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Funding Information: The authors gratefully thank J?rgen Berger and Katharina Hipp (both Max Planck-Institute for Developmental Biology, T?bingen, Germany) for the electron microscopy dis-played in Figure 1.This research was funded by the European Union?s Horizon 2020 research and innovation program in a project named Viral and Bacterial Adhesin Network Training (ViBrANT) under Marie Sk?odowska-Curie Grant Agreement No. 765042. A.G. also acknowledges support from the BBSRC (grant number BB/M021610/1). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Infectious diseases are an existential health threat, potentiated by emerging and re-emerging viruses and increasing bacterial antibiotic resistance. Targeted treatment of infectious diseases requires precision diagnostics, especially in cases where broad-range therapeutics such as antibiotics fail. There is thus an increasing need for new approaches to develop sensitive and specific in vitro diagnostic (IVD) tests. Basic science and translational research are needed to identify key microbial molecules as diagnostic targets, to identify relevant host counterparts, and to use this knowledge in developing or improving IVD. In this regard, an overlooked feature is the capacity of pathogens to adhere specifically to host cells and tissues. The molecular entities relevant for pathogen-surface interaction are the so-called adhesins. Adhesins vary from protein compounds to (poly-)saccharides or lipid structures that interact with eukaryotic host cell matrix molecules and receptors. Such interactions co-define the specificity and sensitivity of a diagnostic test. Currently, adhesin-receptor binding is typically used in the pre-analytical phase of IVD tests, focusing on pathogen enrichment. Further exploration of adhesin-ligand interaction, supported by present high-throughput "omics" technologies, might stimulate a new generation of broadly applicable pathogen detection and characterization tools. This review describes recent results of novel structure-defining technologies allowing for detailed molecular analysis of adhesins, their receptors and complexes. Since the host ligands evolve slowly, the corresponding adhesin interaction is under selective pressure to maintain a constant receptor binding domain. IVD should exploit such conserved binding sites and, in particular, use the human ligand to enrich the pathogen. We provide an inventory of methods based on adhesion factors and pathogen attachment mechanisms, which can also be of relevance to currently emerging pathogens, including SARS-CoV-2, the causative agent of COVID-19.

Many gastrointestinal pathogens use a type III secretion system (T3SS) to manipulate host cells. Protein secretion by the T3SS injectisome is activated upon contact to any host cell, and it has been unclear how premature effector secretion is prevented during infection. We found that at low external pH, such as in the stomach, the components at the proximal interface of the injectisome are temporarily released to the bacterial cytosol, preventing protein secretion. Low external pH is sensed in the periplasm and leads to a partial dissociation of the inner membrane injectisome component SctD, which in turn causes the dissociation of the cytosolic T3SS components. This effect is reversed upon restoration of neutral pH, allowing a fast activation of the T3SS at the native target regions within the host. These findings indicate that the cytosolic components form an adaptive regulatory interface, which regulates T3SS activity in response to environmental conditions.

Adhesion of bacteria to surfaces, abtiotic and biotic, is a key step in pathogenesis as well as symbiosis. Adhesins on the bacterial cell surface are therefor crucial for interactions. One class of adhesins are adhesins of the Type V autotransporter class. In this review we give an overview of Type V autotransporter proteins and their passenger domain function.