The cereus matter of Bacillus endophthalmitis.
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ABSTRACT:
SUBMITTER: Mursalin MH
PROVIDER: S-EPMC7113113 | biostudies-literature | 2020 Apr
REPOSITORIES: biostudies-literature
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The cereus matter of Bacillus endophthalmitis.
Mursalin Md Huzzatul MH Livingston Erin T ET Callegan Michelle C MC
Experimental eye research 20200204
Bacillus cereus (B. cereus) endophthalmitis is a devastating intraocular infection primarily associated with post-traumatic injuries. The majority of these infections result in substantial vision loss, if not loss of the eye itself, within 12-48 h. Multifactorial mechanisms that lead to the innate intraocular inflammatory response during this disease include the combination of robust bacterial replication, migration of the organism throughout the eye, and toxin production by the organism. Theref ...[more]
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Project description:BackgroundEndophthalmitis is a serious intraocular infection that frequently results in significant inflammation and vision loss. Because current therapeutics are often unsuccessful in mitigating damaging inflammation during endophthalmitis, more rational targets are needed. Toll-like receptors (TLRs) recognize specific motifs on invading pathogens and initiate the innate inflammatory response. We reported that TLR4 contributes to the robust inflammation which is a hallmark of Bacillus cereus endophthalmitis. To identify novel, targetable host inflammatory factors in this disease, we performed microarray analysis to detect TLR4-dependent changes to the retinal transcriptome during B. cereus endophthalmitis.ResultsC57BL/6 J and TLR4-/- mouse eyes were infected with B. cereus and retinas were harvested at 4 h postinfection, a time representing the earliest onset of neutrophil infiltration. Genes related to acute inflammation and inflammatory cell recruitment including CXCL1 (KC), CXCL2 (MIP2-α), CXCL10 (IP-10), CCL2 (MCP1), and CCL3 (MIP1-α)) were significantly upregulated 5-fold or greater in C57BL/6 J retinas. The immune modulator IL-6, intercellular adhesion molecule ICAM1, and the inhibitor of cytokine signal transduction SOCS3 were upregulated 25-, 11-, and 10-fold, respectively, in these retinas. LIF, which is crucial for photoreceptor cell survival, was increased 6-fold. PTGS2/COX-2, which converts arachidonic acid to prostaglandin endoperoxide H2, was upregulated 9-fold. PTX3, typically produced in response to TLR engagement, was induced 15-fold. None of the aforementioned genes were upregulated in TLR4-/- retinas following B. cereus infection.ConclusionsOur results have identified a cohort of mediators driven by TLR4 that may be important in regulating pro-inflammatory and protective pathways in the retina in response to B. cereus intraocular infection. This supports the prospect that blocking the activation of TLR-based pathways might serve as alternative targets for Gram-positive and Gram-negative endophthalmitis therapies in general.
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Project description:Bacillus cereus can cause endophthalmitis through secretion of virulence factors, including hemolysin BL (Hbl) and nonhemolytic entertoxin (Nhe). Carvacrol is an extract from oregano oil, with potential for curtailing B. cereus endophthalmitis, due to antimicrobial and anti-inflammatory qualities. However, sublethal levels of carvacrol increases B. cereus virulence. The goal of this study was to investigate the increase in B. cereus virulence potential in response stress induced by a subinhibitory concentration (SIC) of carvacrol. Enterotoxin production and tissue damage were examined during ocular infections in vitro and in vivo. We hypothesized that the SIC of carvacrol would significantly increase toxin production in B. cereus without progressing systemically. RT-PCR determined SIC carvacrol-treated B. cereus had significantly higher hblC and nheA mRNA expression levels than controls in vitro. ELISA and RPLA analysis revealed a 46.8% and 50% increase in NheA and HblC toxin levels, respectively, in SIC-treated cultures. Caenorhabditis elegans-fed SIC carvacrol-treated B. cereus had a significantly higher mean mortality rate than nematodes fed untreated B. cereus. Significantly higher TNF-α levels were observed in SIC carvacrol-treated B. cereus mice compared to other treatment groups except for mice infected with B. cereus alone. Significantly higher IL-6 levels were also found in SIC-B. cereus mice. Histological analysis using Rose-Bengal and DAPI determined that the eyes of mice infected with SIC carvacrol-treated B. cereus had significantly more damage than eyes treated with B. cereus alone. The SIC of carvacrol increased B. cereus virulence in vitro and in vivo, with a mild systemic infection noted.
