These parasites increased expression of arginase to decrease nitric oxide levels, according to Nature Immunology paper.

Researchers have discovered a new pathway used by disease-causing bacteria to evade the host immune system and survive and grow within the macrophages meant to destroy them.


White blood cells make compounds that in most cases kill pathogens. One of these chemicals is the free radical nitric oxide (NO), which is made through Toll-like receptor (TLR) signaling in macrophages. A natural NO inhibitor made by macrophages is the enzyme arginase. It steals and degrades the material required to make NO.


The research team discovered that intracellular pathogens increase levels of arginase, thereby reducing the amount of NO the macrophages produce, enabling intracellular pathogens to survive.


The research team discovered that intracellular pathogens induced expression of the arginine hydrolytic enzyme arginase 1 (Arg1) in mouse macrophages through the TLR pathway. Specific elimination of Arg1 in macrophages favored host survival during T. gondii infection and decreased lung bacterial load during tuberculosis infection.


For the study, the investigators generated mice lacking the arginase gene in their macrophages. After infecting the arginase knockout mice with Mycobacterium tuberculosis (TB), they observed that the mice had fewer bacteria and higher levels of NO in their lungs.


The team then infected arginase knockout mice with an intracellular parasite that causes toxoplasmosis, a disease that also is controlled by NO. They observed that mice lacking arginase had higher survival rates than mice that produced arginase. When knockout mice were infected with bacteria that are not killed by NO, though, the lack of arginase did not affect the macrophages’ ability to clear the infection.


The scientists hope to next determine what other parts of the immune system are affected when arginase is blocked.


The article appears in the November issue of Nature Immunology and was completed by researchers at St. Jude Children’s Research Hospital and the Laboratory of Parasitic Diseases at NIAID.

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