Have you ever wondered if bacteria that infect us actively modify lipids found in the membrane that surround our cells, and if that actually determines the outcome of infections? More so, if this is actually a determinant of where in the body specific bacteria are able to colonize? Our research demonstrated that this may indeed be the case.
In our recent study titled “Untargeted lipidomic analysis to broadly characterize the effects of pathogenic and non-pathogenic staphylococci on mammalian lipids” published in the Public Library of Science (PLOS ONE), we applied high-resolution mass spectrometry and found that these bacteria not only hydrolyze and breakdown lipids for yet undetermined reasons but also have a preference for specific lipids abundant in human cells.
There are indications of an active lipid metabolism that is at play between bacteria and our cells. It is possible that this piracy of lipids by the bacteria may be a mechanism for the bacteria to degrade host lipids while enriching its own stores to survive and adapt to select niches in our body during the process of infection. We looked at well-studied isolates of staphylococci, a gram-positive opportunistic pathogen commonly found in the nose and skin of individuals, and studied their ability to modify lipids.
Staphylococcus aureus and lipid metabolism
It has been long known that these bacteria, better known as methicillin-resistant staphylococci (MRSA), produce enzymes that mediate the breakdown of lipids leading to the production of fatty acids. While we know that these bacteria do not use fatty acids as a nutrient source, there is some indication of the usefulness of these fatty acids in the regulation virulence factor production in the bacteria. These fatty acids are recycled into the bacterial cell for the regulation of its own machinery and influences the production of other enzymes that impair the defenses of our immune system against the bacteria.
While 70 years of research on staphylococci have led to the identification of proteins that affect the immune system, the role played by lipid molecules and their partner enzymes in the process of infection have been elusive.
Improving resolution in the study of lipases
Classically, researchers have focused on the use of matrix-embedded lipid formulations to study the action of enzymes that degrade lipids. Microbiologists have typically used naturally-occurring, food-based extracts like egg yolk or chemically synthesized products that resemble lipids found in the body to study these enzymes. This is not ideal, as the enzymes that interact with lipids have exquisite specificity for lipid structure and stereochemistry and are not present in abundance in the mammalian cells. Thus, any information gained from using substrate analogues fall short of identifying endogenous lipid substrates for these enzymes that mediate the processes of infection and interact with other components of the cell and influence signaling inside the mammalian cell.
With the application of high-resolution mass spectrometry, we demonstrated a comprehensive identification of lipids and thereby captured the diverse interactions of extracellular enzymes produced by pathogenic staphylococci on the host lipidome. In doing so, we demonstrated that lipid-modifying enzymes produced by select classes of pathogenic staphylococci not only degrade the lipids as seen in classical studies but also use these lipids such as phosphocholine (PC), a lipid-rich in egg yolk and mammalian cell membranes, as a sink for removing undesirable and toxic fatty acids detrimental to their growth. Moreover, we found that this ability to modify lipids is absent in non-pathogenic and commensal strains of staphylococci such as S. epidermidis, found on human skin, and S. carnosus, used for sausage production.
Understanding infections better
Most of the research in the field of infections and infectious diseases focus on the mechanism by which proteins produced by the bacteria or the host contribute to infection processes. The part missing and not appreciated so far due to the technical limitations is the interaction of these bacteria with the immediate lipid environment at the site they infect and its role in the resulting infection.
Based on our work and some other work by other researchers, we believe the ability to modify lipids available at the site of infection to provide a survival advantage to infecting bacteria. While more work is required to draw out the causality of the observed correlations, there appears to be a greater lipid metabolism in the more virulent strains of staphylococci isolates being detected in the community in the past decade as compared to other historical isolates of staphylococci.
New avenues for research
With the availability of new technologies that employ mass spectrometry-based methods to analyze lipids based on molecular mass and characteristic fragmentation patterns, we believe our work could provide the basis for future studies in this field. Understanding the role of lipid modifying enzymes and the role they play in the interactions with the human host lipidome is important in developing new strategies for managing infections that are becoming ever-more antibiotic resistant.
These findings are described in the article entitled Untargeted lipidomic analysis to broadly characterize the effects of pathogenic and non-pathogenic staphylococci on mammalian lipids, recently published in the journal PLOS One. This work was conducted by Naren Gajenthra Kumar, Daniel Contaifer Jr, Kimberly K. Jefferson, and Dayanjan S. Wijesinghe from the Virginia Commonwealth University, Paul RS Baker from SCIEX, and Kim Ekroos from Lipidomics Consulting Ltd.