HMN 2025: How Zika virus knocks out our immune defenses

Zika virus and dengue virus are very shut kin. Both are mosquito-borne flaviviruses, and each specialise in infecting a number’s dendritic cells.

But a study in Nature Communications, led by scientists at La Jolla Institute for Immunology (LJI) and UC Diego, exhibits that these two viruses have vastly other ways of constructing us sick.

Zika virus makes use of stealth mode. Zika virus slips into dendritic cells and blocks the dendritic cells from alerting close by T cells to hazard. It’s the traditional horror film cliché—the creeper is already in the home, and the cellphone traces have been reduce.

Dengue virus prefers shock and awe. Dengue virus pushes dendritic cells to churn out molecules referred to as pro-inflammatory cytokines, which ship the immune system into overdrive. The virus spreads to new host cells because the physique grapples with this overwhelming immune response.

Understanding these totally different an infection methods is essential to growing life-saving vaccines, says LJI Professor Sujan Shresta, Ph.D. Her group is working to develop vaccines that harness virus-fighting T cells to fight Zika virus, dengue virus, and different flaviviruses with pandemic potential.

“Our final objective is to develop vaccines in opposition to these very tough viruses,” says Shresta, who co-led the brand new study with UC San Diego Professor Aaron Carlin, M.D., Ph.D. “Understanding how these viruses manipulate the immune response may help information the event of the perfect vaccine method.”

Why Zika-infected dendritic cells cannot name for assist

This new collaboration is the primary to indicate precisely how Zika virus accomplishes its sneak assault. Using a method pioneered by Carlin throughout his postdoctoral work at UC San Diego and LJI, the researchers remoted solely Zika- or dengue-infected dendritic cells derived from human blood samples. Then they examined gene expression in these cells to see how they responded to the an infection.

The Zika-infected dendritic cells did little or no—and the researchers might lastly see why. They discovered that Zika virus actively suppresses an vital molecule in cells, referred to as NF-?B p65. Without NF-?B p65, dendritic cells get caught in an immature state and can’t promote T cells to battle the an infection.

In distinction, dengue virus actually stimulates dendritic cells to make numerous pro-inflammatory cytokines and reply aggressively to the presence of the virus.

This discovery helps clarify why many individuals develop a weaker immune response to Zika virus versus dengue virus, says Ying-Ting Wang, Ph.D, former LJI postdoctoral fellow and first writer of the present study. The new analysis additionally supplies a clue to how Zika virus manages to interrupt past immune defenses within the placenta to contaminate growing fetuses.

“Zika virus inhibits any type of productive dendritic cell response,” says Carlin. “We suppose that is a key to its pathogenesis, its skill to unfold silently and persist inside people that it infects.”

Right now, there are not any efficient vaccines or therapeutics in opposition to Zika virus or dengue virus. The new findings could assist scientists outsmart these viruses.

“Looking at these human cell cultures helps us perceive what is going on on in individuals,” says Shresta. “Our findings inform how we’d develop vaccines and antivirals that manipulate these mobile pathways.”

Why Zika and dengue vaccines are essential

Shresta and Carlin are keen to maneuver ahead with flavivirus analysis. They know there isn’t any time to lose.

Many mosquito-borne viruses are spreading quickly as disease-carrying Aedes mosquitoes increase into new habitats. In truth, final yr was the worst on file for reported dengue virus circumstances. Dengue virus contaminated between 100 million and 400 million individuals in 2024, in line with the World Health Organization (WHO). These circumstances included the first-ever circumstances of regionally transmitted dengue virus an infection in San Diego County.

Many flaviviruses even have pandemic potential. In a 2024 report, WHO listed Zika virus, dengue virus, West Nile virus, tick-borne encephalitis virus, and yellow fever virus among the many prime pathogens for analysis “prioritization” in preparation for the subsequent pandemic.

Shresta has monitored the unfold of those viruses in recent times. As she explains, many of those viruses overlap in the identical areas. As a outcome, hundreds of thousands of persons are vulnerable to an infection from a wide range of flaviviruses that assault dendritic cells from totally different angles.

Shresta is main efforts at LJI to develop a “pan-flavivirus” vaccine which may fight many flaviviruses without delay.

“Our problem is to develop vaccines which are each secure and efficient in opposition to not only one virus, however all these carefully associated flaviviruses,” says Shresta.

At the identical time, Carlin is trying to develop antivirals which may intervene with Zika’s skill to suppress NF-?B p65. He’d additionally like to research precisely how dengue virus over-stimulates the immune system.

“Understanding how dengue virus stimulates that shock-like phenotype in individuals would permit for precision-guided therapies that stop demise and hospitalization with out inhibiting our immune system’s skill to clear the virus,” says Carlin.

Additional authors of the research embody 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.