The coordination of anti-phage immunity mechanisms in bacterial cells

A work published in Nature Communications by the group of Dr. Federica Bertocchini and led by Dr. Clemente F. Arias proposes that the defensive response of bacteria against phages varies according to the speed at which the virus replicates inside infected cells. The study indicates that bacteria would select cell suicide (Abi systems) against fast infections, but would apply immunological memory (CRISPR system) against slow phage viruses.

The coordination between innate and adaptive immunity would naturally emerge from the rates of activity of the enzymes that participate in anti‐phage responses. This approach suggests the existence of a simple molecular mechanism that would account for the decision of bacteria to incorporate new phages into the immune memory.

The viruses that infect bacterial cells (known as bacteriophages or phages) are the most abundant biological entities on Earth. Bacteria have evolved a variety of immune mechanisms to defend themselves from phage attacks. These mechanisms range from nuclease enzymes that detect and destroy foreign DNA to sets of proteins (labeled as Abi systems) that trigger the suicide of the infected cell to prevent the spread of the phage across the population. Bacterial cells can also keep track of past infections. The CRISPR systems, which have become a powerful biotechnological tool in the last years, cleave and store fragments of phage DNA, creating an immune memory that can then be used against the phage in case of future reinfections.

Although many of the bacterial immune mechanisms have been described, basic aspects remain unexplained. For instance, not all phage infections entail the suicide of the infected cell or the creation of new immune memory and the way the bacterial cells decide what immune mechanism to use in each episode of infection has not been unveiled yet.

To address this question, Arias et al. have formulated mathematical models that simulate the intracellular events that take place during phage infections. Phages interact with the host’s immunity in complex ways and exploring the dynamics that emerge from these interactions is key to understanding the outcome of anti-phage responses. To that end, mathematical modeling provides valuable insight that would be unattainable using only qualitative descriptions.

According to the models proposed by the researchers, phages may use two alternative strategies to evade bacterial immunity. First, they can outrun the host’s immune response by replicating very fast. Second, and less intuitively, replicating very slowly would also allow phages to deceive the host’s immunity. By keeping a low profile, phages would create persistent, chronic infections in bacterial populations, a puzzling phenomenon known as the carrier state life cycle.

The models suggest that Abi and CRISPR systems target fast and slow phages respectively. Cell suicide would be the best solution to fight phages that replicate too fast to be attacked by bacterial immune defenses. On the other hand, the bacterial immune memory would only be effective against phages that replicate slowly. Accordingly, bacterial cells would be able to discriminate between fast and slow phages and selectively incorporate the latter into their CRISPR memory.

The study provides a coherent and comprehensive picture of bacterial immunity and sheds light on how anti-phage mechanisms operate inside infected cells. The results also contribute to a better understanding of how CRISPR systems work during phage infections, which could help to improve its biotechnological applications.

The work is the result of a collaboration between the CIB Margarita Salas (CSIC), the Complutense University of Madrid, and the Molecular Medicine Institute of Lisbon.

Reference: The coordination of anti-phage immunity mechanisms in bacterial cells. Clemente F. Arias, Francisco J. Acosta, Federica Bertocchini, Miguel A. Herrero, Cristina Fernández-Arias (2022) Nat Commun. DOI: https://doi.org/10.1038/s41467-022-35203-7

More information:

CSIC Press Release (in Spanish): link.