This April, Akiko Iwasaki, PhD, Sterling Professor of Immunobiology and Professor of Dermatology and Molecular, Cellular, and Developmental Biology, and of Epidemiology at Yale, was named to the TIME100 by TIME Magazine. The TIME100 recognizes the most influential people of 2024 in a variety of categories, including Iwasaki’s category of innovator.
“Her expertise in innate immunity – or how the immune system first reacts to pathogens – is providing key insights into Long COVID, validating patient experiences and informing treatment strategies,” writes Anthony Fauci, MD, of Iwasaki. “Her leadership and her compassion, including championing women and people of color in science, has enormously benefited the scientific enterprise, and all of us.”
Just two weeks after the first announcement, Iwasaki appeared on a second TIME100 list – the TIME100 Health – celebrating her work in disease prevention.
“I was really surprised to be listed twice. I’m absolutely floored by this recognition in both cases,” said Iwasaki. “This really brings to the forefront that scientists are people of influence. The fact that there were several women scientists included in this list hopefully shows the next generation of girls and women thinking about getting into science as a career that it’s a really worthy pursuit.”
Iwasaki is a three-time funded Women’s Health Research at Yale Investigator who has used Pilot Project Program funding to explore innovation in immunology. Her most recent Women’s Health Research at Yale study focused on sex differences in COVID-19.
Helpful Definitions
Immune signatures: Specific patterns of immune system markers that indicate a particular immune response or state. Such markers within these patterns can include gene expression, cytokines, cell surface markers, and antibodies.
Immunobiology: A branch of biology focused on the study of the immune system and its physiological response to foreign substances including pathogens as well as its role in health and disease.
Immunology: The science of the immune system, including all aspects of immunity and the immune response.
Long COVID: A chronic condition that occurs after a SARS-CoV-2 infection and is present for at least three months.
Systemic Immunization: The induction of a protective immune response throughout the entire body, typically achieved through vaccination.
T-cells: Also known as T lymphocytes, T-cells are a type of white blood cell that plays a central role in adaptive immune response.
Sex Differences in COVID-19
Early reports at the onset of the SARS-CoV-2 outbreak suggested that men were dying from COVID-19 at a greater rate than women. As a consequence, Women’s Health Research at Yale Director Carolyn M. Mazure, PhD, contacted Iwasaki to determine if these reports indicated there might be a sex difference in immune response to the coronavirus. Iwasaki agreed that this was important to explore and provided an application, which Mazure fast-tracked for review. Ultimately Iwasaki and her team were awarded a pilot project grant to examine sex differences in the immune response to the coronavirus.
In Nature August 2020, Iwasaki and her co-authors revealed initial biological explanations for why men were more likely than women to suffer from severe cases of COVID-19 and die from the disease.
When the body is attacked by a pathogen, such as a virus, it mounts an inflammatory response to fight the infection. This innate immune response includes the production of inflammatory proteins called cytokines. Although cytokines are key to managing infection, overproduction of these proteins can cause harm. The research found that male patients often had higher plasma levels of cytokines than female patients. Additionally, female patients were more likely to have a robust activation of an adaptive immune response that produces T-cells, which are white blood cells that can recognize individual invading viruses and eliminate them.
As stated by the authors, “These findings provide a possible explanation for the observed sex biases in COVID-19 and provide an important basis for the development of a sex-based approach to the treatment and care of male and female patients with COVID-19.”
Iwasaki and her team continue to examine sex differences, now in Long COVID – which is more common in women than men and in which women and men experience different sets of symptoms and distinct patterns of organ system involvement. In this work, both the role of the immune system as well as the endocrine system – a complex network of glands and organs that produce and release hormones in fighting infection – are targets of investigation.
Their findings suggest both a distinct immunological processes in females and males and illuminate the crucial role of immune-endocrine disruption in sex-specific pathology.
