Summary
Microbial access to host nutrients is a fundamental
aspect of infectious diseases. Pathogens face
complex dynamic nutritional host microenviron-
ments that change with increasing inflammation
and local hypoxia. Since the host can actively limit
microbial access to nutrient supply, pathogens
have evolved various metabolic adaptations to
successfully exploit available host nutrients for
proliferation. Recent studies have unraveled an
emerging paradigm that we propose to designate
as ‘nutritional virulence’. This paradigm is based
on specific virulence mechanisms that target
major host biosynthetic and degradation path-
ways (proteasomes, autophagy and lysosomes)
or nutrient-rich sources, such as glutathione, to
enhance host supply of limiting nutrients, such as
cysteine. Although Cys is the most limiting cellular
amino acid, it is a metabolically favourable source
of carbon and energy for various pathogens that
are auxotrophic for Cys but utilize idiosyncratic
nutritional virulence strategies to generate a gra-
tuitous supply of host Cys. Therefore, proliferation
of some intracellular pathogens is restricted by a
host nutritional rheostat regulated by certain limit-
ing amino acids, and pathogens have evolved
idiosyncratic strategies to short circuit the host
nutritional rheostat. Deciphering mechanisms of
microbial ‘nutritional virulence’ and metabolism in
vivowill facilitate identification of novel microbial
and host targets for treatment and prevention of
infectious diseases. Host–pathogen synchroniza-
tion of amino acid auxotrophy indicates that
this nutritional synchronization has been a major
driving force in the evolution of many intracellular
bacterial pathogens.
SummaryMicrobial access to host nutrients is a fundamentalaspect of infectious diseases. Pathogens facecomplex dynamic nutritional host microenviron-ments that change with increasing inflammationand local hypoxia. Since the host can actively limitmicrobial access to nutrient supply, pathogenshave evolved various metabolic adaptations tosuccessfully exploit available host nutrients forproliferation. Recent studies have unraveled anemerging paradigm that we propose to designateas ‘nutritional virulence’. This paradigm is basedon specific virulence mechanisms that targetmajor host biosynthetic and degradation path-ways (proteasomes, autophagy and lysosomes)or nutrient-rich sources, such as glutathione, toenhance host supply of limiting nutrients, such ascysteine. Although Cys is the most limiting cellularamino acid, it is a metabolically favourable sourceof carbon and energy for various pathogens thatare auxotrophic for Cys but utilize idiosyncraticnutritional virulence strategies to generate a gra-tuitous supply of host Cys. Therefore, proliferationof some intracellular pathogens is restricted by ahost nutritional rheostat regulated by certain limit-ing amino acids, and pathogens have evolvedidiosyncratic strategies to short circuit the hostnutritional rheostat. Deciphering mechanisms ofmicrobial ‘nutritional virulence’ and metabolism invivowill facilitate identification of novel microbialand host targets for treatment and prevention ofinfectious diseases. Host–pathogen synchroniza-tion of amino acid auxotrophy indicates thatthis nutritional synchronization has been a majordriving force in the evolution of many intracellularbacterial pathogens.
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