In the Press

Catherine Blish: Immunology is on the trail of a killer

A globally recognized expert in infectious disease and immunology discusses how her lab quickly remade itself to study the virus behind COVID-19.

April 27, 2020
By Stanford Engineering Staff
This article is part of the series: The Future of Everything

A rendering of two hands reaching toward each other, one with pink particles covering it, and the pink particles spreading to the second hand

How can we end the pandemic for good? | Stocksy/Colin Anderson

As she tells it, the life of immunologist Catherine Blish has not changed all that much from what it was just a couple months ago.

Her lab still studies deadly infectious diseases, but instead of myriad killers like HIV, dengue fever, influenza and the like, her team is now focused solely on the SARS-CoV-2 virus that causes COVID-19. Only a select group of researchers in the world are qualified to work with such serious viruses, and fewer still are properly equipped with the protective gear and sophisticated ventilation systems needed to guarantee the safety in the lab.

Blish recently joined Russ Altman for this special COVID-19 edition of Stanford Engineering’s The Future of Everything podcast, to talk about the unique character of the virus, a few surprises she and others have unearthed in their research, and how once-competitive scientists around the world have united to find treatments and a vaccine that are critical to ending the pandemic for good.


Senior Author Dr. Catherine Blish researches link HIV susceptibility to little-understood immune cell class

cells attacking viruses

The white cells are responsible for attacking viruses and tumors

Juan Gaertner/Shutterstock

By Bruce Goldman, Department of Medicine News

High diversity among certain cells that help fight viruses and tumors is strongly associated with the likelihood of subsequent infection by HIV, Stanford University School of Medicine researchers have found.

Natural killer cells, or NK cells, are lymphocytes, a type of white blood cell. NK cells’ increased diversity, the scientists learned, may stem from prior exposures to viruses.

The findings, described in a study published July 22 in Science Translational Medicine, could spur the development of blood tests capable of flagging individuals’ susceptibility to viral infection. The study also offers insights into the workings of NK cells, a somewhat poorly understood but crucial group of immune cells. 

“This puts NK-cell diversity on the map as a metric of immune function,” said Catherine Blish, MD, PhD, assistant professor of infectious diseases and geographical medicine and the study’s senior author. “But it was a first foray. Before we can say definitively that NK-cell diversity predicts a person’s susceptibility to infection, we need to validate these findings by looking at large numbers of individuals in a different population.

“NK cells are particularly suited to detecting and demolishing virally infected or cancerous cells,” Blish added. “They arrive on the scene quickly, and they act quickly. An NK cell can kill an infected cell in 10 minutes.”

 More Unexpected finding

Unexpectedly, it was higher, rather than lower, diversity in this immune-cell population that turned out to be associated with increased HIV susceptibility in the study. The investigators had figured that, as is the case with B cells and T cells — the two other, better-known types of lymphocytes — diversity in NK cells would be a strength, not a detriment, Blish said.

“Our hypothesis was wrong,” she said. “We didn’t think NK-cell diversity would be a bad thing, or that NK cells’ diversification would occur to the extent that it does with viral exposure.”

Using a cutting-edge, single-cell analytic technology called mass cytometry, Blish and her colleagues, including the study’s lead author, graduate student Dara Strauss-Albee, showed that overall diversity in people’s NK-cell repertoires is low at birth and steadily accumulates over the course of a lifetime.

An individual T cell has surface receptors that recognize unique protein snippets, called peptides, on other cells’ surfaces. The structures of these receptors, which can discern “healthy” versus “suspect” peptides, differs from T cell to T cell. So a healthy person’s legion of T cells can surveil and sort out hundreds of millions of different peptides representing possible invaders.

Unlike their T cell cousins, NK cells don’t have surface receptors that recognize unique peptides. Instead, these lymphocytes harbor various combinations of generic receptors. Some receptors recognize signs of other cells’ normalcy, and others recognize signs that a cell is stressed — due, say, to viral infection or cancerous mutation. On recognizing their targeted features on other cells’ surfaces, an NK cell’s “normalcy” receptors tend to inhibit it, while its stress-recognizing receptors activate it.

All told, NK cells can have many thousands of different combinations of these receptors on their surfaces, with each combination yielding a slightly different overall activation threshold. An NK cell’s surface features also vary depending on its degree of maturation.

Mass cytometry analysis of NK cells exposed in a dish to HIV — as well as to West Nile virus, which differs substantially from HIV in its makeup and its modus operandi — showed that exposure to virus-infected cells leads to differentiation of NK cells and to an increased diversity among them. But diversification in the NK-cell population, the experiments indicated, was associated with a diminished ability of these cells’ ability to replicate and kill.

The researchers also showed that while healthy human adults differ considerably from one another in the diversity of their NK-cell populations, a given adult’s NK-cell population remains quite stable, changing little over periods of many months. An examination of NK cells extracted from umbilical-cord blood showed that newborns’ NK-cell population is much less diverse.

Blish said she believes that viral exposure during one’s lifetime is the driving force behind the maturation, differentiation and diversification of NK cells.