Although women and men produce both the hormones testosterone and estradiol, which vary by sex, Iwasaki’s research finds a reduction in usual testosterone levels in females with Long COVID. This reduction correlates with many of the immune signatures – specific immune patterns that indicate a particular response or state – that are also uniquely affected in people with Long COVID within the female population. Of note, when examining men with Long COVID, there are lower levels of estradiol than normally found in men. These findings both suggest distinct immunological processes in females and males, and they highlight the crucial role of immune-endocrine disruption in sex-specific pathology. Iwasaki believes these mechanistic findings offer the potential to inform interventions for Long COVID and help the more than 65 million people around the world who suffer from it.
“The more we look, the more we find,” says Iwasaki. “It’s a fascinating area of research and I hope to continue to bring immunological insights through a sex and gender lens to our research.”
The Importance of Understanding the Immune System
As an immunologist, Iwasaki has researched a variety of infections over the course of her storied career. In 2003, Iwasaki received her first Pilot Project Program grant from Women’s Health Research at Yale to study genital herpes, which is more common and more severe in women than men. In her study, she determined how the HSV-2 virus (Herpes Simple Virus Type 2) enters the cells of the genital tract.
Specifically, her research, published in the Journal of Virology, found that it was difficult to infect female vaginal tissues and mucus membranes with herpes at certain stages of the estrous cycle in in a mouse model. This observation led to the finding that risk for infection depends upon the presence of viral entry receptors – specific protein molecules on the surface of a host cell used by a virus to bind to the cell and gain entry into the cell – which vary over the course of hormonal cycles. This provided an important foundation of how the virus operates and greater understanding of mechanisms that could be targeted for treatment and prevention.
In an associated study leveraging Women’s Health Research at Yale Pilot Project funding, Iwasaki explored a novel way to provide a vaccine for genital herpes. Building on her earlier research, Iwasaki and team developed a “prime and pull” vaccine strategy that begins with exposure to the virus at the mucosal site of infection to prepare or “prime” the system to recognize the HSV-2 herpes virus. This creates a baseline level of immune response in which there is the capacity to “pull” or mobilize the system to respond at the tissue being affected. In response to exposure to HSV-2 via this immunization (prime), virus-specific T-cells were shown to be activated by the application of chemokines – small, secreted proteins – to combat the infection. This strategy allows immune cells to form a defensive frontline within the genital tissues to combat herpes infection. And the approach proved successful. Using “prime and pull,” Iwasaki and team protected mice from a lethal herpes infection with a 100 percent survival rate.
“Hopefully, we can use ‘prime and pull’ as a mechanism for treatment of humans in the future,” said Iwasaki. Today, a post-doctoral associate in the Iwasaki Laboratory is developing therapeutic vaccines to treat genital herpes.
The Importance of Studying Sex and Gender Differences
“We’ve learned a lot over the years about how women and men respond quite differently to the same pathogen,” says Iwasaki. Current research in her lab investigating sex differences in immune response are studies on chronic fatigue syndrome, genital herpes, Long COVID, lung disease, lupus, Lyme disease, post-acute infection syndromes, and more. Comparing results to male and female immune signatures is key.
“Innovation is found through this kind of basic research because it is designed to inform clinical interventions, the clinical experience then tells us what mechanisms need to be uncovered next in the laboratory. This is exactly the kind of work that I hope will help us find immune signatures that signal improvement,” said Iwasaki.
Currently, Iwasaki is leading a randomized clinical trial with Harlan Krumholz, MD, Harold J. Hines, Jr. Professor of Medicine (Cardiology) at Yale, centered on Paxlovid for Long COVID. Enrollment is complete, and data analysis of blood and saliva samples has begun to shed light on potential ways to improve health outcomes for women and men experiencing long-term effects of COVID-19.
“Women’s health research anywhere is important, but the fact that Yale is at the forefront considering this type of research for so many years, with a dedicated center, is amazing,” said Iwasaki. “Women’s Health Research at Yale has been a catalytic and initiating force for so many people, including myself, who conduct research related to sex and gender differences that end up showing something very important.”