Nav: Home

On the way to fighting staph infections with the body's immune system

May 15, 2019

Researchers have gained a greater understanding of the biology of staphylococcus skin infections in mice and how the mouse immune system mobilizes to fight them. A study appears this week in the Proceedings of the National Academy of Sciences of the United States of America. Community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) typically causes skin infections but can spread throughout the body to cause invasive infections such as sepsis, and possibly death.

These CA-MRSA bacteria are becoming increasingly resistant to multiple antibiotics, making them especially difficult to treat. In healthy people, the body's natural immune defenses typically keep CA-MRSA infections in the skin, and appropriate antibiotics can effectively treat them. However, patients who are immunocompromised have difficulty fighting the bacteria, which can become invasive and cause life-threating infections.

"While the human immune responses that protect against S. aureus infections have remained elusive, we have as a start determined in mice that protective immunity against MRSA is orchestrated by specific immune cells called gamma/delta T cells, which upon infection travel from the lymph nodes to the infected skin to initiate the protective host response," says Lloyd Miller, M.D., Ph.D., an associate professor of dermatology at the Johns Hopkins University School of Medicine.

Miller notes that CA-MRSA and other multidrug resistant bacteria are becoming a bigger problem in health care, as most antibiotics no longer work against these infections and few new antibiotics are being developed in the pipeline. In the case of CA-MRSA, sometimes only two or three oral antibiotics remain that can treat these infections.

Miller and his team are working to understand the specific details of the mouse immune system's MRSA-fighting program to develop a way to probe the human immune system to develop alternative immune-based treatments that could work along with antibiotic regimens, or eliminate the need for antibiotics altogether.

In their previous research, Miller and his team discovered that a cytokine protein called IL-17 is critical for turning on the host defense against staph infections. However, until know, they did not know which cell produced it, particularly which type of T cell. Also, there are two types of IL-17, one called IL-17A and the other IL-17F, but the researchers didn't know if one or the other or both are required to mount the host response against CA-MRSA. So they teamed up with colleagues at the National Institutes of Health (NIH) who had engineered mice that would glow different colors depending on which form of IL-17 the mouse was making. The researchers then injected MRSA in the skin of these mice and found that the infected skin glowed green and red. They concluded this to mean that both types of IL-17 are involved in the immune response to the bacteria.

"We were fairly certain that IL-17 was being made by T cells but we didn't know if it was the T cells that are normally in the skin or T cells that were migrating from the lymph nodes to the site of infection," says Miller. Using the same glowing mice, the team asked what would happen if it blocked T cells from leaving the lymph nodes and treated the mice with FTY720 (fingolimod), a drug normally used to treat multiple sclerosis by keeping T cells from mobilizing from lymph nodes and minimizing inflammatory responses. After administering FTY720 to the mice that had an MRSA infection, the researchers saw no glowing, which informed them that the IL-17 seen at the site of the MRSA infection in the skin was made solely by T cells that had migrated from the lymph nodes.

The researchers then extracted cells from the infection site as well as cells from the lymph nodes both before and after infecting the mice with MRSA. They labeled these cells with different colors depending on the types of proteins found on the surface of each cell. In mice without MRSA, a particular type of T cells called gamma/delta T cells expanded dramatically after infecting the mice with MRSA.

The team then set out to determine which exact cells were expanding. Working with colleagues at the University of California, Davis, the team determined the genetic sequences of all of the T cell receptors in the mouse lymph nodes before and after infecting the mice with MRSA. They found that only one type of gamma/delta T cell clone expanded with a specific T cell receptor. What's called the V gamma 6/Vdelta 4(+) expanded from 2% to over 20% to fight MRSA.

"We think that this one single gamma/delta T cell clone is mediating the protective IL-17 response in mice," says Miller. "What's more is that these results really relied on having the latest technologies available to scientists today. We couldn't have figured this out 10 years ago, for example.

"While it is not known if there is an exact parallel cell type in humans, we're encouraged that we can find something similar, which means we could be well on our way to developing new T cell-based therapies against MRSA."

Next steps for this team involve examining the T cell responses in humans to determine if a similar mechanism exists.
-end-
Other authors on this paper include Mark Marchitto, Carly Dillen, Haiyun Liu, Robert Miller, Nathan Archer, Roger Ortines, Martin Alphonse, Alina Marusina, Advaitaa Ravipati, Yu Wang, Angel Byrd, Bret Pinsker, Isabelle Brown, Emily Zhang, Shuting Cai, Nathachit Limjunyawong and Xinzhong Dong of Johns Hopkins; Alexander Merleev, Scott Simon and Emanual Maverakis of the University of California, Davis; Michael Yeaman of the University of California, Los Angeles; Wei Shen and Scott Durum of the National Institutes of Health and Rebecca O'Brien of National Jewish Health.

This work was supported by the National Institutes of Arthritis and Musculoskeletal and Skin Diseases (R01AR069502 and R01AR073665), the National Institute of Allergy and Infectious Diseases (R21AI126896 [L.S.M.], U01AI124319 [to MRY] and R01AI129302 [to SIS]), and federal funds from the National Cancer Institute under Contract Number HHSN261200800001E (MRA) (to S.D.) and the Office of the National Institutes of Health Director (1DP2OD008752 [to EM]).

Johns Hopkins Medicine

Related Antibiotics Articles:

Antibiotics: City dwellers and children take the most
City dwellers take more antibiotics than people in rural areas; children and the elderly use them more often than middle-aged people; the use of antibiotics decreases as education increases, but only in rich countries: These are three of the more striking trends identified by researchers of the NRW Forschungskolleg ''One Health and Urban Transformation'' at the University of Bonn.
Metals could be the link to new antibiotics
Compounds containing metals could hold the key to the next generation of antibiotics to combat the growing threat of global antibiotic resistance.
Antibiotics from the sea
The team led by Prof. Christian Jogler of Friedrich Schiller University, Jena, has succeeded in cultivating several dozen marine bacteria in the laboratory -- bacteria that had previously been paid little attention.
Antibiotics not necessary for most toothaches, according to new ADA guideline
The American Dental Association (ADA) announced today a new guideline indicating that in most cases, antibiotics are not recommended for toothaches.
Antibiotics with novel mechanism of action discovered
Many life-threatening bacteria are becoming increasingly resistant to existing antibiotics.
Resistance can spread even without the use of antibiotics
Antibiotic resistance does not spread only where and when antibiotics are used in large quantities, ETH researchers conclude from laboratory experiments.
Selective antibiotics following nature's example
Chemists from Konstanz develop selective agents to combat infectious diseases -- based on the structures of natural products
Antibiotics can inhibit skin lymphoma
New research from the LEO Foundation Skin Immunology Research Center at the University of Copenhagen shows, surprisingly, that antibiotics inhibit cancer in the skin in patients with rare type of lymphoma.
Antibiotics may treat endometriosis
Researchers at Washington University School of Medicine in St. Louis have found that treating mice with an antibiotic reduces the size of lesions caused by endometriosis.
How antibiotics help spread resistance
Bacteria can become insensitive to antibiotics by picking up resistance genes from the environment.
More Antibiotics News and Antibiotics 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.