Scientists show lack of single protein results in persistent viral infection
Scientists from The Scripps Research Institute have shown a single protein can make the difference between an infection clearing out of the body or persisting for life. The results also show where the defects occur in the immune system without the protein and offer the possibility that targeting this signaling pathway could be beneficial for treatment of persistent viral infections in humans. Currently hundreds of millions of people around the world are afflicted with persistent viral infections such as HIV, HCV, and HBV.
The new study is published in the June 14, 2012 issue of the journal Cell Host & Microbe.
In the new study, a team led by Scripps Research Professor Michael Oldstone showed what happened when a mouse engineered without the protein TLR7 was infected with lymphocytic choriomeningitis virus (LCMV), a virus employed to study the response of the immune system to microbes. While normal mice infected with a LCMV variant called Cl 13 could clear a persistent infection in 60 to 90 days, TLR7-deficient mice were unable to purge the infection throughout their lives.
"It is well known that RNA from many viruses, including influenza, HIV, and hepatitis C, induce signaling through TLR7," said Kevin Walsh, a research associate in Oldstone's lab and the first author of the study. "We demonstrated that TLR7 plays a significant role in the generation of immune responses required to clear persistent LCMV infection."
In terms of the constant biological warfare between host and microbes, the body is not so much a temple as it is a medieval city. An infectious agent can invade through the skin or mucosa, essentially scaling the walls. Once it's inside it has to deal with the body's first responders, called Toll-like receptors (TLR). These receptors are a pattern-recognition system to alert the immune system. TLRs form the first line of defense specifically by recognizing molecules of the invading pathogen.
Ten TLRs have been identified in humans. One of these, TLR7, is located inside the cell within endosomes and the RNA of viruses are detected after they have entered the cell. "TLR7 is a very important receptor in terms of viruses," noted Oldstone.
In the current study, the researchers chose to use LCMV to understand the role of TLR7. LCMV is, according to Oldstone, "has been, and continues to be a Rosetta Stone to explain basic concepts in immunology and virology."
Once it was clear that the absence of TLR7 compromised the immune system's ability to clear LCMV infection, Oldstone, Walsh, and their colleagues explored what was happening downstream of the receptor.
Interestingly, the research demonstrated that even when immune memory cells, which "learn" to fight an infection and impart long-term immunity, were transferred from TLR7-sufficient mice to TLR7-deficient mice, those deficient mice still couldn't clear the infection.
"The environment within TLR7-deficient mice suppressed the ability of these memory cells to clear the infection," said Walsh.
Surprisingly Tired Cells
The team noticed several unexpected things. First, in the TLR7-deficient mice, there was a profusion of tired T cells. "You see more T cells in TLR7-deficient mice early after infection, but they don't actually clear the infection," said Walsh. "Even though there were more of them, they were less functional." Second, immune system B cells were severely hampered; specifically, the differentiation and maturation of B cells to plasma cells, cells responsible for generating antiviral antibody, was aborted. Thus, both essential arms of the immune system, cellular and humoral, required to clear viral infection were compromised.
Exhausted T cells produce fewer molecules to attack and destroy infected cells. Exhaustion occurs in TLR7-sufficient environments, toobut in those cases there is a resurrection of the T cells 60 to 90 days following infection with LCMV Cl 13, which allows the body to purge the virus. In the TLR7-deficient environment, this resurrection never happens. The exhausted T cells linger, as does the infection. T cell exhaustion is also found in HIV and hepatitis B and C infection.
"A number of phenomena that LCMV uses to cause a persistent infection is the same that HIV, hepatitis C and B use," said Oldstone. "That's what makes our observation important. It means that if you understood what is in the environment with loss of TLR7 signaling and how to correct that, you'd have a better chance of treating those persistent human infections. We know how to treat it in the mouse, and people are working very hard to do the treatments in humans."
More information: "Toll-like receptor 7 is required for effective adaptive immune responses that prevent persistent virus infection," Cell Host & Microbe.
Journal reference: Cell Host & Microbe
Provided by The Scripps Research Institute
- Molecules help the immune system to detect cells infected with West Nile virus Feb 05, 2009 | not rated yet | 0
- Genome-wide study reveals how key immune sensors arrive at the front lines of infection Mar 14, 2012 | not rated yet | 0
- 'Pep talk' can revive immune cells exhausted by chronic viral infection Dec 13, 2011 | not rated yet | 0
- Resistant mice provide clues about successful immune response to retroviruses Jun 30, 2011 | not rated yet | 0
- Immune exhaustion driven by antigen in chronic viral infection May 13, 2009 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Why is zone 1 in liver more prone to ischemic injury?
May 23, 2013 Hi, Is it because around central vein, there is only deoxygenated blood from the vein where as in the periphery there is hepatic artery. Also why...
How can there be villous adenoma in colon, if there are no villi there
May 22, 2013 As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
- More from Physics Forums - Medical Sciences
More news stories
By discovering the new mechanism by which estrogen suppresses lipid synthesis in the liver, UC Irvine endocrinologists have revealed a potential new approach toward treating certain liver diseases.
Medical research May 23, 2013 | 5 / 5 (1) | 0 |
Aortic arch pulse wave velocity, a measure of arterial stiffness, is a strong independent predictor of disease of the vessels that supply blood to the brain, according to a new study published in the June issue the journal ...
Medical research May 23, 2013 | not rated yet | 0
Since the discovery of Prontosil in 1932, sulfonamide antibiotics have been used to combat a wide spectrum of bacterial infections, from acne to chlamydia and pneumonia. However, their side effects can include serious neurological ...
Medical research May 23, 2013 | 3 / 5 (1) | 0 |
Scientists at the National Institutes of Health report they have discovered in mouse studies that a small molecule released in the spinal cord triggers a process that is later experienced in the brain as ...
Medical research May 23, 2013 | 5 / 5 (3) | 0 |
Spanish researchers have discovered that the daily clearance of neutrophils from the body stimulates the release of hematopoietic stem cells from the bone marrow into the bloodstream, according to a report published today ...
Medical research May 23, 2013 | 5 / 5 (2) | 0
Coenzyme Q10 decreases all cause mortality by half, according to the results of a multicentre randomised double blind trial presented today at Heart Failure 2013 congress. It is the first drug to improve heart failure mortality ...
11 hours ago | 5 / 5 (2) | 5
(HealthDay)—Animals make great companions for senior citizens, but elderly people who always drive with a pet in the car are far more likely to crash than those who never drive with a pet, researchers have ...
3 hours ago | not rated yet | 0
Heart failure accelerates the aging process and brings on early andropausal syndrome (AS), according to research presented today at the Heart Failure Congress 2013. AS, also referred to as male 'menopause', was four times ...
11 hours ago | not rated yet | 1
Mortality and length of stay are highest in heart failure patients admitted in January, on Friday, and overnight, according to research presented today at the Heart Failure Congress 2013. The analysis of nearly 1 million ...
11 hours ago | not rated yet | 0
(AP)—Department of Justice lawyers have again asked a federal appeals court in New York to delay lifting age restrictions and prescription requirements on an emergency contraceptive popularly known as the morning-after ...
11 hours ago | not rated yet | 0