ADVERTISEMENT

Fighting Histoplasma Capsulatum Infection With IFN-γ Macrophage Activation

Unlike opportunistic fungal pathogens, Histoplasma capsulatum can infect and cause disease in otherwise healthy individuals. Infections result from inhalation of infectious fungal conidia (spores) following disturbance of soils where it grows as a mycelium.

In the lung, exposure to the mammalian body temperature triggers the conidia to convert into pathogenic yeast cells which invade phagocytic cells of the immune system. Normally, these phagocytic cells are adept at eliminating fungal invaders, but H. capsulatum yeasts are able to survive and proliferate within these immune cells. With time, and only after generation of adaptive immunity, these phagocytic cells become activated, eventually leading to control of the pathogen. How H. capsulatum grows within phagocytic cells and how the macrophage changes during activation to control the infection are not well understood.

ADVERTISEMENT

We identified a copper transporter (Ctr3) that contributes to H. capsulatum growth in macrophages. H. capsulatum can grow in high levels of copper, normally toxic to other microbes, but the Ctr3 transporter enables H. capsulatum to acquire copper when copper becomes limiting. During the innate immune response, macrophages are unable to control H. capsulatum and we found that Ctr3 was not required during this stage of infection. However, the onset of adaptive immunity and subsequent activation of macrophages led to rapid control of a Ctr3-deficient strain. These findings suggest that during early stages of the immune response, there is sufficient copper within the macrophage, but that activation of macrophages causes restriction of copper from H. capsulatum in the macrophage.

To verify this, we created a strain of H. capsulatum as a biosensor for copper levels in the H. capsulatum-containing compartment within the macrophage. We constructed a copper-sensing probe by fusing the copper-responsive CTR3 promoter with green fluorescence protein to estimate copper concentrations in H. capsulatum– infected macrophages. In resting and alveolar macrophages, which H. capsulatum first encounters, the H. capsulatum-containing compartment had high levels of copper, thereby permitting H. capsulatum growth. However, treatment of with pro-inflammatory IFN-γ created a copper-restricted environment for intracellular H. capsulatum cells. This change from a copper-high to a copper-limiting intracellular compartment was substantiated in vivo during lung infection.

These findings demonstrate that the macrophage initially infected by H. capsulatum during infection (i.e., during the innate immunity stage), has ample copper which supports intracellular fungal growth but is not toxic to H. capsulatum. With the later onset of adaptive immunity, the production of IFN-γ activates the macrophages that include switching to a copper-restricted intracellular environment in order to limit the growth of intracellular pathogens. Thus, macrophages use both high and low copper in the attempt to control pathogens by copper toxicity or nutritional immunity, respectively. We show for the first time that the activation of immune cells to control fungal pathogens mechanistically includes restriction of available copper, forcing intracellular H. capsulatum to rely on Ctr3 transporter to maintain fungal copper homeostasis.

These findings are described in the article entitled Macrophage activation by IFN-γ triggers restriction of phagosomal copper from intracellular pathogens, recently published in the journal PLOS Pathogens.

ADVERTISEMENT

Comments

READ THIS NEXT

After Earthquakes And Evacuations Hawaii Braces For More Eruptions

Last Thursday, March 3rd, saw a new eruption episode of the volcano Kilauea, located on the Big Island of Hawaii. […]

Female And Male Gamete Cells: Called Sex Cells

Gamete cells, also known as sex cells, are the cells responsible for sexual reproduction. A male gamete is called sperm […]

Helping Sturgeon Survive – Studies On Swimming Performance And Fishways Can Make A Contribution

Sturgeons (Acipenseridae) are primitive fishes that mature late and display migratory behavior. There are 25 species of sturgeon in the […]

Targeting The Polyamine Addiction Of Neuroblastoma

Neuroblastoma is the most common solid tumor of early childhood and arises from the primitive cells of the sympathetic nervous […]

Divided By: Meaning And Steps To Divide Anything

Division in mathematics is one of the 4 major arithmetic operations, along with addition, subtraction, and multiplication (sometimes exponentiation). At […]

Sequence-Defined Molecules Can Be Used To Create 2D Nanomaterials

The unique sequence-defined property endows materials scientists with the ability to precisely tailor and adjust the combination of functional groups […]

Lipidomics Study Reveals Possible Associations Between Staphylococcus Aureus Virulence And Metabolism Of Host Lipids

Have you ever wondered if bacteria that infect us actively modify lipids found in the membrane that surround our cells, […]

Science Trends is a popular source of science news and education around the world. We cover everything from solar power cell technology to climate change to cancer research. We help hundreds of thousands of people every month learn about the world we live in and the latest scientific breakthroughs. Want to know more?