| S-EPMC6261914 | biostudies-literature
Project description:Bacillus endophthalmitis is a devastating eye infection that causes rapid blindness through extracellular tissue-destructive exotoxins. Despite its importance, knowledge of the phylogenetic relationships and population structure of intraocular Bacillus spp. is lacking. In this study, we sequenced the whole genomes of eight Bacillus intraocular pathogens independently isolated from 8/52 patients with posttraumatic Bacillus endophthalmitis infections in the Eye Hospital of Wenzhou Medical University between January 2010 and December 2018. Phylogenetic analysis revealed that the pathogenic intraocular isolates belonged to Bacillus cereus, Bacillus thuringiensis and Bacillus toyonensis To determine the virulence of the ocular isolates, three representative strains were injected into mouse models, and severe endophthalmitis leading to blindness was observed. Through incorporating publicly available genomes for Bacillus spp., we found that the intraocular pathogens could be isolated independently but displayed a similar genetic context. In addition, our data provide genome-wide support for intraocular and gastrointestinal sources of Bacillus spp. belonging to different lineages. Importantly, we identified five molecular signatures of virulence and motility genes associated with intraocular infection, namely, plcA-2, InhA-3, InhA-4, hblA-5, and fliD using pangenome-wide association studies. The characterization of overrepresented genes in the intraocular isolates holds value to predict bacterial evolution and for the design of future intervention strategies in patients with endophthalmitis.IMPORTANCE In this study, we provided a detailed and comprehensive clinicopathological and pathogenic report of Bacillus endophthalmitis over the 8 years of the study period. We first reported the whole-genome sequence of Bacillus spp. causing devastating endophthalmitis and found that Bacillus toyonensis is able to cause endophthalmitis. Finally, we revealed significant endophthalmitis-associated virulence genes involved in hemolysis, immunity inhibition, and pathogenesis. Overall, as more sequencing data sets become available, these data will facilitate comparative research and will reveal the emergence of pathogenic "ocular bacteria."
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Project description:Bacillus cereus is a rare cause of serious human infection but, paradoxically, causes one of the most severe posttraumatic or endogenous infections of the eye, endophthalmitis, which frequently results in blindness. The virulence of B. cereus endophthalmitis historically has been attributed to toxin production. We therefore sought to examine the contribution of the dermonecrotic toxin, hemolysin BL, to the pathogenesis of B. cereus infection in an endophthalmitis system that is highly amenable to study. The pathogenesis of infection resulting from intravitreal injection of 10(2) CFU of either a clinical ocular isolate of B. cereus producing hemolysin BL (HBL+) or an isogenic mutant in this trait (HBL-) was assessed bacteriologically and by slit lamp biomicroscopy, electroretinography, histology, and inflammatory cell enumeration. Both HBL+ and HBL- strains evoked severe intraocular inflammatory responses as early as 12 h postinfection, with complete loss of retinal responsiveness by 12 h. The infections caused by both strains spread of the infection to adjacent tissues by 18 h. No significant differences in intraocular bacterial growth (P >/= 0.21) or inflammatory changes (P >/= 0.21) were observed in eyes infected with either HBL+ or HBL- strains during the course of infection. The level of retinal responsiveness was greater in HBL- infected eyes than in HBL+-infected eyes at 6 h only (P = 0.01). These results indicate that hemolysin BL makes no essential contribution to the severe and rapid course of infection in the endophthalmitis model.
