Herrero, M. A. | bioRxiv Science

bioRxiv2022

The coordination of innate and adaptive immunity in bacteria

Bacteria have evolved a variety of innate and adaptive immune strategies to fight bacteriophage (phage) infections. Innate defenses (unspecific mechanisms directed against any phage infecting the cell) range from the identification and cleavage of the viral DNA by restriction nucleases to the suicidal death of infected host cells, an extreme solution that prevents the spread of the infection throughout the population. Adaptive immunity, on the other hand, involves the creation of an immune memory that targets specific phages in case of reinfection. It is obvious that not every infection leads to the suicide of the host cell or to the formation of immune memory against the infecting phage, so what determines the outcome of an anti-phage response? In this work, we suggest that the dynamic aspects of phage infections are key to addressing this question. We show that the rates of viral DNA replication and cleavage define functional categories of phages that differ in their susceptibility to the immune strategies evolved by bacteria. From this viewpoint, the combined action of diverse bacterial defenses would be necessary to reduce the chances of phage immune evasion. This perspective allows us to formulate simple molecular mechanisms that could account for the decision of infected cells to undergo suicidal cell death or to incorporate new phages into the immune memory. This work highlights the importance of dynamics to understand bacterial immunity and formulates explicit hypotheses that could inspire a new and original empirical approach to the study of phage/bacteria interactions.

microbiology↗

bioRxiv2018

Bone remodeling: A tissue-level process emerging from cell-level molecular algorithms

Human skeleton undergoes constant remodeling during the whole life. By means of such process, which occurs at a microscopic scale, worn out bone is replaced by new, fully functional one. Multiple bone remodeling events occur simultaneously and independently throughout the body, so the whole skeleton is completely renewed about every ten years.\n\nBone remodeling is performed by groups of cells called Bone Multicellular Units (BMU). BMUs consist of different cell types; some are specialized in destroying old bone, whereas others produce new bone to replace the former. The whole process is tightly regulated so that the amount of new bone produced exactly balances that of old one removed and bone microscopic structure is maintained.\n\nTo date, many regulatory molecules involved in bone remodeling have been identified, but the precise mechanism of BMU operation remains to be fully elucidated. Given the complexity of the signaling pathways already known, the question arises of ascertaining whether such complexity is an inherent requirement of the process, or a consequence of operational redundancy.\n\nIn this work we propose a minimal model of BMU function which involves a small number of signals and accounts for fully functional BMU operation. Our main assumptions are i) at any given time, any cell within a BMU can select only one among a reduced choice of decisions: divide, die, migrate or differentiate, ii) such decision is irreversibly determined by depletion of an appropriate internal inhibitor and iii) the dynamics of any such inhibitor is coupled to that of a few external mediators. It is shown that efficient BMU operation then unfolds as an emergent property, which results from individual decisions taken by cells in the BMU unit in the absence of any external planning.\n\nAuthor summaryOur skeleton is a living organ that is being renewed throughout our life. This task is accomplished by teams of bone cells termed as Bone Multicellular Units (BMUs) that are recruited when and where needed, to operate at places where bone has lost functionality either for an excess of mechanical stress or because loss of activity. Once assembled, BMU remove old bone and replace it by new one, and disband as soon as their mission has been accomplished. No single bone evades BMU screening, so that the whole human skeleton is completely renewed approximately every ten years.\n\nIt is natural to wonder how such robust and fascinating process is regulated. Many signaling pathways involved in bone remodeling have been identified so far, but whether all of them are necessary for BMU operation remains unclear. In this work we show that just a reduced number of such signals could suffice for that purpose. This suggests that a large degree of redundancy might have been kept in place, perhaps as a consequence of different convergent strategies developed in the course of evolution.

systems biology↗