In the ongoing understanding of microbial infections, the bulk of the investment is often made in studying toxin formation or vaccine development for pathogen destruction. While this approach is sensical and appropriate given the need to eliminate microbes for the restoration of host health, it does not explain why they target particular tissues or how they are able to stick around. The driving force behind this study was the exploration of the latter, which may offer novel therapeutic options targeting the lifestyle and proliferation of the pathogen rather than its virulence.

Motivation behind the study: Explaining microbial metabolic adaptation

Especially in light of the most recent pandemic we can identify the lung as an unprotected organ in perpetual communication with the external environment. Thus, it is a common target for bacterial and viral pathogens which sometimes persist despite the efficiency of our immune system and antimicrobials. We observe persistence in fibrotic lung diseases like Cystic Fibrosis, where patients are colonized by staphylococcal strains since very early in life. Our studies specifically aimed at explaining the evolution of staphylococcal metabolic adaptation and identifying some factors contributing to the propensity of chronicity.

The results implicate the versatile carbon catabolite repression (CCR) system, which exploits substrate sensing to reprogram pathogen metabolism by upregulating translation of relevant proteins. The CCR puzzle with its movable pieces is reliant on master regulators which had only been published in vitro by incubating bacteria in high concentrations of substrates. Here, we mapped how CCR regulates proline uptake in the complex in vivo environment of the lung, by simultaneously tracking the organism’s gene expression and host metabolic output.

Immunometabolism and Beyond

We initially focused on immunometabolism, which involved the pathogen indirectly triggering the release of a permissive metabolite following a cascade of immune cell activation. Indeed, we considered T regulatory cell proliferation and adenosine release to be advantageous to staph, as the host could dampen inflammation and protect its tissue, while simultaneously prevent pathogen killing.

Instead, our results expanded the limits of immunometabolism and framed a process in which the pathogen can directly trigger a non-immune cell to obtain substrates for survival. In the setting of injury, collagen destruction triggers fibroblast activation for replacement. In this study we present a circular interplay between fibroblasts, responding to injury and collagen breakdown, and staph, sourcing proline from synthesized collagen. This consistent breakdown and replacement process allows for a direct action of the pathogen on substrate supply. More so, it shifts the focus upstream, on what facilitates the ability of the organism to inflict damage, on the need to sustain itself before initiating processes required to generate toxins and penetrate host defenses.

Conclusion: Shifting Perspectives

The robust preclinical research on vaccine development and structural biology for microbial targeting is a necessity, especially in times like our most recent pandemic where massive efforts are mobilized to reach quick and practical solutions. Simultaneously we must maintain a flexible perspective outside the canonical approach to infection resolution for a deeper understanding of microbial persistence. Given the swift evolution of organisms, it is a clinical imperative to investigate the basic metabolic requirements for their survival and attempt to modulate their ability to establish chronic infections.