Yale investigators have identified significant differences in how the immune systems of women and men respond to the virus that causes COVID-19. In a study launched by Women’s Health Research at Yale and published Aug. 26 in Nature, the authors revealed possible biological explanations for why men are more likely than women to suffer severe cases of COVID-19 and die of the disease. “We now have clear data suggesting that the immune landscape in COVID-19 patients is considerably different between the sexes and that these differences may underlie heightened disease susceptibility in men,” said senior author Akiko Iwasaki, Ph.D., the Waldemar Von Zedtwitz Professor of Immunobiology and Molecular, Cellar and Development Biology, and an investigator of the Howard Hughes Medical Institute. “Collectively, these data suggest we need different strategies to ensure that treatments and vaccines are equally effective for both women and men.” Around the world, men account for about 60 percent of deaths from COVID-19, which has sickened 23.7 million people and killed more than 814,000. In England, researchers studying 17 million adults found that men could face nearly twice the risk of death from the disease as women. Drawing on extensive prior research revealing significant differences in the immune systems of women and men, Iwasaki led a team of researchers to examine sex differences in immune response to SARS-CoV-2, the virus that causes COVID-19. The team included Dr. Saad B. Omer, the Susan Dwight Bliss Professor of Epidemiology, Professor of Microbial Diseases, Director of the Yale Institute for Global Health, and Associate Dean for Global Health Research, and Dr. Aaron Ring, Assistant Professor of Immunobiology. The researchers collected nasal, saliva, and blood samples from non-infected control subjects as well as patients with the disease. The team followed patients over time to observe how initial immune responses differ in patients who recover from the disease and those who progress to worse stages of the disease. When comparing male and female patients, the researchers found key differences in the immune response during the early phases of infection. These differences included higher levels for men of several types of inflammatory proteins called cytokines, including two known as IL-8 and IL-18. Cytokines are deployed as part of the body’s innate immune reaction. This a first general counterattack to invading pathogens, in which immune cells are called to the site of an infection, creating inflammation of the affected tissue as a physical barrier against the invading pathogen to promote healing. These findings answer questions about COVID-19 that point the way toward a more effective, targeted response to this disease.Dr. Carolyn M. Mazure However, in severe cases of COVID-19, an excessive buildup of cytokines, referred to as a “cytokine storm,” causes fluid to build up in the lungs, depriving the body of oxygen and potentially leading to shock, tissue damage, and multiple organ failure. The earlier higher concentrations of cytokines in men make these outcomes more likely. In contrast, the researchers found that female patients had more robust activation than men of T-cells, white blood cells of the adaptive immune system that can recognize individual invading viruses and eliminate them. Observations over time revealed that poor T-cell responses in men led to worsening of the disease. When female patients had highly elevated innate cytokine levels, they too did worse. In addition, older men — but not older women — were observed to have significantly worse T-cell responses than younger patients. Based on these findings, the researchers suggest exploring therapeutic interventions and vaccine strategies that elevate T-cell immune response to the virus in male patients and that dampen innate immune activation during early stages of the disease in female patients. “These findings answer questions about COVID-19 that point the way toward a more effective, targeted response to this disease,” said Women’s Health Research at Yale Director Carolyn M. Mazure, Ph.D. “As Dr. Iwasaki and her colleagues conclude, researchers racing to develop treatments and vaccines should consider separate strategies for women and men so that everyone can benefit.” Other authors on the study include Takehiro Takahashi, Patrick Wong, Mallory K. Ellingson, Carolina Lucas, Jon Klein, Benjamin Israelow, Julio Silva, Ji Eun Oh, Tianyang Mao, Maria Tokuyama, Peiwen Lu, Arvind Venkataraman, Annsea Park, Feimei Liu, Amit Meir, Jonathan Sun, Eric Y. Wang, Anne L. Wyllie, Chantal B.F. Vogels, Rebecca Earnest, Sarah Lapidus, Isabel M. Ott, Adam J. Moore, Arnau Casanovas-Massan, Charles Dela Cruz, John B. Fournier, Camila D. Odio, Shelli Farhadian, Nathan D. Grubaugh, Wade L. Schulz, Albert I. Ko, and the Yale IMPACT research team.