EWU Researcher Seeks Insights Into Immunity

For patients with asthma, arthritis, lupus and related conditions, glucocorticoid-based drugs, often referred to as corticosteroids, play a crucial role in tamping down immune-related inflammation. For those with organ transplants, glucocorticoids often serve as critical, life-preserving barriers against immune system attacks on their new organs.

Unfortunately, a suppressed immune system is a weakened immune system. Long courses of glucocorticoids put patients at greater risk for opportunistic infections that a healthy person would likely shrug off. Transplant recipients are especially vulnerable.

Savini Thrikawala, an assistant professor of biology at EWU, is among an international cohort of researchers laying the groundwork for treatments that aim to minimize such immune-response hazards.

From her soon-to-be-up-and-running laboratory in Eastern’s newly renovated Science Building, Thrikawala and her student collaborators will use a new-to-EWU animal model —  zebrafish larva — to explore the still little-understood, molecular-level mechanisms behind glucocorticoids’ effects on immune cells. She says the research, funded by a recently announced $362,000 grant from the National Institutes of Health, could provide important clues toward developing drugs that strike a “just-right” balance between immune responses’ suppression and aggression.

“An ideal immunosuppressant would be immunosuppressant just enough so that you don’t reject the transplant, but you still keep that capability of fighting off infections,” says Thrikawala. For now, she adds, there is no such treatment.

 

Glucocorticoid drugs are chemical look-alikes of cortisol, the hormone our bodies release under stress. Cortisol effectively dampens immunity. But it can also do the opposite, switching immune cells on rather than off. Scientists don’t know exactly why, when or how the switch gets turned.

“It’s like you try to find this glucocorticoid drug that’s perfect, but you don’t even know how your own hormone is regulating your immune cells,” Thrikawala says. “That fundamental biological information is lacking.”

Zebrafish may provide answers. Because their larvae are nearly transparent, Thrikawala says she can use them to watch immune cells chase down and eliminate infectious invaders in real time. And because zebrafish larvae haven’t yet developed the “adaptive” aspect of their immune systems, Thrikawala and her students will be able to more easily focus on the “innate” form of immunity that is active in cortisol regulation.

“In your immune system, you have two parts — what we call innate and adaptive. Innate system is basically the front-line defense, that’s capable of fighting off many of the common infectious agents,” Thrikawala says. “The idea behind this grant is, ‘How can we still keep these innate immune cells active with a glucocorticoid-like treatment to avoid transplant rejection, for example?’”

For now, she says, the zebrafish model will help her identify the cellular mechanisms lying behind cortisol’s regulation of innate immune cells. The grant will also help her explore how gene-editing tools might be useful in altering cortisol levels in individual cells, work that will involve the time-consuming task of developing new lines of transgenic fish.

“I’m hoping to be able to manipulate — change — the cortisol levels inside a single immune cell, [or] in a group of immune cells,” Thrikawala says. “There’s a high risk of failure, but if it works, a high reward. I think that’s probably why I got this particular grant, which is usually a high-risk, high-reward type.”

 

“The current understanding is that when you have a higher level of cortisol in your body, that’s going to be immunosuppressive. And if you have a lower level of cortisol, that’s going to be immune promoting. So if I can manipulate cortisol level in individual cells, then I can show, in a live animal, that yes, this is what the cell is doing.”

The NIH funding will not just help to establish Thrikawala’s zebrafish research program at EWU, it will also fund the purchase of a fluorescence microscope to observe the tiny, glowing larvae. In addition, it will include financial support for undergraduate and graduate researchers, funds to help these students attend national scientific conferences, and include support for additional project-based courses.

Thrikawala joined the EWU biology faculty last fall after earning a doctoral degree at the University of Houston and completing a post-doctoral appointment at Clemson University. She says she’s excited to move into her laboratory, and that her new colleagues at Eastern have been both welcoming and supportive. She adds that she’s been especially impressed by the students with whom she has worked thus far.

“They’re independent, they’re smart and they are really responsible — something that I expect from whoever is working in my lab,” Thrikawala says. “Really, they’ve been amazing.”