A cell surface protein known to regulate innate immune responses also affects the adaptive immune system

April 15, 2015, Agency for Science, Technology and Research (A*STAR), Singapore
A cell surface protein known to regulate innate immune responses also affects the adaptive immune system
Each Chikungunya virus particle in the above micrograph is about 30 nanometers in diameter. Credit: A*STAR Singapore Immunology Network

Understanding the immune response triggered by the mosquito-borne Chikungunya virus (CHIKV) is key to developing effective treatments. Now, an international team led by A*STAR researchers has shown that a cell surface protein—the toll-like receptor 3 (TLR3)—plays a critical role in controlling the antibody response to CHIKV, viral replication and pathology.

CHIKV starts with a fever and often debilitating joint pain that can last for weeks to months. First discovered in Tanzania, the virus has spread worldwide—it poses a threat to public health since no specific anti-viral treatment exists.

The human body marshals defenses against the virus: the innate immune system kicks in as an immediate response to an infection. Cells express proteins, such as TLR3, that bind viruses like CHIKV (see image) and trigger the expression of cytokines. These cytokines in turn recruit immune cells, like macrophages and neutrophils that destroy the virus.

Lisa Ng from the Singapore Immunology Network and her team sought to clarify the role of TLR3 in CHIKV infection and disease progression.

The team showed that in human and mouse fibroblasts, TLR3 inhibits replication of CHIKV. Mice lacking TLR3 had higher levels of than those with normal TLR3—as more virus entered the blood stream and spread through the body from the infection site. Mice without TLR3 also exhibited more joint inflammation due to higher recruitment of macrophages and neutrophils.

To dissect the role of TLR3 in different cell types, Ng and her team targeted hematopoietic stem cells, the that give rise to all . They introduced that do not express TLR3 into wild-type mice without functional bone marrow. In response to a CHIKV infection, these chimeric mice had higher levels of virus in the blood and took longer to clear the virus.

This delayed clearance pointed to a role of TLR3 in B cell function, cells that produce antibodies in response to a pathogen as part of acquired immunity. "The most surprising finding in our study," says Ng, "is the additional role of TLR3 in adaptive ." The team showed that the loss of TLR3 led to antibodies that could no longer neutralize the virus efficiently.

The next step toward effective therapy is to dissect the molecular mechanism that drives virus-mediated inflammation, says Ng. "These data will allow the definition of unique molecular signatures that can be combined with our results to introduce appropriate mechanistic intervention."

Explore further: Targeted stimulation of immune pathway may help body fight back against liver cancer

More information: "Loss of TLR3 aggravates CHIKV replication and pathology due to an altered virus-specific neutralizing antibody response." EMBO Molecular Medicine 7, 24–41 (2015). dx.doi.org/%2010.15252/emmm.201404459

Related Stories

Targeted stimulation of immune pathway may help body fight back against liver cancer

June 5, 2013
Though it originates from the body's own cells, a tumor is as much of a hostile invader as any virus or bacterium. If the immune system is sufficiently sensitized, it can mount a counterattack just as it might fight an infection. ...

Details of monkey antibodies against chikungunya virus could help to fight the disease in humans

September 24, 2014
Chikungunya fever can cause severe and long-lasting joint pain, with several epidemics affecting multiple continents in the past decade. The illness is caused by chikungunya virus (CHIKV), but there is no effective vaccine ...

Virology: Seeking solutions to viral migration

July 3, 2013
Although seldom fatal, persistent infection by chikungunya virus (CHIKV) afflicts patients with joint pain lasting months or even years. This insect-borne virus has received relatively little scientific attention in the 50 ...

A single enzyme plays a critical role in helping the body effectively fight viral infection

August 15, 2012
The body’s initial response to invading bacteria or viruses is mediated by the innate immune system, wherein cells secrete signaling factors called cytokines that promote inflammation and stimulate a generalized counterattack ...

Exploiting the early immune response in Chikungunya fever promises to provide protection

July 4, 2012
(Medical Xpress) -- Chikungunya fever is a viral disease that has re-emerged to cause epidemics in the Pacific region within the last decade. It is caused by the Chikungunya virus (CHIKV), which is transmitted by mosquitoes ...

Targeting key cells for a dengue virus infection model

November 5, 2014
Dengue virus infects hundreds of millions of people living in tropical countries every year. Transmitted via mosquito bites, the virus typically causes fever, but may also lead to potentially fatal organ failure. The development ...

Recommended for you

A Trojan horse delivery method for miRNA-enriched extracellular vesicles

November 20, 2018
A method for large-scale production of extracellular vesicles enriched with specific microRNAs (miRNAs) has been developed in the Wake Forest Institute for Regenerative Medicine (WFIRM) labs, offering a manufacturing standardization ...

Researchers stop 'sneaky' cancer cells in their tracks

November 20, 2018
A new study by University of Minnesota biomedical engineers shows how they stopped cancer cells from moving and spreading, even when the cells changed their movements. The discovery could have a major impact on millions of ...

Machine learning can be used to predict which patients require emergency admission

November 20, 2018
Machine learning—a field of artificial intelligence that uses statistical techniques to enable computer systems to 'learn' from data—can be used to analyse electronic health records and predict the risk of emergency hospital ...

Researchers hope to be able to replace dysfunctional brain cells

November 20, 2018
A new study by researchers at Karolinska Institutet supports the theory that replacement of dysfunctional immune cells in the brain has therapeutic potential for neurodegenerative diseases like ALS and Alzheimer's disease. ...

RNAi therapy mitigates preeclampsia symptoms

November 19, 2018
A collaboration of scientists from the University of Massachusetts Medical School, Beth Israel Deaconess Medical Center and Western Sydney University, have shown that an innovative new type of therapy using small interfering ...

Skeletal imitation reveals how bones grow atom-by-atom

November 19, 2018
Researchers from Chalmers University of Technology, Sweden, have discovered how our bones grow at an atomic level, showing how an unstructured mass orders itself into a perfectly arranged bone structure. The discovery offers ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.