Opportunistic bacterium increases its virulence by ‘poaching’ zinc and iron from hosts

Researchers at the University of São Paulo have unraveled the strategy used by Chromobacterium violaceum, a pathogen found in water and soil in tropical and subtropical regions, to increase its capacity to replicate and infect host organisms. The discovery offers a route for the development of novel therapies.

By Luciana Constantino  |  Agência FAPESP – Researchers at the University of São Paulo (USP) in Brazil have unraveled the strategy used by the bacterium Chromobacterium violaceum to ‘poach’ zinc and iron from a host organism and use the metals to increase its virulence. The discovery offers a route for the development of novel therapies.

Found in the water and soil of tropical and subtropical regions, the bacillus is considered an opportunistic pathogen and can causes abscesses in the liver, lungs and skin, leading to severe sepsis in humans and other animals. The main symptoms are fever, abdominal pain, skin lesions, and metastatic abscesses. It is usually transmitted when wounds and lesions are exposed to contaminated water or soil.

In studies conducted at the Ribeirão Preto Medical School (FMRP-USP), and reported in three articles published between 2019 and 2021, the scientists showed that the bacterium subverts “nutritional immunity”, a process whereby the host organism’s cells make zinc and other metals unavailable to invading microorganisms.

In the latest study, published in Infection and Immunity, a journal of the American Society for Microbiology (ASM), the group shows that the zinc ion transporter ZnuABC, a protein complex, is critical to the virulence of C. violaceum and contributes to several physiological processes that depend on zinc. The investigation was conducted in partnership with Vanderbilt University, in Tennessee (USA), and was supported by FAPESP via four projects (18/01388-6, 20/00259-8, 17/03342-0, and 18/14737-9). 

“The three articles tell a story showing how the bacterium obtains key metals from the host in order to multiply, and how this acts as a virulence factor. The bacterium subverts the host’s nutritional immunity to gain access to metals that are essential to all organisms. Our group has pioneered the investigation of virulence factors in this bacterium,” said José Freire da Silva Neto, a professor in the Department of Cellular and Molecular Biology and Pathogenic Bioagents at FMRP-USP and principal investigator for all four projects.

Understanding this process is important to the search for novel approaches to the treatment of bacterial infections and molecules that mitigate the pathogen’s virulence. In addition, knowledge of the bacterium’s “lifestyle” can to some extent be extrapolated to others, such as Pseudomonas, which causes opportunistic infections in hospitalized patients.

“It’s possible to use what we’ve discovered so far to look for molecules that act on systems involving zinc and iron, and reduce the bacterium’s virulence. If efficient uptake of the metals is blocked, it won’t be able to multiply,” Silva Neto explained.

Previous research showed that the bacterium is resistant to several antibiotics and that treatments with ciprofloxacin and meropenem were best able to control infection.

Albeit rare, infection by C. violaceum is characterized by rapid dissemination and high mortality. A compilation of data reported between 1952 and 2009 shows that 106 people were infected by the bacterium in the period. A review of clinical studies described in journal articles published in 2017 by the FMRP-USP group found more than 150 cases.

Zinc and iron uptake

In a study involving mice, the researchers showed how the bacterium uses the zinc uptake system ZnuABC to overcome the constraints on availability of the metal imposed by the host. Inhibition of ZnuABC reduced the bacterium’s virulence in the animals, and a mutant lineage with altered ZnuABC was less virulent and less able to colonize the liver, demonstrating that zinc uptake is essential to the virulence of C. violaceum.

In an article published in October 2020, in Applied and Environmental Microbiology, another ASM journal, with PhD student Renato Santos as first author, the FMRP-USP group described the role of the ferric iron uptake regulator Fur in the physiology and virulence of C. violaceum. 

The importance of the role played by iron was also demonstrated in another study by the group. In this case, PhD student Bianca Batista was first author. The article showed how the bacterium produces siderophores (ferric iron-binding compounds) to scavenge iron and colonize a host.

The article “The zinc transporter ZnuABC is critical for the virulence of Chromobacterium violaceum and contributes to diverse zinc-dependent physiological processes” by Renato E. R. S. Santos, Waldir P. da Silva Júnior, Simone Harrison, Eric P. Skaar, Walter J. Chazin and José Freire da Silva Neto is at: journals.asm.org/doi/10.1128/IAI.00311-21.