When your plasmid is a control freak

A golden opportunity to study multidrug resistant Acinetobacter urinary tract infection

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Jun 24, 2019
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Bacteria capable of causing human infections belong to one of two classes. The “professional pathogens” usually only cause one type of infection in mostly healthy people, such as Salmonella enterica which causes gastroenteritis or Mycobacterium tuberculosis the causative agent of tuberculosis. The second group, “opportunistic pathogens”, cause a variety of different infections and are considered more generalist in the types of disease that they can cause. Also, these pathogens usually infect clinically-ill or immunosuppressed patients and are associated with nosocomial infections. One of these pathogens is Acinetobacter baumannii, a bacterium often associated with nosocomial infections, mainly hospital acquired pneumonia, bacteremia, soft tissue infections, and urinary tract infections (UTI). Moreover, A. baumannii is a serious threat to public health as it is extremely resistant to antibiotics, which leaves physicians with few options for treatment.

We are all aware that treating bacterial infections is becoming increasingly difficult as we are running out of antibiotics that are effective against drug resistant bacteria. By 2050, it is estimated that more than 10 million people will die from drug resistant bacterial infections. Thus, we are in urgent need of new strategies to fight infections, but we first need to understand how bacteria cause disease to develop a way of fighting back. Because what we know of A. baumannii biology is lacking, we need to research Acinetobacter infections. Under the assumption that A. baumannii is an opportunistic pathogen equally capable of establishing all sorts of infections, previous research was done without considering the clinical history of the isolate. For example, researchers have used strains isolated from a wound or bone infection to study how Acinetobacter causes pneumonia. In our work we challenge the current paradigm and show that a modern A. baumannii strain isolated from a patient with a UTI can cause UTI, but not pneumonia, in mouse models. Furthermore, a lab domesticated strain commonly used for Acinetobacter research was not at all pathogenic in the UTI model. These results have 2 strong implications. First, old lab domesticated strains are not good models for studying virulence even though most of the research done regarding A. baumannii infections has been done with strains isolated more than 50 years ago. Second, A. baumannii is not a generalist where every strain can cause any type of infection.

Afterwards, we discovered that UPAB1 harbors a large plasmid that increases UPAB1 virulence in the mouse UTI model but reduces UPAB1 performance in the pneumonia model. We linked this behavior to the remarkable ability of this plasmid to control the expression of multiple bacterial virulence factors. We already knew that similar plasmid control the T6SS to allow their dissemination. Now we discovered that the plasmid controls expression of several virulence factors including diverse pili and surface glycans. Hijacking host machinery is not a common feature of plasmids but is reminiscent to the behavior of viruses during infection.

Our findings are a first step towards the understanding of A. baumannii uropathogenesis, a largely neglected type of infection. This opens new avenues to find potential targets for fighting bacterial infections. For example, we discovered that A. baumannii relies on pili to establish UTI. Pili are bacterial structures commonly used by other uropathogens to attach to surfaces and cause disease. The study of these pili in other uropathogens has led to the development of pilicides, small molecules that inhibit the formation of pili and prevent the establishment of UTI. Now we can use our model to test the effectiveness of these compounds in treating drug resistant Acinetobacter infections.

https://www.nature.com/articles/s41467-019-10706-y

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