| S-EPMC116518 | biostudies-literature
Project description:BackgroundBacillus cereus (Bc) can cause self-limiting gastrointestinal infections, but when infecting the eye, can cause rapid and irreversible blindness. This study investigated whether clinical ocular and gastrointestinal Bc isolates differed in terms of virulence-related genotypes and endophthalmitis virulence.MethodsTwenty-eight Bc ocular, gastrointestinal, and laboratory reference isolates were evaluated. Hemolysis assays were performed to assess potential differences in hemolytic activity. The presence of twenty Bc virulence-related genes was assessed by PCR. A subset of ocular and gastrointestinal isolates differing in PCR positivity for 5 virulence genes was compared to strain ATCC14579 in an experimental murine model of endophthalmitis. At 8 hours post infection, retinal function was evaluated by electroretinography, and intraocular bacterial concentrations were determined by plate counts.ResultsGastrointestinal Bc isolates were more hemolytic than the Bc ocular isolates and ATCC14579 (p < 0.0001). Bc ocular isolates were more frequently PCR-positive for capK, cytK, hblA, hblC, and plcR compared to the gastrointestinal isolates (p ≤ 0.0002). In the endophthalmitis model, mean A-wave retention did not differ significantly between eyes infected with ATCC14579 and eyes infected with the selected ocular or gastrointestinal isolates (p ≥ 0.3528). Similar results were observed for mean B-wave retention (p ≥ 0.0640). Only one diarrheal isolate showed significantly greater B-wave retention when compared to ATCC14579 (p = 0.0303). No significant differences in mean A-wave (p ≥ 0.1535) or B-wave (p ≥ 0.0727) retention between the selected ocular and gastrointestinal isolates were observed. Intraocular concentrations of ATCC14579 were significantly higher than the selected ocular isolate and 3 of the gastrointestinal isolates (p ≤ 0.0303). Intraocular concentrations of the selected ocular isolate were not significantly different from the gastrointestinal isolates (p ≥ 0.1923).ConclusionsAmong the subset of virulence-related genes assessed, 5 were significantly enriched among the ocular isolates compared to gastrointestinal isolates. While hemolytic activity was higher among gastrointestinal isolates, retinal function retention and intraocular growth was not significantly different between the selected ocular and gastrointestinal isolates. These results suggest that Bc strains causing gastrointestinal infections, while differing from ocular isolates in hemolytic activity and virulence-related gene profile, are similarly virulent in endophthalmitis.
| S-EPMC10722173 | biostudies-literature
Project description:Bacillus cereus is recognized as a causative agent of gastrointestinal syndromes, but can also cause a devastating form of intraocular infection known as endophthalmitis. We have previously reported that the PlcR/PapR master virulence factor regulator system regulates intraocular virulence, and that the S-layer protein (SlpA) contributes to the severity of B. cereus endophthalmitis. To better understand the role of other B. cereus virulence genes in endophthalmitis, expression of a subset of factors was measured at the midpoint of disease progression in a murine model of endophthalmitis by RNA-Seq. Several cytolytic toxins were expressed at significantly higher levels in vivo than in BHI. The virulence regulators codY, gntR, and nprR were also expressed in vivo. However, at this timepoint, plcR/papR was not detectable, although we previously reported that a B. cereus mutant deficient in PlcR was attenuated in the eye. The motility-related genes fla, fliF, and motB, and the chemotaxis-related gene cheA were detected during infection. We have shown previously that motility and chemotaxis phenotypes are important in B. cereus endophthalmitis. The sodA2 variant of manganese superoxide dismutase was the most highly expressed gene in vivo. Expression of the surface layer protein gene, slpA, an activator of Toll-like receptors (TLR)-2 and -4, was also detected during infection, albeit at low levels. Genes expressed in a mouse model of Bacillus endophthalmitis might play crucial roles in the unique virulence of B. cereus endophthalmitis, and serve as candidates for novel therapies designed to attenuate the severity of this often blinding infection.
| S-EPMC8345767 | biostudies-literature
Project description:Comparative Genomic Hybridization. Analysis of genomic content of closely related Bacillus species. Refer to individual records for strain information. Refer to platform and individual sample records for experimental protocols. Keywords: other
2004-10-28 | GSE568 | GEO
Project description:The aim of the study was to carry out a CGH study utilizing a set of 39 diverse Bacillus isolates. Thirty four B. cereus and five B. anthracis strains and isolates were chosen so as to represent different lineages based on previous characterizations, including MLEE and MLST (Helgason, Okstad et al. 2000; Helgason, Tourasse et al. 2004). They represent the spectrum of B. cereus phenotypic diversity by including soil, dairy and periodontal isolates in addition to virulent B. anthracis strains.
