New Approach to Fighting Infection

A new study describes the use of conditional gene targeting to examine the contribution of hypoxia-inducible factor 1-alpha subunit (HIF-1-alpha) to myeloid cell innate immune function, suggesting a new way to fight infection.

In the days following infection, when the human body develops and refines antibodies and prepares to mount an adaptive immune response, the bulwark of innate host defense against microbial infection is the polymorphonuclear leukocyte (PMN). PMNs seek out, identify, engulf, and sterilize invading microbes using both oxygen-dependent and oxygen-independent antimicrobial systems. A decrease in PMN numbers or function caused by immunosuppression or disease increases the risk of infection. Previous studies have identified a novel and essential role for HIF-1-alpha in regulating several important PMN functions relevant to host defense, including transcription of cationic antimicrobial polypeptides and induction of nitric oxide (NO) synthase.

In the current study, investigators at the University of California, San Diego (USA), worked with a line of mice lacking HIF-1-alpha in their myeloid cells. They reported in the July 2005 issue of the Journal of Clinical Investigation that the PMNs in these animals showed decreased bactericidal activity and failed to restrict systemic spread of infection from an initial tissue focus. On the other hand, normal mice chemically treated so their white blood cells contained elevated levels of HIF-1-alpha demonstrated an enhanced capacity to kill bacteria.

"These findings suggest a potential novel approach to treatment of difficult infections such as those produced by antibiotic resistant bacteria or those affecting patients with weakened immune systems due to chronic disease, cancer chemotherapy or AIDS,” said contributing author Dr. Victor Nizet, associate professor of pediatrics at the University of California, San Diego, School of Medicine. "Rather than designing drugs to target the bacteria, medications that promote HIF-1 activity could be used to boost the bacterial killing ability of white blood cells and promote the resolution of infection through the actions of our natural immune defenses.”




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University of California, San Diego