Programmed death in bacteria

Abstract

Programmed cell death (PCD) in bacteria plays an important role in developmental processes, such as lysis of the mother cell during sporulation of Bacillus subtilis and lysis of vegetative cells in fruiting body formation of Myxococcus xanthus. The signal transduction pathway leading to autolysis of the mother cell includes the terminal sporulation sigma factor Esigma(K), which induces the synthesis of autolysins CwlC and CwlH. An activator of autolysin in this and other PCD processes is yet to be identified. Autolysis plays a role in genetic exchange in Streptococcus pneumoniae, and the gene for the major autolysin, lytA, is located in the same operon with recA. DNA from lysed cells is picked up by their neighbors and recombined into the chromosome by RecA. LytA requires an unknown activator controlled by a sensory kinase, VncS. Deletion of vncS inhibits autolysis and also decreases killing by unrelated antibiotics. This observation suggests that PCD in bacteria serves to eliminate damaged cells, similar to apoptosis of defective cells in metazoa. The presence of genes affecting survival without changing growth sensitivity to antibiotics (vncS, lytA, hipAB, sulA, and mar) indicates that bacteria are able to control their fate. Elimination of defective cells could limit the spread of a viral infection and donate nutrients to healthy kin cells. An altruistic suicide would be challenged by the appearance of asocial mutants without PCD and by the possibility of maladaptive total suicide in response to a uniformly present lethal factor or nutrient depletion. It is proposed that a low rate of mutation serves to decrease the probability that asocial mutants without PCD will take over the population. It is suggested that PCD is disabled in persistors, rare cells that are resistant to killing, to ensure population survival. It is suggested that lack of nutrients leads to the stringent response that suppresses PCD, producing a state of tolerance to antibiotics, allowing cells to discriminate between nutrient deprivation and unrepairable damage. High levels of persistors are apparently responsible for the extraordinary survival properties of bacterial biofilms, and genes affecting persistence appear to be promising targets for development of drugs aimed at eradicating recalcitrant infections. PCD in unicellular eukaryotes is also considered, including aging in Saccharomyces cerevisiae. Apoptosis-like elimination of defective cells in S. cerevisiae and protozoa suggests that all unicellular life forms evolved altruistic programmed death that serves a variety of useful functions.

FIG. 1

Programmed death of mother cell in sporulation development of B. subtilis. Environmental as well as internal signals are integrated at the level of Spo0A, which in turn activates a cascade of sporulation sigma factors. The terminal sigma factor ς^k controls the final stages of sporulation—formation of the spore cortex, coat synthesis, and expression of autolysins CwlC and CwlH. Activation of autolysins by an unknown factor causes mother cell lysis and liberation of the spore.

FIG. 2

PCD in autolysis of S. pneumoniae. At high cell density, the concentration of a released peptide pheromone (CSP) increases and activates a two-component signal transduction kinase (ComD) and its response regulator (ComE) ( and references therein). Phosphorylated ComE in turn activates transcription of a competence operon containing genes required for recombination of incoming DNA and the lytA gene, responsible for autolysis. Released DNA is picked up by other cells and recombined with the aid of RecA. LytA requires activation, which is controlled by the sensory kinase VncS. Signals originating from cell damage by antibiotics and possibly by other factors converge prior to or at the level of VncS and activate LytA, causing elimination of defective cells by autolysis.

FIG. 3

Programmed death of E. coli cells with damaged DNA. Mutagens produce DNA damage, which is sensed by the RecA protein. In turn, RecA induces hydrolysis of a transcriptional repressor (LexA), activating expression of SOS DNA repair proteins (including RecA). Expression of SulA causes inhibition of cell division. If damage is effectively repaired, the level of activated RecA decreases, the level of SulA drops due to the constant hydrolysis by the Lon protease, and cell division resumes. If damage is considerable, prolonged inhibition of division causes cell elongation and production of autolysin activator (of unknown nature), and the cell is lysed.

FIG. 4

Model of the fate of a bacterial population. Upon entering stationary state, the majority of cells die, which decreases the mutant load. Eventually, existing or arising GASP mutants carrying defects in global regulator (rpoS) that can proliferate under conditions of this particular stationary culture take over. When conditions improve, such as by the appearance of carbohydrate nutrients, the population consisting of GASP mutants will be outcompeted by an unrelated wild-type clone B. The likely end result is the elimination of clone A due to the emergence of GASP mutants. A low mutation rate, preventive suicide upon entering the stationary state, and death of GASP mutants due to decreased survival (loss of tolerance) of dividing cells in the presence of deleterious factors will contribute to delaying a takeover by GASP mutants.