Illuminating the hidden power of cell-autonomous immunity
In the evolutionary arms race with pathogens, humans have evolved various branches of natural defenses. The most ancient of these is the cell-autonomous immunity, which builds upon the intrinsic capacity of eukaryotic cells to detect invading microbes and to react to the threat by inducing cellular responses that can limit pathogen replication and spread. Beside the induction of microbicidal and microbial growth-restricting responses, this also includes the induction of host cell death programs, by which the self-sacrifice of an individual infected cell can withdraw the pathogen from its replicative niche. The significance of the protection conferred by these responses is highlighted by the observation that genetic deficiencies that compromise their execution can predispose animals to infections with usually non-pathogenic environmental species. Moreover, many bacteria and viruses actively block cell-autonomous immune responses, suggesting that the existence of these defenses imposes strong pressure on pathogens to evolve countermeasures. Indeed, it can be assumed that a microbe’s ability to suppress cell-autonomous immunity is a key determinant of its pathogenic potential and likely also its host range, tissue tropism, and disease spectrum.
The Sixt lab strives to apply state-of-the-art tools in molecular genetics, microscopic imaging, high-throughput screening, and next generation sequencing technology to uncover the hidden protective potential of pathogen-suppressed cellular defense pathways, to identify the molecular determinants of host defense and pathogenic countermeasures, and to find means to disturb their balance to the benefit of the host.
Our main experimental model is the interaction of human cells with the obligate intracellular bacterial pathogen Chlamydia trachomatis. There are several reasons that make this species a particularly attractive system for studies on cell-autonomous immunity. First, C. trachomatis is a significant human pathogen. It is one of the leading causes of preventable blindness and the most frequent bacterial agent of sexually transmitted disease with over 100 million annual new cases. Second, their obligate intracellular lifestyle and their developmental cycle, during which the bacteria alternate between the replicative reticulate body (RB) and the infectious elementary body (EB), make Chlamydia spp. particularly dependent on their host cell and thus a prominent target for cell-autonomous immunity. And third, in the light that molecular genetic analyses in obligate intracellular bacteria are still challenging and rarely applied, the recent “genetic revolution” in the Chlamydia field, which for the first time enables us to generate and study mutant Chlamydia strains, offers unique possibilities to discover so far unexplored mechanisms of host-pathogen interaction.
Human epithelial cells infected with the intracellular bacterial pathogen Chlamydia trachomatis (bacteria (green), host cell nuclei (red), host cytoplasmic pathogen-associated molecular pattern sensor protein STING (white); confocal fluorescence microscopic image)
A better understanding of the protective significance and the molecular mechanisms of cell-autonomous immune responses will facilitate a better assessment of their suitability as drug targets and will thus pave the way for the development of innovative new treatment regimens that exploit our cell-intrinsic defenses to fight infectious disease.