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Body and mind

Bacteria have developed an ingenious defence against the human immune system

When people’s immune system attacks bacteria by blocking their metabolic options, the bacteria just start obtaining nutrients from the environment. Researchers have now mapped how this happens.

Some of the bacteria that live in and on people have developed ingenious ways to defend themselves against our immune system.

When the immune system bombards the bacteria with substances that eliminate their ability to produce amino acids, the bacteria simply stop producing the amino acids and instead obtain them from the environment.

The immune system can then struggle in vain while the bacteria live on as chronic infections.

Researchers have now investigated in depth this type of survival technique – auxotrophy. This may strongly influence the understanding of a wide range of chronic infections among people, such as in connection with cystic fibrosis.

“In this study, we investigated the mechanisms and metabolism of auxotrophy. We wanted to determine how the bacteria become auxotrophic to better understand what happens to the bacteria when, for example, they become chronic infections,” explains a researcher behind the new study, Bernhard Palsson, CEO, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby.

The study has been published in the Proceedings of the National Academy of Sciences of the United States of America.

Improving understanding of cystic fibrosis

The new study is interesting in understanding the development of persistent infections with Pseudomonas aeruginosa among people with cystic fibrosis, says Helle Krogh Johansen, Clinical Professor, Department of Clinical Medicine, Rigshospitalet, who also works alongside Bernhard Palsson at the Technical University of Denmark.

Helle Krogh Johansen did not participate in the research on the new study, but she has read it and sees great perspectives in it.

She thinks that the insight into auxotrophy can be used to interpret the genomes of the bacteria and determine how far they are in the process of turning into chronic infections.

“Whole-genome sequencing of Pseudomonas aeruginosa is routine for people with cystic fibrosis. In this situation, we can use the genome sequences to determine how far the bacteria have adapted to living permanently in people’s lungs and how soon the infection is likely to become chronic. We may be able to use this type of knowledge to figure out how much and how intensely we need to treat people with antibiotics,” explains Helle Krogh Johansen.

People are also auxotrophic

The new study focuses on auxotrophy, which is the ability to take up amino acids from the environment.

For example, people must use 20 types of amino acids to construct all the necessary proteins and enzymes to sustain our lives and well-being.

We can make about half of these amino acids ourselves, but we obtain the other half through food.

We are auxotrophic for the amino acids we need to get from food.

For people, these are histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine.

Bacteria can make all the amino acids

Unlike people, most bacteria are not auxotrophic.

According to Bernhard Palsson, bacteria can be described as biology’s response to organic chemists, because they can make all the amino acids themselves if they have access to glucose.

However, researchers have long known that some bacteria can become auxotrophic under various conditions.

This applies, for example, to the lungs of people with cystic fibrosis. In this scenario, the bacteria start to take up the amino acids in the lungs and lose the ability to produce the amino acids themselves.

They also lose the genes to make the amino acids, or these genes break down and become dysfunctional.

“In this study, we examined why the genes lose their capabilities and what the mechanisms are. This depends on the individual bacteria and their metabolism. Acquired auxotrophy occurs differently from organism to organism,” explains Bernhard Palsson.

Bacteria become especially auxotrophic for four amino acids

The researchers concluded that the bacteria mostly become auxotrophic for the same amino acids – often tryptophan, valine, isoleucine and lysine. These are branched-chain or aromatic amino acids.

The researchers uploaded the whole-genome sequences of bacteria that had become auxotrophic into an advanced computer model.

They examined how the genes for producing the various amino acids had been removed or broken down in the auxotrophic bacteria.

“Our genome-scale metabolic models can calculate these things and show us how many enzymes are needed before a given production of amino acids can progress in the bacteria. Then we can examine whether the genes for the given enzymes are still intact and thereby conclude whether the bacteria have become auxotrophic,” says Bernhard Palsson.