Blish said she believes that viral exposure during one’s lifetime is the driving force behind the maturation, differentiation and diversification of NK cells.

HIV link

In order to assess the impact of NK-cell diversity on adult humans’ viral susceptibility, Blish and her associates turned to blood samples that had been drawn during the Mama Salama Study, a longitudinal study of just over 1,300 healthy pregnant or postpartum Kenyan women. In that study, 25 of the women were found to have HIV. For 13 of these women, blood drawn both before and after infection was available.

This puts NK-cell diversity on the map as a metric of immune function.

Using mass cytometry, the researchers carried out a precise analysis of NK cells in the women’s blood and observed a strong positive correlation between the diversity of a woman’s NK cell population and her likelihood of becoming infected with HIV. This correlation held up when the scientists controlled for age, marital status, knowledge of sexual partners’ HIV status and history of trading sex for money or goods. The two groups of women were also statistically indistinguishable with respect to their sexually transmitted disease status or their reported frequency of recent unprotected sex.

The NK-diversity-dependent difference in these women’s likelihood of HIV infection was huge. Those with the most NK-cell diversity were 10 times as likely as those with the least diversity to become infected.

A 10-fold risk increase based solely on NK-cell diversity is far from negligible, said Blish. “By way of comparison, having syphilis increases the risk of contracting HIV two- to four-fold, while circumcised men’s HIV risk is reduced by a factor of 2.5 or 3,” she said.

The observations could have clinical potential, most immediately by spotlighting people who need to be closely monitored for possible viral infections and, perhaps, prophylactically treated. But Blish cautioned that the study remains preliminary.

Other Stanford co-authors are professor of statistics Susan Holmes, PhD; statistics graduate student Julia Fukuyama; research assistant Emily Liang (now a medical student at UCLA); and immunology graduate student Justin Jarrell.

The study was funded by a Beckman Young Investigator Award, a National Institutes of Health New Innovator Award (grant DP2AI11219301) and a National Science Foundation training grant.


Zika infection causes developing cranial cells to secrete neurotoxic levels of immune molecules

New research shows that cranial neural crest cells can be infected by the Zika virus, causing them to secrete high levels of cytokines that can affect neurons in the developing brain.

SEP 29 2016

    Illustration of a normal head and one affected by microcephaly

Babies born to women infected with the Zika virus can suffer from a birth defect called microcephaly, or abnormally small heads. A new study from Stanford found that the infection can affect the cells that give rise to the bones and cartilage of the skull and face.
Alila Medical Media/Shutterstock

Infection by the Zika virus causes a population of cells in the cranium of a developing embryo to secrete neurotoxic levels of immune signaling molecules called cytokines, according to a new study by researchers at the Stanford University School of Medicine.

Although the study was conducted solely in cells grown in a laboratory dish, it may provide one possible explanation for why babies born to women infected with the virus can suffer from a birth defect called microcephaly, or abnormally small heads.

“Affected babies have small brains and small skulls,” said assistant professor of medicine Catherine Blish, MD, PhD. “Cells in the cranial neural crest give rise to the bones and cartilage of the skull and face, and they also form an important supportive niche for the developing brain. We wondered if the Zika virus could infect cranial neural crest cells, perhaps giving rise to deficits in skull formation and altered neural development.”

The study was published online Sept. 29 in Cell Host & Microbe. Blish is the senior author. Graduate students Nicholas Bayless and Rachel Greenberg share lead authorship of the study.

 More A reservoir for the virus

Cranial neural crest cells are cells that arise in humans within about five to six weeks of conception. Although they first appear along what eventually becomes the spinal cord, the neural crest cells migrate over time to affect facial morphology and differentiate into bone, cartilage and connective tissue of the head and face. They also provide critical molecular signals that support nearby developing neurons in the brain. 

Bayless and Greenberg used a technique developed in the laboratory of study co-author Joanna Wysocka, PhD, a professor of chemical and systems biology and of developmental biology, to convert human embryonic stem cells into cranial neural crest precursors in the laboratory. Wysocka’s research focuses on understanding how these cells affect the embryonic development of facial features, including those of humans and chimpanzees.

Recent research has focused on the effect of Zika virus infection of the neural precursor cells that give rise to neurons in the developing brain. But Bayless and Greenberg found that not only can cranial neural crest cells also be infected by the Zika virus, they respond differently than their neighboring neural precursor cells to the infection. Rather than rapidly dying, as the neural precursors do, the cranial neural crest cells act as a reservoir for the virus by allowing it to replicate repeatedly. In addition, they begin to secrete high levels of cytokines, including leukemia inhibitory factor and vascular endothelial growth factor, known to affect neural development.

“The magnitude of altered cytokine secretion caught us by surprise,” said Blish. “These molecules are important for neurogenesis, and the infected cells are secreting them at high levels.”

Abnormally shaped cells

When Bayless and Greenberg incubated neural precursor cells together with infected neural crest cells, the neural precursors appeared abnormal and were more likely to initiate a program of cellular suicide.

