Bladder Exposure to Gardnerella Activates Host Pathways Necessary for Escherichia coli Recurrent UTI

Recurrent urinary tract infections (rUTI) are a costly clinical problem affecting millions of women worldwide each year. The majority of rUTI cases are caused by uropathogenic Escherichia coli (UPEC). Data from humans and mouse models indicate that some instances of rUTI are caused by UPEC emerging from latent reservoirs in the bladder. Women with vaginal dysbiosis, typically characterized by high levels of Gardnerella and other anaerobes, are at increased risk of UTI. Multiple studies have detected Gardnerella in urine collected by transurethral catheterization (to limit vaginal contamination), suggesting that some women experience routine urinary tract exposures. We recently reported that inoculation of Gardnerella into the bladder triggers rUTI from UPEC bladder reservoirs in a mouse model. Here we performed whole bladder RNA-seq to identify host pathways involved in Gardnerella-induced rUTI. We identified a variety host pathways differentially expressed in whole bladders following Gardnerella exposure, such as pathways involved in inflammation/immunity and epithelial turnover. At the gene level, we identified upregulation of Immediate Early (IE) genes, which are induced in various cell types shortly following stimuli like infection and inflammation. One such upregulated IE gene was the orphan nuclear receptor Nur77 (aka Nr4a1). Pilot experiments in Nur77-/- mice suggest that Nur77 is necessary for Gardnerella exposure to trigger rUTI from UPEC reservoirs. These findings demonstrate that bladder gene expression can be impacted by short-lived exposures to urogenital bacteria and warrant future examination of responses in distinct cell types, such as with single cell transcriptomic technologies. The biological validation studies in Nur77-/- mice lay the groundwork for future studies investigating Nur77 and the Immediate Early response in rUTI.

MOV10 Helicase Interacts with Coronavirus Nucleocapsid Protein and Has Antiviral Activity

Coronaviruses (CoVs) are emerging pathogens causing life-threatening diseases in humans. Knowledge of virus-host interactions and viral subversion mechanisms of host pathways is required for the development of effective countermeasures against CoVs.

The Toxoplasma Polymorphic Effector GRA15 Mediates Seizure Induction by Modulating Interleukin-1 Signaling in the Brain

Inflammation in the brain caused by infections lead to seizures and other neurological symptoms. But the microbial products that induce seizures as well as the host pathways downstream of these factors are largely unknown.

A triple threat: the Parastagonospora nodorum SnTox267 effector exploits three distinct host genetic factors to cause disease in wheat

Parastagonospora nodorum is a fungal pathogen of wheat. As a necrotrophic specialist, it deploys a suite of effector proteins that target dominant host susceptibility genes to elicit programmed cell death (PCD). Nine effector-host susceptibility gene interactions have been reported in this pathosystem, presumed to be governed by unique pathogen effectors. This study presents the characterization of the SnTox267 necrotrophic effector that hijacks two separate host pathways to cause necrosis. An association mapping approach identified SnTox267 and the generation of gene-disrupted mutants and gain-of-function transformants confirmed its role in Snn2-, Snn6-, and Snn7-mediated necrosis. The Snn2 and Snn6 host susceptibility genes were complementary, and together they functioned cooperatively to elicit SnTox267-induced necrosis in the same light-dependent PCD pathway. Additionally, we showed that SnTox267 targeted Snn7, resulting in light-independent necrosis. Therefore, SnTox267 co-opts two distinct host pathways to elicit PCD. SnTox267 sequence comparison among a natural population of 197 North American P. nodorum isolates revealed 20 protein isoforms conferring variable levels of virulence, indicating continuing selection pressure on this gene. Protein isoform prevalence among discrete populations indicated that SnTox267 has likely evolved in response to local selection pressures and has diversified more rapidly in the Upper Midwest. Deletion of SnTox267 resulted in the upregulation of the unrelated effector genes SnToxA, SnTox1, and SnTox3, providing evidence for a complex genetic compensation mechanism. These results illustrate a novel evolutionary path by which a necrotrophic fungal pathogen uses a single proteinaceous effector to hijack two host pathways to induce cell death.

Molecular Mimicry: a Paradigm of Host-Microbe Coevolution Illustrated by Legionella

ABSTRACT Through coevolution with host cells, microorganisms have acquired mechanisms to avoid the detection by the host surveillance system and to use the cell’s supplies to establish themselves. Indeed, certain pathogens have evolved proteins that imitate specific eukaryotic cell proteins, allowing them to manipulate host pathways, a phenomenon termed molecular mimicry. Bacterial “eukaryotic-like proteins” are a remarkable example of molecular mimicry. They are defined as proteins that strongly resemble eukaryotic proteins or that carry domains that are predominantly present in eukaryotes and that are generally absent from prokaryotes. The widest diversity of eukaryotic-like proteins known to date can be found in members of the bacterial genus Legionella, some of which cause a severe pneumonia in humans. The characterization of a number of these proteins shed light on their importance during infection. The subsequent identification of eukaryotic-like genes in the genomes of other amoeba-associated bacteria and bacterial symbionts suggested that eukaryotic-like proteins are a common means of bacterial evasion and communication, shaped by the continuous interactions between bacteria and their protozoan hosts. In this review, we discuss the concept of molecular mimicry using Legionella as an example and show that eukaryotic-like proteins effectively manipulate host cell pathways. The study of the function and evolution of such proteins is an exciting field of research that is leading us toward a better understanding of the complex world of bacterium-host interactions. Ultimately, this knowledge will teach us how host pathways are manipulated and how infections may possibly be tackled.