Abstract

The innate immune system in humans consists of both cellular and humoral components that collaborate to eradicate invading bacteria from the body. Here, we discover that the gram-positive bacterium Bacillus anthracis, the causative agent of anthrax, does not grow in human serum. Fractionation of serum by gel filtration chromatography led to the identification of human transferrin as the inhibiting factor. Purified transferrin blocks growth of both the fully virulent encapsulated B. anthracis Ames and the non-encapsulated Sterne strain. Growth inhibition was also observed in serum of wild-type mice but not of hypotransferrinemic mice that only have approximately 1% circulating transferrin levels. We were able to definitely assign the bacteriostatic activity of transferrin to its iron-binding function: neither iron-saturated transferrin nor a recombinant transferrin mutant unable to bind iron could inhibit growth of B. anthracis. Additional iron could restore bacterial growth in human serum. The observation that other important gram-positive pathogens are not inhibited by transferrin suggests they have evolved effective mechanisms to circumvent serum iron deprivation. These findings provide a better understanding of human host defense mechanisms against anthrax and provide a mechanistic basis for the antimicrobial activity of human transferrin.

Highlights

  • The innate immune system in humans consists of both cellular and humoral components that collaborate to eradicate invading bacteria from the body

  • B. anthracis was propagated on Todd Hewitt agar (THA) plates and grown under aerobic conditions at 30 °C; for liquid cultures, bacteria were grown in TH broth (THB) at 37 °C

  • Human Serum Inhibits Growth of B. anthracis—While studying the role of humoral blood components in the defense against Gram-positive pathogens, we observed that growth of B. anthracis Sterne is strongly impaired in the presence of normal human serum (Fig. 1A)

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Summary

Human Transferrin Confers Serum Resistance against Bacillus anthracis*

We discover that the Gram-positive bacterium Bacillus anthracis, the causative agent of anthrax, does not grow in human serum. The observation that other important Gram-positive pathogens are not inhibited by transferrin suggests they have evolved effective mechanisms to circumvent serum iron deprivation. These findings provide a better understanding of human host defense mechanisms against anthrax and provide a mechanistic basis for the antimicrobial activity of human transferrin. The most lethal form, respiratory anthrax, is caused by inhalation of dormant bacterial spores, which are taken up by alveolar macrophages and dendritic cells. We determine that serum resistance is provided by transferrin, identifying a novel antibacterial function of this human iron homeostasis protein

EXPERIMENTAL PROCEDURES
Transferrin Is a Critical Defense Molecule against Anthrax
RESULTS
DISCUSSION
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