Weizmann Institute scientists have developed a new method that allows an unprecedented glimpse into the relationship between a bacterium and a host cell towards a solution to the problem of bacterial resistance to antibiotics
Bacteria, like people, differ in their mate preferences. Some are completely independent, while others prefer company. Salmonella and many other bacteria are of the social variety: they can exist and even thrive inside a host cell. But unlike us, these bacteria do not court the cell for a long time so that it gives in to them and opens its doors - they inject it with proteins that take over its systems. In recent years, thanks, among other things, to the studies that came out of the group of Prof. Roy Avraham At the Weizmann Institute of Science, differences were discovered in the proteins that different subspecies inject into their hosts, and this may also be the reason why some are more violent than others. For example, there are more than 2,500 subspecies of Salmonella, but only a minority of them will cause serious illness. in the article published in the scientific journal "Records of the American Academy of Sciences" (PNAS), researchers from Prof. Avraham's group presented a research method that sheds new light on the relationships between bacteria and their hosts and reveals what makes some of them particularly violent.
In the last decade, a revolution is taking place in the life sciences that makes it possible to understand molecular processes with an unprecedented resolution. This revolution is made possible, among other things, thanks to methods for sequencing the genetic material at the single cell level. But when it comes to the molecular relationships between thousands of bacterial subspecies and an equally impressive array of hosts, sequencing at the single cell level is simply not possible with existing tools. For example, in order to map the differences in the infectivity and the degree of violence of different subspecies of Salmonella, it is necessary to sequence not only the genetic material of the bacterial cells at the single cell level, but also the genetic material of the specific host cells that were infected - and then link the findings of the guest and the host .
The new method developed in the laboratory of Prof. Avraham from the Department of Immunology and Biological Regeneration makes it possible to do this thanks to two central anchors: the first anchor of the method developed under the leadership of Dr. Uri Heyman, allows taking a group of bacterial strains, each of which has a specific genetic change (mutation) and attaching genetic barcodes to them - DNA sequences that make it possible to identify each strain later in the study, even when it is inside the host cell. The second anchor is a computerized model called MAESTRO developed under the leadership of Dr. Naa Ben Moshe, which matches the sequencing results of each bacterial barcode to the sequencing results of the specific host cell it infected. Using the model, it is possible to analyze how each mutant strain of bacteria affects the behavior of the host, while proteins are uniquely expressed only in host cells infected with a certain strain. In this way, the method allows to carry out "paired sequencing" of the bacterium and the host at the single cell level.
In a published study, the researchers demonstrated the new method on 25 mutant strains of Salmonella that infected phagocytic cells of the immune system. Using it, they learned about the relationship between each bacterial strain and a host cell and identified that there is a particular strain that provokes an abnormally powerful immune response in the host. That strain lacked a protein that all the other strains produced and injected into the host successfully. The researchers concluded that this protein is essential for suppressing the host's immune system. "We uncovered a new role for a known protein and showed that it sabotages the host's defense mechanisms," explains Prof. Avraham. "In fact, there are many proteins that bacteria inject into their hosts and the function of most of them has not yet been deciphered. The method we developed will allow us to systematically reveal the roles of these proteins. Moreover, our method can be translated to any bacterial species, including friendly bacteria that are important for the functioning of our various systems, and groups around the world are already using it."
Besides promoting basic research, the importance of the method is in promoting the ability to defend against disease-causing bacteria in an era where antibiotic resistance is defined by the World Health Organization as one of the greatest threats to human health and its nutritional security. "There are two possible new defense strategies whose development is still in the initial stages," Prof. Avraham points out, "reducing the degree of violence of disease-causing bacteria or strengthening the immune response of the host cells. The new method allows both: to simultaneously understand both how the bacterium attacks and how the host cell defends itself."
Dror Yehezkel, Dr. Kamila Tsioli Matiuli, Neta Blumberger, Dr. Gili Rosenberg, Aryeh Solomon and Dr. Dotan Hoffman from the Institute's Department of Immunology and Biological Regeneration also participated in the study.
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