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CheV is one of the least understood chemosensory signaling proteins. Our demonstration that CheV interacts only with certain chemoreceptors offers fundamental new insights. These findings, combined with the observation that CheV is present in bacteria with numerous chemoreceptors, suggest that CheV plays a role in coordinating chemotactic outputs in complex chemosensory systems. Understanding the mechanisms by which chemotactic responses are defined in bacteria with a high number of chemoreceptors is a major research priority in the field of chemotaxis. While previous studies, including this one, show that the ability to be phosphorylated is crucial for CheV function, the molecular consequences of CheV phosphorylation have remained unclear. Our discovery that phosphorylation is essential for CheV binding to certain chemoreceptors fills in this critical gap in understanding the molecular mechanism of CheV. This study is likely to inspire further research into CheV function in other bacteria using similar approaches.

Iron homeostasis in the mammalian host limits the availability of iron to invading pathogens and is thought to restrict iron availability for microbes inhabiting mucosal surfaces. The presence of surface receptors for the host iron-binding glycoproteins transferrin (Tf) and lactoferrin (Lf) in globally important Gram-negative bacterial pathogens of humans and food production animals suggests that Tf and Lf are important sources of iron in the upper respiratory or genitourinary tracts, where they exclusively reside. Lf receptors have the additional function of protecting against host cationic antimicrobial peptides, suggesting that the bacteria expressing these receptors reside in a niche where exposure is likely. In this review we compare Tf and Lf receptors with respect to their structural and functional features, their role in colonization and infection, and their distribution among pathogenic and commensal bacteria.

The present study describes a previously unknown universal system that orchestrates the interaction of bacteria with the environment, named the Teazeled receptor system (TR-system). The identical system was recently discovered within eukaryotes. The system includes DNA- and RNA-based molecules named “TezRs”, that form receptor’s network located outside the membrane, as well as reverse transcriptases and integrases. TR-system takes part in the control of all major aspects of bacterial behavior, such as intra cellular communication, growth, biofilm formation and dispersal, utilization of nutrients including xenobiotics, virulence, chemo- and magnetoreception, response to external factors (e.g., temperature, UV, light and gas content), mutation events, phage-host interaction, and DNA recombination activity. Additionally, it supervises the function of other receptor-mediated signaling pathways. Importantly, the TR-system is responsible for the formation and maintenance of cell memory to preceding cellular events, as well the ability to “forget” preceding events. Transcriptome and biochemical analysis revealed that the loss of different TezRs instigates significant alterations in gene expression and proteins synthesis.

Extracorporeal hemoadsorption for treating bacteremia has exhibited limited success due to the lack of a clear strategy for effectively bringing bacterial cells into contact with the surface and universal bacteria‐capturing substances. Here, a novel extracorporeal device is reported that can eliminate various intact bacteria from whole blood, employing microfluidic bacterial margination and engineered cell‐depleted thrombus (CDT) presenting bacterial adhesin receptors. The critical strain rate of red blood cells (RBCs) (0.83 × 10−2) and the flow path height within about 300 µm required for RBC axial migration in the flows are found. The subsequent RBC‐bacteria collisions induced bacterial margination, facilitating their effective capture on the CDT surface on the channel wall. Fibrinogen and fibronectin in CDT are found to primarily contribute to capturing various bacteria. The extracorporeal CDT filters (eCDTF), which integrate all these principles, demonstrate significant depletion of major antibiotic‐resistant and human fecal bacteria from the whole blood in vitro. Remarkable reductions in bacterial load and inflammatory markers in the rats lethally infected with methicillin‐resistant Staphylococcus aureus are further confirmed, resulting in the restoration from bacteremia following extracorporeal treatment. The demonstration may propose a new design principle for hemoadsorption devices and elucidate the limited success of conventional treatments. A highly efficient extracorporeal device for treating bacteremia is developed by integrating microfluidic bacterial margination and engineered cell‐depleted thrombi strategically constructed in the device. The rodent models, severely infected with antibiotic‐resistant bacteria, recover from bacteremia after two subsequent extracorporeal blood treatments. This approach offers new insight into the design of hemoadsorption devices, overcoming the limitations of conventional extracorporeal therapies.

The transferrins are a family of proteins that bind free iron in the blood and bodily fluids. Serum transferrins function to deliver iron to cells via a receptor-mediated endocytotic process as well as to remove toxic free iron from the blood and to provide an anti-bacterial, low-iron environment. Lactoferrins (found in bodily secretions such as milk) are only known to have an anti-bacterial function, via their ability to tightly bind free iron even at low pH, and have no known transport function. Though these proteins keep the level of free iron low, pathogenic bacteria are able to thrive by obtaining iron from their host via expression of outer membrane proteins that can bind to and remove iron from host proteins, including both serum transferrin and lactoferrin. Furthermore, even though human serum transferrin and lactoferrin are quite similar in sequence and structure, and coordinate iron in the same manner, they differ in their affinities for iron as well as their receptor binding properties: the human transferrin receptor only binds serum transferrin, and two distinct bacterial transport systems are used to capture iron from serum transferrin and lactoferrin. Comparison of the recently solved crystal structure of iron-free human serum transferrin to that of human lactoferrin provides insight into these differences.

