Explore the vast range of titles available.

Bacterial pathogens have evolved to regulate virulence gene expression at critical points in the colonization and infection processes to successfully cause disease. The Shigella species infect the epithelial cells lining the colon to result in millions of cases of diarrhea and a significant global health burden. As antibiotic resistance rates increase, understanding the mechanisms of infection is vital to ensure successful vaccine development. Despite significant gains in our understanding of Shigella infection, it remains unknown how the bacteria initiate contact with the colonic epithelium. Most pathogens harbor multiple adherence factors to facilitate this process, but Shigella was thought to have lost the ability to produce these factors. Interestingly, we have identified conditions that mimic some features of gastrointestinal transit and that enable Shigella to express adherence structural genes. This work highlights aspects of genetic regulation for Shigella adherence factors and may have a significant impact on future vaccine development. The Shigella species are Gram-negative, facultative intracellular pathogens that invade the colonic epithelium and cause significant diarrheal disease. Despite extensive research on the pathogen, a comprehensive understanding of how Shigella initiates contact with epithelial cells remains unknown. Shigella maintains many of the same Escherichia coli adherence gene operons; however, at least one critical gene component in each operon is currently annotated as a pseudogene in reference genomes. These annotations, coupled with a lack of structures upon microscopic analysis following growth in laboratory media, have led the field to hypothesize that Shigella is unable to produce fimbriae or other traditional adherence factors. Nevertheless, our previous analyses have demonstrated that a combination of bile salts and glucose induces both biofilm formation and adherence to colonic epithelial cells. The goal of this study was to perform transcriptomic and genetic analyses to demonstrate that adherence gene operons in Shigella flexneri strain 2457T are functional, despite the gene annotations. Our results demonstrate that at least three structural genes facilitate S. flexneri 2457T adherence for epithelial cell contact and biofilm formation. Furthermore, our results demonstrate that host factors, namely, glucose and bile salts at their physiological concentrations in the small intestine, offer key environmental stimuli required for adherence factor expression in S. flexneri . This research may have a significant impact on Shigella vaccine development and further highlights the importance of utilizing in vivo -like conditions to study bacterial pathogenesis. IMPORTANCE Bacterial pathogens have evolved to regulate virulence gene expression at critical points in the colonization and infection processes to successfully cause disease. The Shigella species infect the epithelial cells lining the colon to result in millions of cases of diarrhea and a significant global health burden. As antibiotic resistance rates increase, understanding the mechanisms of infection is vital to ensure successful vaccine development. Despite significant gains in our understanding of Shigella infection, it remains unknown how the bacteria initiate contact with the colonic epithelium. Most pathogens harbor multiple adherence factors to facilitate this process, but Shigella was thought to have lost the ability to produce these factors. Interestingly, we have identified conditions that mimic some features of gastrointestinal transit and that enable Shigella to express adherence structural genes. This work highlights aspects of genetic regulation for Shigella adherence factors and may have a significant impact on future vaccine development.

INTRODUCTION Emerging evidence has connected Alzheimer's disease (AD) to systemic inflammation, intestinal abnormalities, and altered gut microbiota, highlighting the significance of the gut–brain axis. Here, we investigated the impact of acute experimental colitis (acute colitis) on AD pathology. METHODS Acute colitis was induced in 2‐month‐old 5xFAD mice using dextran sodium sulfate (DSS) to assess the effects of intestinal inflammation on the microbiome, systemic inflammation, neuroinflammation, and beta‐amyloid deposition. RESULTS Induction of acute colitis in 5xFAD mice led to microbial dysbiosis and systemic inflammation. As a result, monocyte infiltration was observed in the brain accompanied by reduced cerebral beta‐amyloid deposition and increased beta‐amyloid efflux into the bloodstream. DISCUSSION Increased infiltration of monocytes and elevated beta‐amyloid release into the bloodstream could both be responsible for the reduced beta‐amyloid deposition in 5xFAD mice following acute colitis. These results further highlight an important connection between gut‐induced peripheral inflammation and the progression of AD. Highlights Microbial dysbiosis occurs as a result of acute colitis in 5xFAD mice. Acute colitis in 5xFAD mice affects beta‐amyloid deposition. Increased IL‐2 and IL‐6 cytokine levels in the hippocampus of 5xFAD colitis mice. Colitis in 5xFAD mice increases serum proinflammatory cytokine levels and endotoxins. Acute colitis in 5xFAD mice increases monocyte infiltration and serum beta‐amyloid.

[...]the high stability of Aβ multimers suggests that AMP oligomer preparations are also likely to resist environmental degradation and show enhanced shelf-lives compared with monomeric peptides. Aβ also shows a broad activity spectrum, showing activity against fungi, bacteria and viruses. [...]data suggest that Aβ or Aβ derivatives are feasible candidates for development as peptide antibiotics. [...]among eukaryotic cells, high Aβ cytotoxicity appears limited to neurons. [...]neurotoxicity requires highly specific and uncommon Aβ oligomer species. At the concentrations likely to be used clinically, Aβ host cytotoxicity seems unlikely to preclude the peptides use as an antibiotic. [...]selectively removing or inhibiting the generation of rare problematic species in Aβ preparations seems a viable strategy should neurotoxicity prove a problem. β-amyloid deposition in host tissues is also a likely concern for systemic use of an Aβ drug.

