includes the first instances of locally transmitted dengue infections in San Diego County.
Flaviviruses are also recognized for their pandemic potential. A WHO report in 2024 identified Zika, dengue, West Nile, tick-borne encephalitis, and yellow fever viruses as top research priorities to prepare for future pandemics.
Shresta has observed the proliferation of these viruses in recent years, noting significant overlap in their geographic distribution. This overlap places millions at risk of multiple flaviviral infections that target dendritic cells through varying mechanisms.
To address this challenge, Shresta is leading efforts at LJI to create a “pan-flavivirus” vaccine that could provide a broad defense against various flaviviruses. “Our objective is to develop vaccines that are safe and effective against these closely related viruses,” she states.
Simultaneously, Carlin aims to formulate antivirals that could disrupt Zika’s ability to inhibit NF-κB p65 while also investigating how dengue virus provokes excessive immune responses.
“Understanding how dengue virus elicits such shock-like responses in patients will enable us to develop targeted therapies capable of averting severe outcomes such as hospitalization and death without compromising the immune system’s ability to eliminate the virus,” explains Carlin.
Additional authors of the study, “Zika but not Dengue Virus Infection Limits NF-κB Activity in Human Monocyte-Derived Dendritic Cells and Suppresses their Ability to Activate T Cells,” include Ying-Ting Wang, Emilie Branche, Jialei Xie, Rachel E. McMillan, Fernanda Ana-Sosa-Batiz, Hsueh-Han Lu, Qin Hui Li, Alex E. Clark, Joan M. Valls Cuevas, Karla M. Viramontes, Aaron F. Garretson, Rubens Prince dos Santos Alves, Sven Heinz, and Christopher Benner.
The study received support from a Career Award for Medical Scientists from the Burroughs Wellcome Fund, a fellowship from Taiwan’s Ministry of Science and Technology, an American Association of Immunologists Career Reentry Fellowship, and various NIH grants.
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