Nutritional Immunity and Fungal Pathogens: a New Role for Manganese

Abstract

Purpose of review: Copper, zinc, iron and manganese are essential micronutrients for all living organisms. Microbial pathogens must acquire these elements from their host. Through a process termed nutritional immunity, animal hosts seek to withhold these vital nutrients from the microbe and the competition for metals can influence survival outcomes during infection. Much is known about the battle for iron, copper and zinc during fungal infections, but a picture is just now beginning to emerge for manganese.

Recent findings: Pathogenic fungi utilize manganese for antioxidant defense, cell wall construction, morphogenesis and survival in animal and plant hosts. The animal host can limit manganese availability for invading fungi at the macrophage, neutrophil and whole tissue levels.

Keywords: fungal pathogenesis; infection; manganese; mannosylation; metals.

Figure 1:

Mn transport and trafficking in a fungal cell: Mn ion uptake is mediated by NRAMP Mn transporters that based on studies in S. cerevisiae, localize to the cell surface and endosomes. The Mn is taken up by the Golgi through Mn and Ca transporters PMR1 and GDT1 that activate Mn requiring mannosyl transferases (MNT) in the secretory pathway. Mn is also delivered to the mitochondria to activate Mn containing SOD2. The mechanism may involve an interaction with NRAMP-containing endosomes (see main text). In certain fungi (e.g., C. albicans), Mn is delivered to the cytosol to activate a cytosolic Mn-SOD3.

Figure 2:

The effects of fungal Mn deficiency on the cell wall. Shown are the layers of the fungal cell wall atop the plasma membrane lipid bilayer. The fungal cell wall can be comprised of inner beta glucan (green balls) and chitin (brown horizontal lines) layers, and an outer mannose layer (blue) derived from heavily mannosylated cell wall proteins (CWP) such as Cu-only superoxide dismutases (Cu-SOD). Left- under Mn replete conditions the fungal cell wall is intact. Right – under Mn starvation conditions, the loss in activity of mannosyl transferases results in very short mannose chains on cell wall proteins and an attenuated mannose layer. The potential implications of such Mn deficiency are listed.