Why do some individuals experience intense flu symptoms? Recent research highlights a lesser-known aspect of the antibodies our immune system produces to combat invading viruses.
Viruses are among the quickest evolving entities on the planet. This is why we require annual flu vaccinations: Seasonal influenza consistently evolves to evade the immunity we’ve built from past vaccinations or infections.
Some strains can be more harmful than others. The 1918 flu pandemic claimed 50 million lives and infected one-fifth of the global population. Other influenza pandemics were recorded in 1957, 1968, and 2009.
“Influenza continues to pose a significant global health threat,” remarked Taia Wang, MD, PhD, an associate professor in infectious diseases and microbiology and immunology.
Wang’s research team discovered that the quantity of a specific sugar molecule on our antibodies—the specialized proteins our immune system creates to prevent viruses and other invaders from entering and multiplying in our cells—plays a crucial role in determining whether we suffer mild or severe symptoms from a flu infection.
They also uncovered the underlying reason. In experiments with mice, they demonstrated how to prevent severe flu symptoms, regardless of the virus strain involved. This knowledge could be invaluable during future flu outbreaks and may also apply to other diseases.
The study, set to be published online on November 13 in Immunity, may clarify why older adults are more likely to experience serious flu cases and various other diseases.
Wang, who is part of Stanford Medicine’s Institute for Immunity, Transplantation, and Infection, is the principal investigator of the study. Key contributors include life scientist Saborni Chakraborty, PhD; postdoctoral researcher Bowie Cheng, PhD; graduate student Desmond Edwards; and former graduate student Joseph Gonzalez, PhD.
Inflammation vs. Replication
Some immune cells have a receptor named CD209 on their surface, which can reduce inflammation related to a flu infection, as demonstrated by the study. Wang and her team managed to activate this anti-inflammatory receptor by altering the makeup of antibodies.
This approach didn’t stop the virus from invading lung cells and replicating but was not necessary for prevention.
The rapid replication of viruses in lung cells is clearly undesirable. However, severe cases of influenza are often caused by a damaging inflammatory response to the infection, which worsens lung damage and obstructs gas exchange, rather than the virus itself, according to Wang.
“We’ve identified a novel method to safeguard against severe influenza by suppressing subsequent inflammation without halting viral replication,” she stated.
The method employed to reduce inflammation is not confined to a singular influenza strain.
The antibodies found in blood, referred to as IgG (short for “immunoglobulin G”), have a Y-shaped structure. The branches of the Y are tailored to attach to specific features on certain pathogens, blocking their entry into cells when the fit is right.
The stem of the antibody’s Y shape, however, does not engage directly with the pathogen. Its purpose is to activate other components of the immune system. Different immune cells may respond differently based on the composition of two long, branching chains connected to the stem.
These chains contain sugar molecules—though not the sugary ones you find in sweets. Carbohydrate scientists recognize “sugar” as comprising around a dozen distinct but chemically related substances that are synthesized by our bodies. Many of these sugars have complex names. When attached to larger molecules, they contribute structural integrity, stability, or signaling functions.
Up to four units of a specific sugar known as sialic acid can be attached at the ends of an IgG molecule’s branching chains. The quantity of these units can significantly impact immune responses.
Introducing the Alveolar Macrophage
Wang’s research began by analyzing antibodies from individuals who either suffered mild illness or developed severe symptoms after contracting H1N1, a common strain of seasonal influenza. The only major distinction observed was the level of sialic acid present on the antibodies of the infected individuals. Those with high sialic acid levels exhibited milder symptoms, while those who fell seriously ill had antibodies with lower sialic acid content.
Wang’s team delved deeper, utilizing bioengineered mice with cells that express human antibody receptors.
“We exposed these mice to human antibodies differing only in their sialic acid content,” Wang explained. The mice then received a normally life-threatening dose of two distinctly different seasonal flu virus subtypes.
The antibodies rich in sialic acid protected the mice against both types of flu, mainly due to the considerably decreased lung inflammation.
“This reduction in inflammation improved the exchange of oxygen and carbon dioxide,” Wang noted. “The lungs maintained their functional capabilities.”
The disparity in sialic acid levels did not affect the virus’s ability to replicate within the lung cells.
The researchers identified that the antibodies with high and low sialic acid contents bound to different receptors on the alveolar macrophages. These specialized immune cells monitor the alveoli—the small air sacs in the lungs through which oxygen and carbon dioxide exchange occurs.
When alveolar macrophages detect a virus, they engulf it and signal for additional immune cells to rush to the site. Ordinarily, this influx controls the intruding microbes. However, sometimes an excess of activated immune cells can be more harmful than beneficial, causing damage to healthy cells and potentially leading to further inflammation.
Typically, antibodies bind to pro-inflammatory receptors on alveolar macrophages, triggering increased inflammatory activity. However, the study proved that when more sialic acid is present on an antibody’s stem, it binds to CD209 instead, shifting the macrophages to an anti-inflammatory state.
“CD209 has previously been recognized for its anti-inflammatory properties in autoimmune conditions,” Wang shared. “But its role in modulating our immune response during infections had not been established before.”
Analysis of genes activated in the alveolar macrophages revealed that the same genes showing varied activity levels in mice receiving high- versus low-sialic acid antibodies could categorize flu patients into “mild” and “severe” groups.
Many of these genes are linked to inflammatory responses. Notably, the binding of sialic acid-rich antibodies to CD209 inhibited the activity of a well-known inflammatory trigger called NF-kappa-B.
The Role of Antibody Arms
While the arms of an antibody can target one or a narrow range of pathogens, the protective effect of sialic acid-rich antibodies did not depend on a specific flu strain and was not a result of clearing the virus. It was solely the anti-inflammatory reaction that mitigated the severity of the disease.
Wang’s team questioned whether the protection against severe illness required the entire antibody or if the stem on its own would suffice.
Conveniently, these high-sialic acid antibody stalks are currently being investigated in clinical trials for autoimmune diseases, which also involve inflammatory responses. These stalks effectively prevented serious symptoms in mice infected with the flu.
Ongoing studies in humans are being conducted by Wang’s team to determine if sialic acid-enriched antibody stalks can predict disease progression risk in flu patients.
The implications of these findings may extend beyond influenza and lung infections to a variety of infectious diseases and a spectrum of inflammatory disorders, she indicated.
“Age is a significant factor in distinguishing individuals whose antibodies typically have higher versus lower sialic acid levels,” Wang noted. The decline of sialic acid in older adults may partially explain the common occurrence of chronic low-level inflammation in this population, increasing their risk for conditions like heart disease, strokes, Alzheimer’s, Parkinson’s disease, cancer, and various other age-related ailments.
Wang serves as a consultant for Nuvig Therapeutics Inc., which is currently testing the efficacy of antibody stalks for treating autoimmune diseases and provided materials utilized in this research.
The study involved collaborations from the University of California, San Diego; Nuvig Therapeutics Inc.; the University of Colorado; National Jewish Health; Washington University School of Medicine; the National Institutes of Health; and the Howard Hughes Medical Institute.
Funding for the study was supplied by the National Institutes of Health (grant numbers R01AI150214, R01AI173203, 75N93029C00051, 5U01AI144616, R01AI178298, and UL1TR001866) and the Howard Hughes Medical Institute.
