Lack of single protein results in persistent viral infection

[Guest guest]

--- [CO-CURE] NOT: RES: Scientists show lack of single protein

results in persistent viral infection

Date: Sun, 17 Jun 2012 16:41:25 -0500

From: kelly <kellylatta66@...>

Reply- kelly <kellylatta66@...>

CO-CURE@...

Note: Toll-like receptor 7, also known as TLR7, is protein that in

humans is encoded by the TLR7 gene. TLR7 is a member of the Toll-like

receptor (TLR) family which plays a fundamental role in pathogen

recognition and activation of innate immunity. TLRs are highly

conserved in humans and share structural and functional similarities.

They recognize pathogen-associated molecular patterns (PAMPs) that are

expressed on infectious agents, and mediate the production of

cytokines necessary for the development of effective immunity.

Scientists show lack of single protein results in persistent viral infection

June 13, 2012 in Medical research

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

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

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. "

'Biological Warfare'

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,

too—but 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

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[Guest guest]

" We know how to treat it in the mouse, and people are working very hard

to do the treatments in humans. "

They said injecting cells from TLR7 sufficient mice didn't help. Did I miss

something since they said they know how to treat it?

Not fully awake yet this morning so may have misread it.

[Guest guest]

One thing I was interested is the " immune exhaustion " state that is apparently

been relatively recently discovered. It's in the article here (was under the

" related articles " tab)

This article:

http://medicalxpress.com/news/2011-12-pep-revive-immune-cells-exhausted.html

The thing is, has anyone studied to see if we fit in the category of " exhausted

immune system " ?

Certainly, if it is a clearly defined concept in immunology then they have a way

to test for it in animals at least... I would assume testing for something like

that would involve counting the numbers of cell types, and the presence/absence/

or large/small quantity of some markers on immune cells. If that is all there is

too it; then this could be done in humans...

I wonder if anyone knows one way or the other? If it is possible, it would be

interesting since finding " immune exhaustion " would indicate a virus of some

sort but without having to identify what it is. As " identifying " viruses has

been such a trouble recently so maybe it would be best simply to perform

experiments to see if one could be implicated based on the state of the immune

system?

I agree it's a bit depressing that the TLR-7 positive cells couldn't hack it in

the diseased mice

" We know how to treat it in the mouse, and people are working very hard

to do the treatments in humans. "

They said injecting cells from TLR7 sufficient mice didn't help. Did I miss

something since they said they know how to treat it?

Not fully awake yet this morning so may have misread it.

[Guest guest]

Look up hypoimmunoglubulemia and Common Variable Immune Deficiency.

My son and best friend diagnosed or misdiagnosed with CFID for many years have

this treatable illness.

We just found out less tha a month ago. They are ordinary blood test but please

go when your sick to see if  the 

immunoglobulings are really low.

[Guest guest]

Hi Barbara,

Isn't it funny that when you learn something new, it pops up everywhere.

I recently was diagnosed with Ehlers-Danlos Syndrome and probably have this and

NOT ME/CFIDS and Fibromyalgia.

One of the co-conditions of EDS is CVID - Common Variable Immune Deficiency. I

was just about to do research to find the type of doctor that would help with

this - immunologist but what sub-specialty.

I think this is a fit for me as is Mast Cell Activation Disorder.

Thanks for posting - any info on good docs or treatment for this would be

appreciated.

Marti

>

> Look up hypoimmunoglubulemia and Common Variable Immune Deficiency.

> My son and best friend diagnosed or misdiagnosed with CFID for many years have

this treatable illness.

> We just found out less tha a month ago. They are ordinary blood test but

please go when your sick to see if  the 

> immunoglobulings are really low.

>

>