Chimeric antigen receptor T cells (CAR-Ts) constitute a novel therapeutic strategy for relapsed/refractory B-cell malignancies. With the extensive application of CAR-T therapy in clinical settings, CAR-T-associated toxicities have become increasingly apparent. However, information regarding the associated infections is limited. We aimed to evaluate the incidence of infection during CAR-T therapy and identify the potential risk factors. Especially, we evaluated infections and the associated risk factors in 92 patients. The cohort included patients with acute lymphoblastic leukemia (n = 58) and non-Hodgkin lymphoma (n = 34). Fifteen cases of infection (predominantly bacterial) were observed within 28 days of CAR-T therapy, with an infection density of 0.5 infections for every 100 days-at-risk. Neutropenia before CAR-T therapy (P = .005) and prior infection (P = .046) were independent risk factors associated with infection within 28 days after CAR-T therapy; corticosteroid treatment during cytokine release syndrome (P = .013) was an independent risk factor during days 29–180 after CAR-T infusions. Moreover, the 2-year survival duration was significantly shorter in patients with infections than in those without (126 vs 409 days; P = .006). Our results suggested that effective anti-infection therapies may improve prognosis of patients who have a high infection risk. The risk of bacterial infections during the early stages of CAR-T therapy and the subsequent risk of viral infections thereafter should be considered to provide the appropriate treatment and improve patient prognosis.

The TEM-1 β-lactamase protein fragment complementation assay was investigated for its applicability in affinity protein-based interaction studies in Escherichia coli, using an affibody-based model system. Results from co-transformation experiments showed that an ampicillin resistant phenotype was specifically associated with cognate affibody–target pairings. Attempts to monitor β-lactamase complementation in vitro with the fluorescent β-lactamase substrates CCF2/AM and CCF2 showed that E. coli lacks an esterase activity necessary for activation of the esterified and membrane-permeable CCF2/AM form of the substrate. Interestingly, supplementation of the assay reaction with a purified fungal lipase (cutinase) resulted in efficient activation of CCF2/AM in vitro. Further, periplasmic expression of cutinase allowed for fluorescent discrimination between β-lactamase positive and negative living E. coli cells using the CCF2/AM substrate, which should open the way for novel applications for this prokaryotic host in protein interaction studies.

Tuberculosis (TB) is one of the leading causes of death worldwide due to infectious diseases. Mycobacterium tuberculosis (M. tb) is the causative agent of the disease where infection is usually initiated by inhalation of aerosols carrying the bacilli. Biochemical studies combined with proteomic analysis have identified that glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) is localized to the cell envelope of M. tb cells. Confocal microscopy confirmed the co‐localization of GAPDH and transferrin (tf) on intracellular bacilli. Additional studies analyzed the significance of the GAPDH‐Tf uptake process during infection using an in vitro THP‐1 cell culture model using co‐localization and biochemical assays. Transmission electron microscopy (TEM) and TEM‐based tomography studies revealed an extremely unusual process whereby the entire GAPDH‐Tf complex is internalized into the bacterium. Likewise, GAPDH from many bacterial species has been reported to possess alternate functions that include adhesion, immune evasion, and plasminogen binding.

The integrity of tight junctions, which regulate paracellular permeability, is challenged by many bacterial pathogens. This is caused by inflammatory responses triggered by pathogens and direct interaction of bacteria or their toxins with host epithelial cells. In some cases, tight junction proteins represent receptors for cell surface proteins or toxins of the pathogen, such as Clostridium perfringens enterotoxin (CPE). CPE causes diarrhea and cramps—the symptoms of a common foodborne illness, caused by C. perfringens type A. It uses a subgroup of the claudin family of tight junction proteins as receptors and forms pores in the membrane of intestinal epithelial cells. Ca 2+ influx through these pores finally triggers cell damage. In this review, we summarize tight junction targeting and alteration by a multitude of different microorganisms such as C. perfringens , Escherichia coli , Helicobacter pylori , Salmonella typhimurium , Shigella flexneri , Vibrio cholerae , Yersinia enterocolitica , protozoan parasites, and their proteins. A focus is drawn towards CPE, the interaction with its receptors, cellular, and pathophysiological consequences for the intestinal epithelium. In addition, we portend to the use of CPE-based claudin modulators for drug delivery as well as diagnosis and therapy of cancer.

Stimulator of interferon genes (STING) is an antiviral signalling protein that is broadly conserved in both innate immunity in animals and phage defence in prokaryotes 1 – 4 . Activation of STING requires its assembly into an oligomeric filament structure through binding of a cyclic dinucleotide 4 – 13 , but the molecular basis of STING filament assembly and extension remains unknown. Here we use cryogenic electron microscopy to determine the structure of the active Toll/interleukin-1 receptor (TIR)–STING filament complex from a Sphingobacterium faecium cyclic-oligonucleotide-based antiphage signalling system (CBASS) defence operon. Bacterial TIR–STING filament formation is driven by STING interfaces that become exposed on high-affinity recognition of the cognate cyclic dinucleotide signal c-di-GMP. Repeating dimeric STING units stack laterally head-to-head through surface interfaces, which are also essential for human STING tetramer formation and downstream immune signalling in mammals 5 . The active bacterial TIR–STING structure reveals further cross-filament contacts that brace the assembly and coordinate packing of the associated TIR NADase effector domains at the base of the filament to drive NAD + hydrolysis. STING interface and cross-filament contacts are essential for cell growth arrest in vivo and reveal a stepwise mechanism of activation whereby STING filament assembly is required for subsequent effector activation. Our results define the structural basis of STING filament formation in prokaryotic antiviral signalling. Through structural analysis of the activation of bacterial STING, the molecular basis of STING filament formation and TIR effector domain activation in antiphage signalling is defined.