Close up view of the ppGpp binding site of the
RNAP/DksA/ppGpp complex. Source.
by Fred Neidhardt
Growth dominates the attention of many bacteriologists. It has done so for over a century, inspiring explorations into the complex biochemistry and physiology that produce new cells able to grow, survive harsh environments, and live to grow another day.
Likewise, since the earliest days of microbiology, virulence has been a central focus. In fact, studies of how bacteria cause disease have in sheer number dominated the field for the simple reason that more than intellectual curiosity has been involved: human health has demanded that one learn to cure infectious diseases and protect against them.
Until recently, researchers in these two arenas of microbial exploration shared precious little beyond basic technology and a knowledge of bacterial cell structure and function. Separate scientific cultures developed, as is so often the case in human endeavors. Not uncommonly, investigations of infectious disease proceeded largely in medical school departments of internal medicine or pediatrics, while explorations of the intricacies of microbial growth processes were pursued at the same schools in basic science microbiology departments. That situation has been changing in the past couple of decades, and finally the frontiers of bacterial physiology and of virulence (molecular pathogenesis) have virtually fused. An international symposium (Metabolism Meets Virulence) held in Höhenkammer (Germany) in April, 2009 helped signal this watershed. A scan of the topics covered [Ref 1] reveals some of the subjects in which these two areas of research have become intertwined. Today, each subject benefits from attention to the other.
Many examples could be used to illustrate this sea-change, but none is more fully documented than the intimate involvement of the bacterial stringent control system in Legionnaire’s disease of humans. The central player in the stringent control system is ppGpp (guanosine 5’diphosphate, 3’diphosphate), a nucleotide long known as a major governor of bacterial growth processes. A recent review [LINK] co-authored by Michael Cashel (who in Jonathan Gallant’s laboratory discovered this “magic spot” [LINK and LINK]) brings the ppGpp story up to date. This nucleotide alarmone (as it is frequently dubbed) and its helper protein, DskA, have now been shown to orchestrate the complex alternation between two differentiated intracellular forms of the bacterium Legionella pneumophila, a process required for its pathogenicity.
For those interested in the direction of current microbiological research, this tale of ppGpp in disease is enthralling. Here we shall concentrate on Legionella virulence, but readers are directed to a recent review [LINK] that presents in scholarly detail the known involvement of ppGpp in many infectious diseases—and suggests the likely extension to many others.
The following account is a brief summary by one who has been a student of growth and ppGpp regulatory effects for four decades. To ease this author’s conscience for not mentioning all the talented researchers who have explored the stringent system or pioneered studies of Legionella virulence, I express my regret at not paying due respect to these fellow adventurers. Their work is the basis of our story, and I trust that the two recent comprehensive reviews [LINK and LINK] of these areas will be consulted to learn their names and their contributions to this community effort.