CXCL1, but not IL-6, significantly impacts intraocular inflammation during infection

Parkunan, Salai Madhumathi; Randall, C. Blake; Astley, Roger; Furtado, Gláucia C.; Lira, Sérgio A.; Callegan, Michelle C.

doi:10.1189/jlb.3a0416-173r

Cited by 39 publications

(59 citation statements)

References 80 publications

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“…Logically, local toxin production would be decreased in an environment with a lower bacterial burden. However, it is only when B. cereus are quorum sensing-deficient (Callegan et al, 2003 and Callegan et al, 2005) or motility-deficient (Callegan et al, 2005 and Callegan et al, 2006) or mice are immunodeficient (Novosad et al, 2012, Parkunan et al, 2015, and Parkunan et al, 2016) that we have noted stark contrasts in infection severity with equivalent bacterial numbers in control and experimental groups. Taken together, these results highlight the sensitivity of the eye to B. cereus burden and the importance of infection control during its earliest stages.…”

Section: Discussionmentioning

confidence: 49%

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The role of pili in Bacillus cereus intraocular infection

Callegan

Parkunan

Randall

et al. 2017

Experimental Eye Research

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Bacterial endophthalmitis is a potentially blinding intraocular infection. The bacterium Bacillus cereus causes a devastating form of this disease which progresses rapidly, resulting in significant inflammation and loss of vision within a few days. The outer surface of B. cereus incites the intraocular inflammatory response, likely through interactions with innate immune receptors such as TLRs. This study analyzed the role of B. cereus pili, adhesion appendages located on the bacterial surface, in experimental endophthalmitis. To test the hypothesis that the presence of pili contributed to intraocular inflammation and virulence, we analyzed the progress of experimental endophthalmitis in mouse eyes infected with wild type B. cereus (ATCC 14579) or its isogenic pilus-deficient mutant (ΔbcpA-srtD-bcpB or ΔPil). One hundred CFU were injected into the mid-vitreous of one eye of each mouse. Infections were analyzed by quantifying intraocular bacilli and retinal function loss, and by histology from 0 to 12 h postinfection. In vitro growth and hemolytic phenotypes of the infecting strains were also compared. There was no difference in hemolytic activity (1:8 titer), motility, or in vitro growth (p>0.05, every 2 h, 0-18 h) between wild type B. cereus and the ΔPil mutant. However, infected eyes contained greater numbers of wild type B. cereus than ΔPil during the infection course (p≤0.05, 3-12 h). Eyes infected with wild type B. cereus experienced greater losses in retinal function than eyes infected with the ΔPil mutant, but the differences were not always significant. Eyes infected with ΔPil or wild type B. cereus achieved similar degrees of severe inflammation. The results indicated that the intraocular growth of pilus-deficient B. cereus may have been better controlled, leading to a trend of greater retinal function in eyes infected with the pilus-deficient strain. Although this difference was not enough to significantly alter the severity of the inflammatory response, these results suggest a potential role for pili in protecting B. cereus from clearance during the early stages of endophthalmitis, which is a newly described virulence mechanism for this organism and this infection.

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Section: Discussionmentioning

confidence: 49%

“…Statistical significance was p<0.05. The Mann Whitney Rank Sum test was used to compare experimental groups to determine the statistical significance for all assays (Parkunan et al, 2015, and Parkunan et al, 2016). All statistical analyses were performed using GraphPad Prism 6.05 (GraphPad Software, Inc., La Jolla CA).…”

Section: Methodsmentioning

confidence: 99%

The role of pili in Bacillus cereus intraocular infection

Callegan

Parkunan

Randall

et al. 2017

Experimental Eye Research

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“…Factors that play a role in this destruction include membrane-damaging toxins such as hemolysins, sphingomyelinases, and phospholipases, virulence factors regulated by the quorum sensing-dependent transcriptional regulator PlcR, rapid intraocular growth, and bacterial motility within the eye (17)(18)(19)(20). Neutrophils themselves cause damage to the retina, and chemokine CXCL1 and other factors contribute to neutrophil recruitment and the damaging inflammation seen during Bacillus endophthalmitis (21). In bleb-related endophthalmitis, Streptococcus pneumoniae is an important pathogen and causes a severe endophthalmitis; the pneumococcal capsule, pneumolysin, and autolysin all appear to contribute to pathogenesis (22,23).…”

Section: Pathogenesismentioning

confidence: 99%

Bacterial and Fungal Endophthalmitis

2017

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Endophthalmitis is a severe eye infection that may result in permanent loss of useful vision in the affected eye. Most cases are exogenous and occur as a complication of cataract surgery, an intravitreal injection, or penetrating ocular trauma. Endogenous endophthalmitis results from hematogenous seeding of the eye by bacteria or fungi, but bacteremia or fungemia may be transient and patients may present without symptoms of systemic infection. Nearly all endophthalmitis patients present with decreased vision, and some also have eye pain. Eye examination usually reveals a hypopyon and intraocular inflammation. Diagnosis is clinical, supported by cultures of the vitreous and/or aqueous or by blood cultures in some endogenous cases. Molecular diagnostic techniques have been used in research laboratories for pathogen identification in endophthalmitis and offer the possibility of rapid diagnosis, including in culture-negative cases. Intravitreal injection of antibiotics is the most important component of treatment; some cases also benefit from surgical debridement of the vitreous by a vitrectomy. The visual outcome depends partly on the pathogen: coagulase-negative staphylococcal endophthalmitis has a better prognosis than does streptococcal endophthalmitis, for example. Endophthalmitis is a medical emergency, and prompt diagnosis and treatment are essential for saving vision.

