Dataset Information

HIF-1? is essential for effective PMN bacterial killing, antimicrobial peptide production and apoptosis in Pseudomonas aeruginosa keratitis.

ABSTRACT: Hypoxia-inducible factor (HIF)-1?, is a transcription factor that controls energy metabolism and angiogenesis under hypoxic conditions, and a potent regulator of innate immunity. The studies described herein examined the role of HIF-1? in disease resolution in BALB/c (resistant, cornea heals) mice after ocular infection with Pseudomonas (P.) aeruginosa. Furthermore, the current studies focused on the neutrophil (PMN), the predominant cell infiltrate in keratitis. Using both siRNA and an antagonist (17-DMAG), the role of HIF-1? was assessed in P. aeruginosa-infected BALB/c mice. Clinical score and slit lamp photography indicated HIF-1? inhibition exacerbated disease and corneal destruction. Real time RT-PCR, immunohistochemistry, ELISA, Greiss and MPO assays, bacterial load, intracellular killing, phagocytosis and apoptosis assays further tested the regulatory role of HIF-1?. Despite increased pro-inflammatory cytokine expression and increased MPO levels after knocking down HIF-1? expression, in vivo studies revealed a decrease in NO production and higher bacterial load. In vitro studies using PMN provided evidence that although inhibition of HIF-1? did not affect phagocytosis, both bacterial killing and apoptosis were significantly affected, as was production of antimicrobial peptides. Overall, data provide evidence that inhibition of HIF-1? converts a normally resistant disease response to susceptible (corneal thinning and perforation) after induction of bacterial keratitis. Although this inhibition does not appear to affect PMN transmigration or phagocytosis, both in vivo and in vitro approaches indicate that the transcriptional factor is essential for effective bacterial killing, apoptosis and antimicrobial peptide production.

SUBMITTER: Berger EA

PROVIDER: S-EPMC3715414 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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HIF-1α is essential for effective PMN bacterial killing, antimicrobial peptide production and apoptosis in Pseudomonas aeruginosa keratitis.

Berger Elizabeth A EA McClellan Sharon A SA Vistisen Kerry S KS Hazlett Linda D LD

PLoS pathogens 20130718 7

Hypoxia-inducible factor (HIF)-1α, is a transcription factor that controls energy metabolism and angiogenesis under hypoxic conditions, and a potent regulator of innate immunity. The studies described herein examined the role of HIF-1α in disease resolution in BALB/c (resistant, cornea heals) mice after ocular infection with Pseudomonas (P.) aeruginosa. Furthermore, the current studies focused on the neutrophil (PMN), the predominant cell infiltrate in keratitis. Using both siRNA and an antagoni ...[more]

PMID: 23874197

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Project description:A worrisome trend in the study and treatment of infectious disease noted in recent years is the increase in multidrug resistant strains of bacteria concurrent with a scarcity of new antimicrobial agents to counteract this rise. This is particularly true amongst bacteria within the Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE) designation. P. aeruginosa is one of the most common causes of bacterial keratitis. Therefore, it is of vital importance to characterize new antimicrobial agents with anti-Pseudomonal activity for use with the ocular surface. MEDI3902 is a multifunctional antibody that targets the P. aeruginosa persistence factor Psl exopolysaccharide, and the type 3 secretion protein PcrV. We initially assessed this antibody for ocular surface toxicity. The antimicrobial activity of the antibody was then tested by treating mice with established P. aeruginosa keratitis with both topical and intravenous treatment modalities. MEDI3902, was shown to be non-toxic to the ocular surface of mice when given topically. It was also effective compared to the control antibody at preventing P. aeruginosa keratitis with a one-time treatment at the time of infection. Both topical and intravenous administration of MEDI3902 has been proved significant in treating established keratitis infections as well, speeding the resolution of infection significantly more than that of the control IgG. We report the first use of a topical immunotherapeutic multifunctional agent targeting Psl and type 3 secretion on the ocular surface as an antimicrobial agent. While MEDI3902 has been shown to prevent Pseudomonas biofilm formation in keratitis models when given prophylactically intravitally, we show that MEDI3902 has the capability to also treat an active infection when given intravenously to mice with Pseudomonas keratitis. Our data indicate antibodies are well tolerated and nontoxic on the ocular surface. They reduce infection in mice treated concurrently at inoculation and reduced the signs of cornea pathology in mice with established infection. Taken together, these data indicate treatment with monoclonal antibodies directed against Psl and PcrV may be clinically effective in the treatment of P. aeruginosa keratitis and suggest that the design of further antibodies to be an additional tool in the treatment of bacterial keratitis.

Dataset Information

HIF-1? is essential for effective PMN bacterial killing, antimicrobial peptide production and apoptosis in Pseudomonas aeruginosa keratitis.

Publications

HIF-1α is essential for effective PMN bacterial killing, antimicrobial peptide production and apoptosis in Pseudomonas aeruginosa keratitis.

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