Nav: Home

Novel model for studying intestinal parasite could advance vaccine development

June 20, 2019

The intestinal parasite Cryptosporidium, which causes a diarrheal disease, is very good at infecting humans. It's the leading cause of waterborne disease from recreational waters in the United States. Globally, it's a serious illness that can stunt the growth of, or even kill, infants and young children. And people with compromised immune systems, such as those with HIV/AIDS, are also highly susceptible. There is no vaccine and no effective treatment.

Surprisingly, the parasite strains that infect humans don't do such a good job at infecting mice. To study the disease, researchers have had to rely on mice with defective immune systems, a model that made it difficult to understand how to elicit an immune response that could protect children.

But that is set to change. Using a naturally occurring species of mouse Cryptosporidium, a team led by researchers from Penn's School of Veterinary Medicine has developed a model of infection that affects immunologically normal mice. They show that mice develop immunity to the parasite after infection, and that a live attenuated vaccine offers the animals protection against it. Their findings appear in the journal Cell Host & Microbe.

"We now have a fantastic mouse model that mirrors the human disease," says Boris Striepen, a biologist at Penn Vet and senior author on the study. "It's a powerful lab model, where we can introduce changes at will and test the importance of different components of the immune response to infection, which is just what we need to develop an effective vaccine."

Mice that received the experimental vaccine, which used a weakened version of the parasite, were as protected from infection as those that had already weathered an initial infection, the researchers found. "We were able to show that the mice were protected --not by sterile immunity--but by very robust protection from disease, which is exactly what is observed in children," says Adam Sateriale, first author on the report and a postdoctoral researcher in Striepen's lab.

Striepen has focused on advancing science on Cryptosporidium for the last several years. One major advance came in 2015, when his lab found success in using the CRISPR-Cas9 technology to genetically modify the organism.

In the new work, Striepen, Sateriale, and colleagues aimed to develop a method to more easily study the parasite in mice, which are resistant to the two species responsible for most human infections. Taking a different tack, they searched for Cryptosporidium DNA in mice feces from farms and found one species, C. tyzzeri, in 30 percent of the samples.

"One of the first things we did was sequence and annotate the genome," says Sateriale, finding it to be an extremely close relative of the species that affect humans. "Once we know the genome, we can not only see how it varies compared to those species, but we can also begin to use our genetic tools to manipulate it."

Among the manipulations the researchers made using CRISPR were introducing genes that make the parasite glow using a gene borrowed from the firefly, allowing them to precisely, but non-invasively, track the infection.

Unlike the more artificial models of infection that used immunocompromised mice, the Penn-led team showed that C. tyzzeri could infect healthy mice, causing an infection that replicated many features of human disease.

"Some of the main immunological components that have been shown to be important in people were also true of this mouse model," Striepen notes.

Specifically, they found that T cells and the protein interferon-gamma, a key player in fighting off a variety of infections, were both critical in the body's response to the parasite. Mice lacking the gene for interferon-gamma and those that lacked T cells had more severe, longer-lasting infections than normal mice.

"Understanding these correlates of immunity--how the parasite triggers an immune response, and by what mechanism the immune system then attacks the parasite--are important aspects of vaccine development," Striepen says.

Knowing that children who become infected with Cryptosporidium can develop resistance to subsequent infections, the researchers wanted to see if the same held true in the mice. After confirming that this was the case, their final effort was to attempt to vaccinate the mice. They exposed C. tyzzeri spores to radiation to weaken them. Mice that received the vaccination with the live attenuated C. tyzzeri were protected from infection, though mice lacking either interferon-gamma or T cells were not protected, again underscoring the importance of these factors in developing anti-Cryptosporidium immunity.

Encouraged by their findings, the researchers are continuing to probe the pathways involved in conferring immune protection against Cryptosporidium infection, and are sharing their model with colleagues to aggressively pursue a vaccine or other treatments for the disease.

"We feel fortunate to be at the vet school and at Penn in general as we work on these questions," says Striepen. "Here we can build larger teams of parasite biologists, and experts in the study of immune responses like our colleague Christopher Hunter, so we're building up an interdisciplinary effort that can overcome the challenges of working on these complex investigations. And hopefully this will lead to advances that protect children."
-end-
Striepen and Sateriale collaborated on the work with Penn Vet's Julie B. Engiles, Jodi A. Gullicksrud, Emily M. Kugler, and Christopher A. Hunter; the University of Sydney's Jan Šlapeta; and the University of Georgia's Rodrigo Baptista, Gillian T. Herbert, Carrie F. Brooks, and Jessica C. Kissinger.

Boris Striepen is a professor in the Department of Pathobiology in the University of Pennsylvania School of Veterinary Medicine.

Adam Sateriale is a postdoctoral researcher in the Striepen laboratory in Penn's School of Veterinary Medicine.

The study was supported in part by the National Institutes of Health (grants AI112427, AI124518, AI055400, and AI137442) and the Bill and Melinda Gates Foundation (grants OPP1161001 and OPP1151701).

University of Pennsylvania

Related Immune Response Articles:

How to boost immune response to vaccines in older people
Identifying interventions that improve vaccine efficacy in older persons is vital to deliver healthy ageing for an ageing population.
Unveiling how lymph nodes regulate immune response
The Hippo pathway keeps lymph nodes' development healthy. If impaired, lymph nodes become full of fat cells or fibrosis develops.
Early immune response may improve cancer immunotherapies
Researchers report a new mechanism for detecting foreign material during early immune responses.
Researchers decode the immune response to Ebola vaccine
The vaccine rVSV-EBOV is currently used in the fight against Ebola virus.
Immune response depends on mathematics of narrow escapes
The way immune cells pick friends from foes can be described by a classic maths puzzle known as the 'narrow escape problem'.
Signature of an ineffective immune response to cancer revealed
Our immune system is programmed to destroy cancer cells. Sometimes it has trouble slowing disease progression because it doesn't act quickly or strongly enough.
Putting the break on our immune system's response
Researchers have discovered how a tiny molecule known as miR-132 acts as a 'handbrake' on our immune system -- helping us fight infection.
Having stressed out ancestors improves immune response to stress
Having ancestors who were frequently exposed to stressors can improve one's own immune response to stressors, according to Penn State researchers.
Researchers discovered new immune response regulators
The research groups of Academy Professor Riitta Lahesmaa and Research Director Laura Elo from Turku Centre for Biotechnology have discovered new proteins that regulate T cells in the human immune system.
Blueprint for plant immune response found
Washington State University researchers have discovered the way plants respond to disease-causing organisms, and how they protect themselves, leading the way to potential breakthroughs in breeding resistance to diseases or pests.
More Immune Response News and Immune Response Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at Radiolab.org/donate.