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Why staph, a common bacteria, induces severe illness

As much as we try to avoid it, ­we constantly share germs with those around us. But, even when two people have the same infection, their response can be dramatically different — mild for one, severe or life-threatening for another.

Now, research from The Rockefeller University offers insights into how this happens. Jean-Laurent Casanova, professor and head of the St. Giles Laboratory of Human Genetics, Infectious Diseases, is senior attending physician at the Rockefeller University as well as a visiting professor at the Necker Hospital for Sick Children, Paris Descartes University, and a Howard Hughes Medical Institute Investigator. He led a team of researchers to uncover how two different conditions — (1) a genetic immunodeficiency and (2) delayed acquired immunity — can combine to produce a life-threatening infection.

In the research, published February 23 in Cell, Casanova and his team focused on the case of an otherwise healthy young girl who developed a life-threatening infection from a very common strain of bacteria. Most of us carry Staphylococcus aureus, on our skin and in our nostrils. It can cause minor "staph infections", but in some people it results in severe disease.

The young girl's illness was mysterious: she had no known risk factors that would lead her to develop the acute form of the disease, and none of her family members had contracted it.

Casanova and team set out to define what caused her disease by searching her DNA for mutations that might make her more susceptible to staph.

They quickly identified a likely culprit — a single letter substitution in two copies of a gene encoding a protein known as TIRAP — which is used by specific immune cells to flag invading bacteria.

In laboratory experiments, researchers found TIRAP to be critical for cells in the immune system's first line of defense against invaders. These cells develop before we are born, with built-in recognition systems for a host of molecules frequently present on the surface of invader bacteria.

"We were sure this was the explanation for the severity of her staphylococcal disease. We thought we had it all figured out."

Jean-Laurent Casanova MD PhD, Professor, Head of the St. Giles Laboratory of Human Genetics of Infectious Diseases, and Senior Attending Physician the Rockefeller University, and Visiting Professor at the Necker Hospital for Sick Children, Paris Descartes University, INSERM, Paris, France and Howard Hughes Medical Institute Investigator.

But, things turned out to be more complicated. To test his hypothesis, Casanova analyzed the DNA of others in the patient's family. None had suffered severe staph infections, so they should have had normal TIRAP genes. However, Casanova found the opposite — all seven members of her family had the same mutation as the young patient.

Researchers now had two questions instead of one: Why did this child get the invasive disease? And why are her family seemingly immune, even though they share her immune-compromising mutation? The answers lie in a second line of immune defense not encoded within our DNA at birth. This secondary defense depends on cells that generate antibodies against foreign compounds.

Casanova: "This is not something we are born with, but instead it is resistance that we acquire over the course of our lifetime when we are exposed to new pathogens."

Researchers found the patient lacked antibodies against a single molecule, LTA. However, its levels were normal in all of her family members.

LTA is present on the surface of staphylococcal bacteria. Normally immune cells recognize it in both lines of defense. Antibodies against LTA were able to restore the function of the patient's immune cells in culture. Researchers went on to confirm their hypothesis using a mouse model of the disease.

"Her illness likely resulted from failures in both lines of immunity. In her family, a second layer of defense compensated for genetic defects in the first.

"More broadly, it offers insight into how two people with the same infection, and even the same DNA, can have very different illnesses."

•Inherited TIRAP deficiency impairs cellular responses to TLR2 and TLR4 stimulation
•Human TIRAP is redundant for protective immunity against most micro-organisms
•Anti-LTA antibodies rescue TLR2-dependent responses to LTA in TIRAP-deficient cells
•TIRAP deficiency causes staphylococcal disease in the absence of anti-LTA antibodies

The molecular basis of the incomplete penetrance of monogenic disorders is unclear. We describe here eight related individuals with autosomal recessive TIRAP deficiency. Life-threatening staphylococcal disease occurred during childhood in the proband, but not in the other seven homozygotes. Responses to all Toll-like receptor 1/2 (TLR1/2), TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes of all TIRAP-deficient individuals. However, the whole-blood response to the TLR2/6 agonist staphylococcal lipoteichoic acid (LTA) was abolished only in the index case individual, the only family member lacking LTA-specific antibodies (Abs). This defective response was reversed in the patient, but not in interleukin-1 receptor-associated kinase 4 (IRAK-4)-deficient individuals, by anti-LTA monoclonal antibody (mAb). Anti-LTA mAb also rescued the macrophage response in mice lacking TIRAP, but not TLR2 or MyD88. Thus, acquired anti-LTA Abs rescue TLR2-dependent immunity to staphylococcal LTA in individuals with inherited TIRAP deficiency, accounting for incomplete penetrance. Combined TIRAP and anti-LTA Ab deficiencies underlie staphylococcal disease in this patient.

Keywords: TIRAP, toll-like receptors, staphylococcus aureus, lipoteichoic acid, LTA, anti-LTA antibodies, primary immunodeficiency, incomplete clinical penetrance

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Mar 10, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   

LTA is a single molecule found on the surface of staphylococcal bacteria.
TIRAP is a protein used to flag such invading bacteria.
In the MIDDLE column - a patient missing antibodies against the LTA molecule.
present on the surface of staphylococcal bacteria, cannot stop the staph infection.
Image Credit: The Rockefeller University



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