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 promote resistance on experimental croplands
Canadian researchers have generated both novel and existing antibiotic resistance mechanisms on experimental farmland, by exposing the soil to specific antibiotics.
Why antibiotics fail
UCSB biologists correct a flaw in the way bacterial susceptibility to these drugs is tested.
Fungi have enormous potential for new antibiotics
Fungi are a potential goldmine for the production of pharmaceuticals.
Antibiotics can boost bacterial reproduction
The growth of bacteria can be stimulated by antibiotics, scientists at the University of Exeter have discovered.
Last-line antibiotics are failing
The ECDC's latest data on antimicrobial resistance and consumption shows that in 2015, antibiotic resistance continued to increase for most bacteria and antibiotics under surveillance.
Two antibiotics fight bacteria differently than thought
Two widely prescribed antibiotics -- chloramphenicol and linezolid -- may fight bacteria in a different way from what scientists and doctors thought for years, University of Illinois at Chicago researchers have found.
Preserving the power of antibiotics
News release describes efforts to address inappropriate antibiotic prescribing in emergency departments and urgent-care centers nationwide, which a JAMA study published this past May found rates as high as 50 percent for acute respiratory infections in US emergency departments.
Antibiotics could be cut by up to one-third, say dairy farmers
Nine in 10 dairy farmers participating in a new survey from the Royal Association of British Dairy Farmers (RADBF) say that the farming industry must take a proactive lead in the battle against antibiotic resistance.
Antibiotics may be inappropriate for uncomplicated diverticulitis
Antibiotics are advised in most guidelines on diverticulitis, which arises when one or more small pouches in the digestive tract become inflamed or infected.
New book on Antibiotics and Antibiotic Resistance from CSHLPress
'Antibiotics and Antibiotic Resistance' from CSHLPress examines the major classes of antibiotics, together with their modes of action and mechanisms of resistance.

Related Antibiotics Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Jumpstarting Creativity
Our greatest breakthroughs and triumphs have one thing in common: creativity. But how do you ignite it? And how do you rekindle it? This hour, TED speakers explore ideas on jumpstarting creativity. Guests include economist Tim Harford, producer Helen Marriage, artificial intelligence researcher Steve Engels, and behavioral scientist Marily Oppezzo.
Now Playing: Science for the People

#524 The Human Network
What does a network of humans look like and how does it work? How does information spread? How do decisions and opinions spread? What gets distorted as it moves through the network and why? This week we dig into the ins and outs of human networks with Matthew Jackson, Professor of Economics at Stanford University and author of the book "The Human Network: How Your Social Position Determines Your Power, Beliefs, and Behaviours".