Research Article: SOD Enzymes and Microbial Pathogens: Surviving the Oxidative Storm of Infection

Date Published: January 7, 2016

Publisher: Public Library of Science

Author(s): Chynna N. Broxton, Valeria C. Culotta, Donald C Sheppard.


Partial Text

Since oxygen appeared in the biosphere some 3–5 billion years ago, all organisms have had to deal with the hazards of potentially damaging reactive oxygen species (ROS), such as superoxide, hydrogen peroxide, and hydroxyl radical. Like all organisms, pathogenic microbes produce ROS as byproducts of aerobic metabolism, but the burden of ROS is magnified when these microbes confront the oxidative burst of the host. As part of the innate immune response, macrophages and neutrophils attack invading microbes with toxic superoxide [1]. To counteract this attack, some microbial pathogens express superoxide dismutase enzymes (SOD).

The accepted nomenclature for bacterial SODs is SodA, SodB, and SodC for the Mn, Fe, and Cu/Zn SODs, respectively. Because superoxide does not generally cross biological membranes, the intracellular SodA and SodB largely remove intracellular or metabolic sources of superoxide while the periplasmic/extracellular SodC directly combats superoxide from the animal host. Not all bacterial pathogens contain extracellular SodC; for example, the Lyme disease pathogen Borrelia burgdorferi contains a single Mn-SodA. This pathogen also does not express Fe-SodB, representing a clever adaptation to limiting Fe supplies in the host [4,5].

As with other eukaryotes, pathogenic fungi express a largely cytosolic Cu/Zn Sod1 and a distinct Mn-containing Sod2 in the mitochondrial matrix (Fig 1). Cu/Zn Sod1 is a documented virulence factor for Cryptococcus neoformans and Candida albicans [17,18]. Activity of fungal Sod1 is limited by the availability of its Cu co-factor [19], and Cu inside the host can vary tremendously. Cu can become very high in activated macrophages [20], and consistent with this, C. albicans mutants defective in Cu detoxification show impairments in macrophage invasion [21]. Cu can also become high in specific host niches, such as in lungs infected with C. neoformans and in the bloodstream during C. albicans and C. neoformans invasion [22,23]. However, in tissues that are targeted by C. neoformans and C. albicans (such as brain and kidney tissues), Cu availability can become very low [23,24]. We have recently shown that C. albicans adapts to such variations in host Cu by adjusting its metal co-factor selection for SODs. When host Cu is high, the yeast expresses Cu/Zn Sod1, but when host Cu is low, C. albicans will switch to a non-Cu alternative, namely a cytosolic Mn-Sod3 (Fig 1) [23]. Cytosolic Mn SODs are extremely rare in biology, and the unusual expression of Mn-Sod3 in the C. albicans cytosol endows this pathogen with uninterrupted SOD activity irrespective of host Cu [23].

While all aerobic organisms express SODs for endogenous superoxide, many pathogens have been armed with additional SODs designed to function in the hostile climate of the host–pathogen interface. This is particularly true for extracellular Cu-SODs of bacteria and fungi that lie in the direct line of fire from host superoxide. The phage-acquired SodCs of pathogenic E. coli and Salmonella are resilient towards host proteases and will not readily surrender their Cu co-factor to the host. Additionally, the Cu-only SODs of Mycobacterium and of fungal pathogens appear optimally designed to function in host environments of low Zn and high Cu. As a final thought, it is worth mentioning that the host cell itself must endure the oxidative insult of its own doing. Like the invading microbe, host cells secrete Cu/Zn SODs to manage extracellular superoxide, but how well this host SOD has evolved to endure the infection battleground remains to be determined.




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