Auxotrophy is a response to the immune system attacking metal-containing enzymes

Bernhard Palsson’s models identify why the bacteria often become auxotrophic to tryptophan, valine, lysine and isoleucine.

This requires analysing how the immune system fights bacterial infections.

In an infection, the immune system tries to stress the bacteria by bombarding them with reactive oxygen species.

The reactive oxygen species oxidize the metal ions present in many enzymes.

One example, which is not relevant to bacteria, is the iron in haemoglobin.

In haemoglobin, iron must be in the Fe2+ state to be active. However, under oxidative stress, reactive oxygen species can steal an electron from iron and make it Fe3+.

Metabolic enzymes that use Fe2+ in their active centres cannot hold on to Fe3+, and then it is replaced by other metal ions such as copper (Cu2+) or zinc (Zn2+). This single-replacement reaction makes the enzyme work less well.

When the immune system attacks, it uses reactive oxygen species to cripple the bacteria.

“Our research results show that the metabolic signalling pathways involved in producing tryptophan, valine, lysine and isoleucine involve enzymes with metal ions that may be targets for the immune response. We therefore hypothesize that the bacteria simply choose to shut them down and instead become auxotrophic for these amino acids, which they then obtain from the environment. In the example of cystic fibrosis, this means the human host,” explains Bernhard Palsson.

Improving insight into the microbiome in the human gut

Bernhard Palsson explains that this discovery does not just improve understanding of how people with cystic fibrosis develop chronic inflammation of the lungs.

In addition, Bernhard Palsson says that not only people acquire auxotrophy. Bacteria can also be mutually auxotrophic with each other and exchange amino acids so that they do not have to make them all themselves.

“This occurs in the gut microbiome, in which several bacteria are auxotrophic for amino acids that other bacteria can make. This new understanding of the mechanisms behind auxotrophy can be used to better understand how the microbiome is constructed and to understand how it works and how it remains stable. This seems to be one of the mechanisms,” says Bernhard Palsson.

Metabolic and genetic basis for auxotrophies in Gram-negative species” has been published in the Proceedings of the National Academy of Sciences of the United States of America. Bernhard Palsson is the CEO of the Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby.

Bernhard O. Palsson
CEO
Bernhard Palsson is a Distinguished and the Galletti Professor of Bioengineering, Professor of Pediatrics, and the Principal Investigator of the Systems Biology Research Group in the Department of Bioengineering at the University of California, San Diego. Dr. Palsson has co-authored more than 500 peer-reviewed research articles and has authored four textbooks, with more in preparation. He is CEO at the Novo Nordisk Foundation Center for Biosustainability in Denmark. His research includes the development of methods to analyze metabolic dynamics (flux-balance analysis, and modal analysis), and the formulation of complete models of selected cells (the red blood cell, E. coli, CHO cells, and several human pathogens). He sits on the editorial broad of several leading peer-reviewed microbiology, bioengineering, and biotechnology journals. He previously held a faculty position at the University of Michigan for 11 years and was named the G.G. Brown Associate Professor at Michigan in 1989. He is inventor on over 40 U.S. patents, the co-founder of several biotechnology companies, and holds several major biotechnology awards. He received his PhD in Chemical Engineering from the University of Wisconsin, Madison in 1984. Dr. Palsson is a member of the National Academy of Engineering and is a Fellow of both the AAAS and the AAM.
Helle Krogh Johansen
Dr. med., Chief Physician
The research area is (shared research between RH and DTU) bacterial airway infections in patients with cystic fibrosis (CF). Most CF patients have bacteria in their lungs from early childhood until they die prematurely. The bacterial lung infections in CF patients, is an excellent model to study infectious disease for which antibiotic treatment is challenged by frequent lack of success. Equally important is that modern human life-style, as well as increases in the average population life span, will create problems with long-term bacterial infections that are difficult or impossible to treat. Moreover, the rising global problem of antibiotic resistance threatens to become the biggest health risk within the next 20-30 years. Our research is directly addressing the problem of antibiotic resistance.