As winter wraps the world in its frosty embrace, respiratory syncytial virus (RSV) infection leaves many babies coughing and wheezing. RSV infects nearly 90 percent of children before they turn two years old, shaping their health long after the sniffles have faded.1
“There’s a very strong link in epidemiology between early-life RSV infection and the probability of developing allergy and asthma later in life,” said Hamida Hammad, an immunology and inflammation researcher at the Flemish Institute for Biotechnology (VIB) and Ghent University. In addition to RSV, parental allergies also predispose kids to allergic asthma.2 To better understand how RSV and parental allergies drive allergy risk, she teamed up with Bart Lambrecht, a pulmonary medicine researcher at VIB and Ghent University.
Now, by combining health registry data with animal experiments, Hammad and Lambrecht uncovered an additive interaction between maternal allergic disease and RSV infection that drives asthma risk in offspring. They discovered that maternal allergen-specific antibodies amplify allergy risk by boosting T cell priming and activation in progeny who experienced RSV infection as infants.3 The findings, published in Science Immunology, offer a deeper understanding of maternal factors that drive RSV-associated allergies.
“[This] is generally a good study,” said Ashley St. John, an immunologist at Duke-National University of Singapore Medical School, who was not associated with the study. She added that scientists know that maternal allergic disease can drive allergies in the progeny, as can RSV infection. “[The study] gives us some idea that indeed these two things that have been identified before as risk factors are reproducibly risk factors here, so that’s interesting.”
Maternal Allergy and Early-Life Viral Infection Increases Asthma Risk
Hammad, Lambrecht, and their team first sought to understand if severe early-life RSV infection increased children’s susceptibility to developing allergic asthma. Searching a database that covers the entire Danish population revealed that infants hospitalized due to RSV infection received an asthma diagnosis more often compared to babies with a mild RSV infection that resolved with minimal intervantion. This risk increased significantly if they were born to mothers with allergic asthma.
The researchers turned to mouse models to investigate the mechanism behind how maternal allergy and early-life RSV exposure amplified asthma risk. They sensitized female mice to an allergen, and once the animals gave birth, the scientists infected newborn pups with pneumonia virus of mice (PVM), a virus related to RSV. Exposing the offspring to an allergen revealed that, compared to pups of non-allergic mothers, those born to allergic mothers developed more severe asthma-like disease.
Using flow cytometry and RNA sequencing, the researchers observed that PVM infection in neonates promoted the maturation of dendritic cells (DCs) that present antigens to T cells to activate them. “Most people would say the immune system is immature in this perinatal period,” said Lambrecht. “And what we’re showing here is that the virus leads to an accelerated maturation of DCs. To me, this was an eyeopener that those DCs are not so immature after all.”
Neonatal Dendritic Cells Hijack Maternal Antibodies to Activate T Cells and Drive Allergic Responses
Next, the researchers investigated why maternal allergy state influenced asthma risk in pups after PVM exposure. They examined whether maternal antibodies transferred through breastmilk or the placenta would augment DC maturation, contributing to severe asthma symptoms. They investigated whether immunoglobulin G (IgG), an antibody class that significantly crosses the placenta to protect the fetus, was involved in the cascade.
Continue reading below…
Like this story? Sign up for FREE Immunology updates:
Intranasally administrating fluorescently labeled allergy-specific IgG to female mice and tracking the label revealed that these antibodies were indeed transferred to the offspring. But instead of conferring protection, these antibodies drove inflammation after PVM infection in neonates: Pups infected with PVM born to mice that received allergen-specific IgG showed increased T cell numbers and activation. This indicated that viral infection programmed DCs to harness allergen-specific maternal IgG to drive T cell activation and allergy.
While transmission of allergen-specific antibodies from the mother to the offspring was expected, “what I was surprised about is the influence of the virus on top of this,” noted Hammad. “Having such a strong effect of the virus and finding how it works was really, for me, very surprising, to be honest.”
Immunoprophylaxis Prevents Asthma Risk in Later Life
Several countries have set guidelines for RSV vaccination programs in pregnant people and treating newborns with antibodies to curb the burden of viral infection and its ensuing complications.4 Hammad, Lambrecht, and their team sought to investigate whether such measures could prevent asthma using their animal models.
Treating allergic lactating mothers with an antibody that prevents PVM infection disrupted the DC-T cell immune cascade. Similarly, treating newborn pups born to allergic mothers with these antibodies prevented them from developing severe asthma even after early-life PVM exposure, indicating that perinatal immunoprophylaxis could protect against viral infection-induced asthma risk.
While the protective effect of such a treatment was not entirely unexpected, “it was super cool and super exciting for us,” said Hammad.
The findings indicate that some people do truly face early-life exposures that heighten their risk of allergic disease, said St. John. “And those exposures can be not only based on genetics but based on environmental aspects, like their viral exposures and the exposures that the mom has experienced.”
While the findings are interesting, St. John noted that IgE antibodies—involved in allergic diseases—are also transferred through the placenta.5 It still remains to be seen whether these antibodies participate in this cascade, she noted. She also cautioned against extending observations from mice and PVM to humans and RSV. “It’s a model system, and we have to be careful [in] extrapolating [the results].”
Lambrecht agreed that animal models may not accurately capture human biology, but quoted oncologist Howard Skipper: A model is a lie that helps you see the truth. “You can never use the mouse for everything, but for us it led to this insight of how it’s working that there’s a maternal vertical transmission factor via antibodies,” said Lambrecht.
