The new findings may allow the development of new treatments for infections, such as tuberculosis, salmonella and shigella, and life-threatening reactions of the immune system.
Encounters between disease-causing bacteria and the loyal soldiers of the immune system can end in a surprising result: turning the latter from lethal killing machines that protect the body into pampering habitats where the bacteria thrive unhindered. Scientists at the Weizmann Institute of Science have recently discovered a new subtype of immune system cells that inevitably contributes to the formation of this deadly scenario. The new findings may allow the development of new treatments for infections, such as tuberculosis, salmonella and shigella, and life-threatening reactions of the immune system.
The laboratory of Dr. Roi Avraham from the Department of Biological Control investigates intracellular bacteria – that is, those that can thrive within the cells of our immune system. Life of the immune system called sepsis In the new study, led by research student Dotan Hoffman, the scientists infected mice with salmonella from a strain leading to the development of an acute disease and monitored the various stages of infection, particularly the immune system’s “first line” cells. The function of these cells is to intercept any foreign agent – from bacteria to cancer cells, and they do this by ingesting the invaders in their entirety (hence the origin of their name: large gluttons, in Greek), while releasing toxic substances aimed at killing them.
Throughout the day after infection, the researchers sampled the amount of salmonella bacteria in the spleen of infected mice. Analysis of the data indicated a clear trend: in the first eight hours of infection, the bacterial load decreased, but then there was a surprising reversal: the bacterial population began to grow, and later to really thrive, leading to the death of the mice within a few days.
Macrophages, found in almost every tissue, can exist in several different configurations, the differences between which are very subtle. Using an advanced genetic analysis method – RNA flooring at the single cell level – Hoffman was able to differentiate between three different populations of macrophages in salmonella-infected mice. One of them is a population of macrophages that has not yet been characterized. The discovery was particularly surprising, as this unfamiliar population grew with the progression of the infection, and when the researchers compared the amount of intracellular bacteria between each of the macrophages, they found that the newly identified macrophage serves as a habitat where the bacteria multiply and thrive. “We found the culprits in the surprising increase in the bacterial population,” Hoffman notes. “Now it remains for us to try to understand what their motives are.”
Macrophages neutralize toxic compounds that release the immune system
Active cells of the immune system release into their environment toxic compounds for bacteria. Beyond a certain level, however, these compounds can be toxic to both the cells themselves and other cells in the environment, thus causing tissue damage. The researchers found that macrophages of the new type they discovered could neutralize these compounds, presumably to protect themselves, as well as perform damage control on immune system function. However, the chemical process of neutralizing the compounds produces a carbon source available to intracellular bacteria such as salmonella. In other words, the macrophages identified in the study inadvertently turn into an as-you-can-eat buffet that is especially inviting to salmonella. To test the hypothesis, the researchers infected engineered mice that could not produce this type of macrophage, and found that they were indeed more resistant to salmonella.
“The population of macrophages we discovered probably plays a control role in moderating the immune system response, but the bacteria take advantage of this to enter cells in the back door,” Hoffman explains. These findings pave the way for a deeper understanding of the course of bacterial infection and break new research directions on the survival strategies of intracellular bacteria of different types and in different body tissues. Dr. Avraham adds: “We have the first evidence that this subspecies of macrophages also exists in health and may play a role in the survival of a bacterium that causes tuberculosis.”
The study also included Yaara Tevet, Gili Rosenberg, Leah Weinman, Aryeh Solomon, Dr. Shelly Chen Avivi and Dr. Noa Bosel Ben-Moshe from the Department of Biological Control and Sebastian Trezbansky from the Department of Immunology at the Weizmann Institute.
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