2009-11-25 | GSE19068 | GEO
Project description:Bacillus endophthalmitis is a severe intraocular infection. Hallmarks of Bacillus endophthalmitis include robust inflammation and rapid loss of vision. We reported that the absence of Bacillus surface layer protein (SLP) significantly blunted endophthalmitis severity. Here, we further investigated SLP in the context of Bacillus-retinal cell interactions and innate immune pathways to explore the mechanisms by which SLP contributes to intraocular inflammation. We compared phenotypes of Wild-type (WT) and SLP deficient (?slpA) Bacillus thuringiensis by analyzing bacterial adherence to and phagocytosis by human retinal Muller cells and phagocytosis by mouse neutrophils. Innate immune receptor activation by the Bacillus envelope and purified SLP was analyzed using TLR2/4 reporter cell lines. A synthetic TLR2/4 inhibitor was used as a control for this receptor activation. To induce endophthalmitis, mouse eyes were injected intravitreally with 100 CFU WT or ?slpA B. thuringiensis. A group of WT infected mice was treated intravitreally with a TLR2/4 inhibitor at 4 h postinfection. At 10 h postinfection, infected eyes were analyzed for viable bacteria, inflammation, and retinal function. We observed that B. thuringiensis SLPs contributed to retinal Muller cell adherence, and protected this pathogen from Muller cell- and neutrophil-mediated phagocytosis. We found that B. thuringiensis envelope activated TLR2 and, surprisingly, TLR4, suggesting the presence of a surface-associated TLR4 agonist in Bacillus. Further investigation showed that purified SLP from B. thuringiensis activated TLR4, as well as TLR2 in vitro. Growth of WT B. thuringiensis was significantly higher and caused greater inflammation in untreated eyes than in eyes treated with the TLR2/4 inhibitor. Retinal function analysis also showed greater retention of A-wave and B-wave function in infected eyes treated with the TLR2/4 inhibitor. The TLR2/4 inhibitor was not antibacterial in vitro, and did not cause inflammation when injected into uninfected eyes. Taken together, these results suggest a potential role for Bacillus SLP in host-bacterial interactions, as well as in endophthalmitis pathogenesis via TLR2- and TLR4-mediated pathways.
| S-EPMC7028758 | biostudies-literature
Project description:PurposeTo explore the consequences of innate interference on intraocular inflammatory responses during Bacillus endophthalmitis.MethodsBacillus endophthalmitis was induced in mice. Innate immune pathway activation was interfered by injecting S layer protein-deficient (∆slpA) B. thuringiensis or by treating wild-type (WT)-infected mice with a TLR2/4 inhibitor (WT+OxPAPC). At 10 hours postinfection, eyes were harvested and RNA was purified. A NanoString murine inflammation panel was used to compare gene expression in WT-infected, WT+OxPAPC, ∆slpA-infected, and uninfected eyes.ResultsIn WT-infected eyes, 56% of genes were significantly upregulated compared to uninfected controls. Compared to WT-infected eyes, the expression of 27% and 50% of genes were significantly reduced in WT+OxPAPC and ∆slpA-infected eyes, respectively. Expression of 61 genes that were upregulated in WT-infected eyes was decreased in WT+OxPAPC and ∆slpA-infected eyes. Innate interference resulted in blunted expression of complement factors (C3, Cfb, and C6) and several innate pathway genes (TLRs 2, 4, 6, and 8, MyD88, Nod2, Nlrp3, NF-κB, STAT3, RelA, RelB, and Ptgs2). Innate interference also reduced the expression of several inflammatory cytokines (CSF2, CSF3, IL-6, IL-1β, IL-1α, TNFα, IL-23α, TGFβ1, and IL-12β) and chemokines (CCL2, CCL3, and CXCLs 1, 2, 3, 5, 9, and 10). All of the aforementioned genes were significantly upregulated in WT-infected eyes.ConclusionsThese results suggest that interfering with innate activation significantly reduced the intraocular inflammatory response in Bacillus endophthalmitis. This positive clinical outcome could be a strategy for anti-inflammatory therapy of an infection typically refractory to corticosteroid treatment.
| S-EPMC7671874 | biostudies-literature