They next exposed the neural precursor cells to leukemia inhibitory factor and vascular endothelial growth factor at levels equivalent to those secreted by the infected cells. After three days, they observed an increase in structures associated with cellular migration and growth, as well as a significant increase in the frequency of cell death.

“At least in vitro, these elevated levels of cytokines appear to induce premature differentiation and migration,” said Wysocka. “This abnormal developmental program then leads to cell death.”

The Zika virus, which is spread by the Aedes genus of mosquito, has sprung into the public eye over the past year as it has become increasingly apparent that pregnant women infected with the virus can pass it to the fetus, causing devastating birth defects. Outbreaks of the virus are currently occurring in multiple countries and in three American territories: American Samoa, Puerto Rico and the U.S. Virgin Islands. Local mosquito-borne transmission has also been identified in two areas of Miami, and the World Health Organization has designated the disease a public health emergency of international significance.

“Our study brings attention to the possibility that other infected embryonic cell types in the developing head can influence Zika-associated birth defects, including microcephaly, perhaps through signaling to neighboring cells or by serving as a viral replication reservoir,” said Wysocka. “Formation of the cranial neural crest cells and a cross-talk between brain and craniofacial development occurs during the first three months of human fetal development, which is when epidemiological studies have suggested that Zika infection correlates with poor birth outcomes.”

The researchers said that although the findings are intriguing and merit further study,  their studies were conducted only on cells grown in a laboratory and it is possible that other factors related to Zika infection may affect brain size and outcomes in affected infants.

Tomek Swigut, PhD, a senior scientist in Wysocka’s lab, is also a co-author of the study.

The research was supported by the National Institutes of Health (grants 1DP2AI112193 and DE024430), the Tashia and John Morgridge Faculty Scholar Program from the Stanford Child Health Research Institute, the March of Dimes Birth Defect Foundation, the Howard Hughes Medical Institute, a seed grant from the Stanford Center for Systems Biology and two Ruth L. Kirschstein awards.

Stanford’s Department of Medicine also supported the work.


Zika Linked to Head Defects as Vaccine Money OK'd

Zika vaccine trials receive funding while researchers discover clues to why the virus leads to deformity.

By Eric Niiler | Published on 9/29/2016 at 1:07 PM

Federal health officials studying how to stop Zika are breathing a bit easier today after Congress finally passed long-overdue funding for vaccine clinical trials next year. At the same time, medical researchers in California announced today they have found how the Zika virus disrupts the skull and face of developing babies.

For the past few months, the National Institutes of Health had been borrowing money from cancer, heart disease and other research programs to pay for research on the virus, which is spread by mosquitoes and sexual contact, and causes birth defects in babies born to Zika-infected mothers.

Congress's last-minute $1.1 billion spending measure will get these trials on track, said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.

"We didn't get all the money we wanted, but we got enough to do the clinical trials," Fauci told Discovery News.

The success of the trials depends on whether researchers can find a big enough population at risk that they can test, he explained.


"If in January (2017), there is a major outbreak that returns in Brazil or Puerto Rico or some eastern Asian countries or anyplace where there is an active outbreak, you may know in year or year and a half whether (a vaccine) works."

Scientists say the only way to stop Zika from spreading is with a effective vaccine. There are few treatments for microcephaly, a birth defect that causes babies to be born with small heads and neurological problems for the remainder of the child's life.

Puerto Rico and several other nations have seen huge spikes in the number of cases of microcephaly in the past two years as Zika has spread.

A research team at Stanford University announced today that it has discovered how the Zika virus disrupts the normal development of neural cranial crest cells, which are responsible for the growth of the skull and face.

"Zika can affect development of the skull, but also disrupts the communication between the crest and the developing brain," said Catherine Blish, associate professor of medicine at Stanford University.

"Zika can affect development of the skull, but also disrupts the communication between the crest and the developing brain," said Catherine Blish, associate professor of medicine at Stanford University.

The finding, reported today in the journal Cell Host & Microbe, offers a possible understanding of why children born with the virus can have smaller-than-average skulls and disproportionate facial features. Curing the birth defect is still a remote possibility.

"You can't undo the development that has been done, but you can treat certain symptoms if you understand the reason for the symptoms," said Rachel Greenberg, a graduate student at Stanford and a co-author on the new paper. "If you understand that multiple tissues are affected, you don't just treat as only the brain is being infected."

There are several promising vaccine candidates in the works, but each one has different potential risks for pregnant mothers, according to Fauci, who is publishing a paper in today's New England Journal of Medicine outlining a strategy for the vaccine trials.

Fauci and colleagues say that vaccinating women of childbearing age and their sexual partners is the best approach. If it works, vaccinating children could be an option in the future. Randomized controlled clinical trials are the preferred approach to Zika vaccine testing because of regional variations in Zika incidence. They are also considering so-called "challenge models" where healthy volunteers are purposely bitten by a Zika-infected mosquito (half with a vaccine and half without) and carefully monitored for their response.

"The design of the trial needs to take into account there are a lot of things we do not know about Zika," Fauci said. "We want to make sure that it's safe for a large number of normal people."