The Role of Galectin-3 in Pathogen Sensing and Cell Autonomous Defense

Abstract

There is a dynamic interplay between pathogens and their hosts. This interplay has resulted in a constant struggle where the host is attempting to clear the pathogen, while the pathogen attempts to subvert the host’s immune system. The result of the back and forth has resulted in what is called the “Red Queen” conflict. This theory states that an adaptation by one party spurs an adaptation by the other, resulting in a never-ending conflict for supremacy. Intracellular pathogenic bacteria have developed multiple ways in which to subvert the host’s cell intrinsic defense systems. One common mechanism is the establishment of a pathogen vacuole (PV) which serves as a replicative niche for growth and shields the pathogen from many host surveillance systems. In order to effectively combat these pathogens, the host must recognize the PV as an aberrant structure and facilitate an effective defense response. One characteristic that is indispensable for pathogens that reside within PVs are bacterial secretion systems. The bacterial secretion system is critical for the pathogen to be able to interact with the host environment, modulate cellular functions, and remodel the PV to facilitate growth. There is evidence that the host can directly recognize the some of the well conserved components of bacterial secretion systems. In this dissertation, I will show that the host has also developed a system for the detection of host ligands, which are used as a danger signal to possible damage induced by a pathogen. These damage patterns are present in the lifestyle of the pathogens, making it nearly impossible for them to avoid completely. Bacterial secretion systems cause vacuolar instability, and when a phagosome or pathogen containing vacuole is damaged, it exposes sugars from the inner leaflet of the membrane to the host cytosol. Galectins, cytosolic host glycan binding proteins, are then able to recognize the exposed sugars and bind them. Subsequently, host defense proteins including the guanylate binding proteins (GBPs) are recruited to the damaged membrane. I propose that this damage sensing ability is broadly applicable for the recruitment of host defense proteins to vacuolar pathogens