Epidemiological studies indicate an inverse correlation between the prevalence of the so-called western diseases, such as obesity and metabolic syndrome, and the exposure to helminths. Obesity, a key risk factor for many chronic health problems, is rising globally and is accompanied by low-grade inflammation in adipose tissues. The precise mechanism by which helminths modulate metabolic syndrome and obesity is not fully understood. We infected high fat diet (HFD)-induced obese mice with the intestinal nematode parasite Heligmosomoides polygyrus and observed that helminth infection resulted in significantly attenuated obesity. Attenuated obesity corresponded with marked upregulation of uncoupling protein 1 (UCP1), a key protein involved in energy expenditure, in adipose tissue, suppression of glucose and triglyceride levels, and alteration in the expression of key genes involved in lipid metabolism. Moreover, the attenuated obesity in infected mice was associated with enhanced helminth-induced Th2/Treg responses and M2 macrophage polarization. Adoptive transfer of helminth-stimulated M2 cells to mice that were not infected with H. polygyrus resulted in a significant amelioration of HFD-induced obesity and increased adipose tissue browning. Thus, our results provide evidence that the helminth-dependent protection against obesity involves the induction of M2 macrophages.

Inflammatory bowel disease (IBD) increases the risk of colorectal cancer, and it has the potential to diminish the quality of life. Recent clinical and experimental evidence demonstrate protective aspects of parasitic helminth infection against IBD. Reports have highlighted the potential use of helminths and their byproducts as potential treatment for IBD. In the current study, we studied the effect of a newborn larvae-specific serine protease from Trichinella spiralis (TsSp) on the host immune and inflammatory responses. A 49-kDa recombinant TsSp (rTsSp) was expressed in Escherichia coli BL21 (DE3) and purified. The cytotoxicity of rTsSp was analyzed. The immune protective effect of rTsSp was studied by using dextran sodium sulfate (DSS)-induced mouse colitis model. The result illustrated that rTsSp has no toxic effects on cells. We further demonstrated that administration of the rTsSp without the additional adjuvant before the induction of DSS-induced colitis reduced the severity of intestinal inflammation and the disease index; it suppressed macrophage infiltration, reduced TNF-α secretion, and induced IL-10 expression. Our findings suggest therapeutic potential of rTsSp on colitis by altering the effect of macrophages. Data also suggest immunotherapy with rTsSp holds promise for use as an additional strategy to positively modulate inflammatory processes involved in IBD.

INTRODUCTION Our previous studies demonstrated the antimicrobial properties of amyloid beta (Aβ) of Alzheimer's disease (AD) against clinically relevant bacteria, yeast, and viruses. In this study, we investigate the antimicrobial function of the 37‐amino acid amylin of type 2 diabetes (T2D), expanding on its potential involvement in AD. METHODS We used in vitro assays, including human three‐dimensional neuronal cell culture models, to test microbicidal, microbiostatic, and synergistic antimicrobial interactions between amylin and Aβ against microbes. RESULTS Our results confirm that amylin is a broad‐spectrum antimicrobial peptide that exhibits both microbicidal and microbiostatic mechanisms. We also identified a synergistic antimicrobial effect between amylin and Aβ in inhibiting Salmonella Typhimurium and Staphylococcus aureus. DISCUSSION The findings show that amylin is an antimicrobial peptide and functions synergistically with Aβ against bacterial pathogens. Increased amylin secretion after bacterial infection suggests a broader biological role for amylin beyond its involvement in T2D. Highlights Amylin is a potent antimicrobial peptide, eliminating ≥99.9% bacteria at low doses. Amylin efficiently traps and neutralizes microbes via a fibril‐driven mechanism. Amylin protects human cells and Caenorhabditis elegans from Salmonella or Candida infection. Synthetic amylin and amyloid beta (Aβ) together amplify antibacterial response against bacteria. Synergy between cell‐derived amylin and Aβ drives dynamic antimicrobial activity against neural infection.

