Luis A. Actis
Professor and Chair of Microbiology
The current research in my laboratory centers on the genetic, molecular and functional analyses of some of the factors responsible for the ability of the bacterium Acinetobacter baumannii to persist in medical environments and cause serious infections in humans. Although A. baumannii has been known for a long time as the etiological agent of a wide range of opportunistic nosocomial infections, it has recently emerged as a more serious threat to human health because of its ability to cause devastating infections among wounded military personnel that are very difficult to treat because of antibiotic resistance. Another serious problem with this bacterial pathogen is the lack of understanding of its virulence factors, which could be used as new and alternative targets to prevent and treat the infections it causes in humans.
Based on these considerations, one of our research projects focuses on the mechanisms A. baumannii uses to acquire iron under limiting conditions such as those encountered in the human host. Our research proved that A. baumannii expresses different iron acquisition systems, including hemin utilization functions and siderophore-mediated systems, one of which is highly similar to a system found in the fish pathogen Vibrio anguillarum. This finding suggests that siderophore-mediated iron acquisition systems are part of mobile genetic elements that can be transferred among bacterial cells belonging to different genera and species, which cause severe infections in unrelated hosts. We have also detected the presence of genes encoding proteins belonging to the efflux pump protein family, which could play a role in siderophore secretion, and identified protein secretory functions that have never been associated with iron acquisition in bacteria. These are significant and exciting observations that have the potential of increasing our understanding of iron utilization and metabolism in bacteria.
Although a large body of knowledge exists regarding iron acquisition in bacteria, almost all of it was obtained with planktonic cells that most likely do not reflect the cell arrangements found in nature. In contrast, little is known about the iron acquisition processes expressed by cells arranged in biofilm structures, which are more representative of bacterial arrangements found in the environment. There is evidence that natural iron chelators such as lactoferrin and transferrin play a role in biofilm formation and that the amount of siderophore secreted by cells in biofilms is different from that produced by planktonic cells. Consequently, we are also interested in testing the effects of biofilm growth on the expression of genes encoding iron acquisition proteins. We have reported that a chaperone-usher secretion system is needed for the assembly of pili, which are required for cell attachment and biofilm formation on abiotic surfaces. Additional work showed that a couple of regulatory functions, encoded by genes similar to other bacterial genes annotated as hypothetical genes that are part of two-component regulatory systems, are also involved in biofilm formation as well as cell morphology. Incubation of A. baumannii cells with Candida albicans filaments provided evidence that this bacterial pathogen also attaches to biotic surfaces, as it was shown for Pseudomonas aeruginosa using this experimental model. Interestingly, the bacterial cells as well as the culture supernatants kill the fungal filaments by apoptosis. This observation indicates that A. baumannii produces factors that affect the viability of eukaryotic cells and supports the utilization of this experimental model for the identification and analysis of virulence factors produced by this poorly characterized bacterial pathogen. Recently, we have expanded this objective by investigating the interactions of this pathogen with human lung cells, a model that has the potential of providing information on the interaction of A. baumannii with vertebrate cells and organisms.
The overall goal of this multifaceted approach is not only to acquire basic knowledge that deepens our understanding of the pathobiology of this bacterium but also to apply this knowledge to develop new strategies to address the difficulties encountered with the treatment of the infections A. baumannii causes in humans.
- Gaddy, J.A. and L.A. Actis. The regulation of Acinetobacter baumannii biofilm formation. Invited Special Report, Future Microbiology, 4, 273-278, 2009.
- de Breij, A., J. Gaddy, J. van der Meer, R. Koning, A. Koster, P. van den Broek, L. Actis, P. Nibbering, and L. Dijkshoorn. CsuA/BABCDE-dependent pili are not involved in the adherence of Acinetobacter baumannii ATCC19606T to human airway epithelial cells and their inflammatory. Research in Microbiology, 160, 213-218. 2009.
- Gaddy, J.A., A.P. Tomaras, and L.A. Actis. The Acinetobacter baumannii 19606 OmpA protein plays a role in biofilm formation on abiotic surfaces and the interaction of this pathogen with eukaryotic cells. Infection and Immunity. Infection and Immunity, 77, 3150-3160, 2009.
- Nwugo, C.C., J.A. Gaddy, D.L. Zimbler, and L.A. Actis. Deciphering the iron response in Acinetobacter baumannii: A proteomics approach. Journal of Proteomics, 2010.
- Mussi, M. , J.A. Gaddy, M. Cabruja, B.A. Arivett, A.M. Viale, R. Rasia, and L.A. Actis. The opportunistic human pathogen Acinetobacter baumannii senses and responds to light. Journal of Bacteriology, 2010.