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“…B. thuringiensis 407 (WT) or its isogenic InhA mutants (ΔinhA1, ΔinhA2, ΔinhA1-3) [35,64] were injected into mouse eyes, as previously described [2,6,21,23,26,65,[65][66][67].…”

Section: Bacterial Strainsmentioning

confidence: 99%

“…Strains were diluted in fresh BHI to approximately 10 CFU/mL and incubated for an additional 10 hours. Every 2 hours, 20-μL aliquots were track diluted in PBS and plated onto BHI agar plates, and counted after 24 hours [2,6,21,23,26,65,[65][66][67]. Values are expressed in percent hemolysis relative to a 100% lysis control, as previously described [16,19,26,61,68].Values represent the means ± SD of two independent experiments.…”

Section: Bacterial Growth Curvesmentioning

confidence: 99%

Immune Inhibitor A Metalloproteases Contribute to Virulence inBacillusEndophthalmitis

Livingston

Mursalin

Coburn

et al. 2020

Preprint

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AbstractBacterial endophthalmitis is a devastating infection that can cause blindness following the introduction of organisms into the posterior segment of the eye. Over half of Bacillus endophthalmitis cases result in significant loss of useful vision. Often, these eyes have to be enucleated. Bacillus produces many virulence factors in the eye that may contribute to retinal damage and robust inflammation. This study analyzed Bacillus immune inhibitor A (InhA) metalloproteases, which digest extracellular matrix, tight junction proteins, and antimicrobial proteins. We hypothesized that InhAs contribute to Bacillus intraocular virulence and inflammation. We analyzed phenotypes and infectivity of wild type (WT), InhA1-deficient (ΔinhA1), InhA2-deficient (ΔinhA2), or InhA1, A2, and A3-deficient (ΔinhA1-3) Bacillus thuringiensis. In vitro analysis of growth, proteolysis, and cytotoxicity were compared between B. thuringiensis strains. WT and InhA mutants were similarly cytotoxic to retinal cells. Mutant ΔinhA1 and ΔinhA2 entered log phase growth earlier than WT. Proteolysis of the ΔinhA1-3 mutant was decreased, but this strain grew similar to WT in vitro. Experimental endophthalmitis was initiated by intravitreally infecting C57BL/6J mice with 200 CFU of B. thuringiensis WT or InhA mutants. Intraocular Bacillus and retinal function loss were quantified. Intraocular myeloperoxidase concentrations were quantified and histology was analyzed. Eyes infected with ΔinhA1 or ΔinhA2 strains contained greater numbers of bacteria than eyes infected with WT throughout the course of infection. Eyes infected with single mutants had inflammation and retinal function loss similar to eyes infected with WT strain. Eyes infected with ΔinhA1-3 cleared the infection, with less retinal function loss and inflammation compared to eyes infected with the WT strain. RT-PCR results suggested that single InhA mutant results may be explained by compensatory expression of the other InhAs in these mutants. These results indicate that together, the InhA metalloproteases contribute to the severity of infection and inflammation in Bacillus endophthalmitis.Author summaryBacterial endophthalmitis is an infection of the eye, which can follow accidental contamination of the posterior segment following ocular surgery (postoperative), a penetrating wound (post-traumatic), or during spread of bacteria into the eye from the bloodstream (endogenous). During bacterial endophthalmitis, virulent pathogens such as Bacillus cause ocular damage via the activities of an array of virulence factors, including proteases. A class of proteases that are expressed by Bacillus during ocular infection are the immune inhibitor A metalloproteases. Here, we used a mouse model of endophthalmitis to test mutant Bacillus that lack single or multiple InhAs to determine if these metalloproteases contributed to the virulence during the disease. In the absence of the production of all InhAs, Bacillus could not cause severe infection. Our study provides new insights into the virulence of Bacillus in the eye, and the contribution of its InhA metalloproteases to establishing infection.

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CXCL1, but not IL-6, significantly impacts intraocular inflammation during infection

Cited by 39 publications

References 80 publications

The role of pili in Bacillus cereus intraocular infection

The role of pili in Bacillus cereus intraocular infection

Bacterial and Fungal Endophthalmitis

Immune Inhibitor A Metalloproteases Contribute to Virulence inBacillusEndophthalmitis

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