The Shigella species are Gram-negative, facultative intracellular pathogens that invade the colonic epithelium and cause significant diarrheal disease. Despite extensive research on the pathogen, comprehensive understanding of how Shigella initiates contact with epithelial cells remains unknown. Shigella maintains many of the same Escherichia coli adherence gene operons; however, at least one critical gene component in each operon is currently annotated as a pseudogene in reference genomes. These annotations, coupled with a lack of structures upon microscopic analysis following growth in laboratory media, have led the field to hypothesize that Shigella is unable to produce fimbriae or other “traditional” adherence factors. Nevertheless, our previous analyses have demonstrated that a combination of bile salts and glucose induce both biofilm formation and adherence to colonic epithelial cells. Through a two-part investigation, we first utilized various transcriptomic analyses to demonstrate that S. flexneri strain 2457T adherence gene operons are transcribed. Subsequently, we performed mutation, electron microscopy, biofilm, infection, and proteomic analyses to characterize three of the structural genes. In combination, these studies demonstrate that despite the gene annotations, S. flexneri 2457T uses adherence factors to initiate biofilm formation as well as epithelial cell contact. Furthermore, host factors, namely glucose and bile salts in the small intestine, offer key environmental stimuli required for proper adherence factor expression in S. flexneri. This research may have a significant impact on vaccine development for Shigella and further highlights the importance of utilizing in vivo-like conditions to study bacterial pathogenesis.

ABSTRACT The Shigella species are Gram-negative, facultative intracellular pathogens that invade the colonic epithelium and cause significant diarrheal disease. Despite extensive research on the pathogen, a comprehensive understanding of how Shigella initiates contact with epithelial cells remains unknown. Shigella maintains many of the same Escherichia coli adherence gene operons; however, at least one critical gene component in each operon is currently annotated as a pseudogene in reference genomes. These annotations, coupled with a lack of structures upon microscopic analysis following growth in laboratory media, have led the field to hypothesize that Shigella is unable to produce fimbriae or other traditional adherence factors. Nevertheless, our previous analyses have demonstrated that a combination of bile salts and glucose induces both biofilm formation and adherence to colonic epithelial cells. The goal of this study was to perform transcriptomic and genetic analyses to demonstrate that adherence gene operons in Shigella flexneri strain 2457T are functional, despite the gene annotations. Our results demonstrate that at least three structural genes facilitate S. flexneri 2457T adherence for epithelial cell contact and biofilm formation. Furthermore, our results demonstrate that host factors, namely, glucose and bile salts at their physiological concentrations in the small intestine, offer key environmental stimuli required for adherence factor expression in S. flexneri. This research may have a significant impact on Shigella vaccine development and further highlights the importance of utilizing in vivo-like conditions to study bacterial pathogenesis. IMPORTANCE Bacterial pathogens have evolved to regulate virulence gene expression at critical points in the colonization and infection processes to successfully cause disease. The Shigella species infect the epithelial cells lining the colon to result in millions of cases of diarrhea and a significant global health burden. As antibiotic resistance rates increase, understanding the mechanisms of infection is vital to ensure successful vaccine development. Despite significant gains in our understanding of Shigella infection, it remains unknown how the bacteria initiate contact with the colonic epithelium. Most pathogens harbor multiple adherence factors to facilitate this process, but Shigella was thought to have lost the ability to produce these factors. Interestingly, we have identified conditions that mimic some features of gastrointestinal transit and that enable Shigella to express adherence structural genes. This work highlights aspects of genetic regulation for Shigella adherence factors and may have a significant impact on future vaccine development.

Methicillin resistant Staphylococcus aureus (MRSA) is a group of S. aureus strains that has acquired resistance to a class of beta lactam antibiotics and is the major cause of hospital associated infections. Their discovery goes back to 1960 when the first cases were identified. Recently community associated MRSA infections have emerged and are caused by strains that are independent of those from the hospital environment, related only because they carry some of the same antibiotic resistance genes. Community associated infections (CA) are more severe, producing pus filled lesions that are painful and capable of invasion of deep tissues. Virulence factors comprised of exported proteins are associated with the invasiveness of CA strains. Most of these proteins are hypothetical in nature with unknown function. The aim of this study is to identify and characterize potential virulence factor proteins that may be involved in the infection pathway of CA-MRSA. This study focuses on a unique gene that encodes an exported protein, SAS1738, found on the chromosome of the CA strain MSSA476. The protein SAS1738 was chosen because it is unique to CA strains and has homology to some proteins identified in other S. aureus strains known for their virulence and host immune evasion. The goal of this work is to characterize SAS1738 and to determine its role in the infection pathway of the organism. The gene of interest has been successfully cloned, expressed, and tested for toxicity in Caenorhabditis elegans, a nematode. The toxicity tests showed that SAS1738 is inhibitory to the growth and development of C. elegans. The actual mode of action of this protein in C. elegans is yet to be established. However, location of SAS1738 using a GFP fusion showed that the highest concentration of the fusion protein was in the gut of the worms. The purified protein when tested in a killing assay against C. elegans, resulted in the death of the worms at an average time point of 8 min after treatment. Microbiological assay results showed that the purified SAS1738 possessed antibacterial activity towards Micrococcus luteus and Proteus vulgaris. This suggests that SAS1738 may play a dual role of antagonizing the commensal flora of the human skin such as Micrococcus luteus and also induce a toxic effect on the human cells as suggested by its toxic effect on C. elegans. Determination of the role of this protein in the infection cycle of CA-MRSA will lead to a better understanding of the pathogenicity of the organism and possible development of new treatment strategies.