Infection with the parasitic nematode Onchocerca volvulus is associated with inflammation of the ... more Infection with the parasitic nematode Onchocerca volvulus is associated with inflammation of the skin and cornea that can lead to blindness. Corneal damage is thought to occur as a result of the host inflammatory responses to degenerating microfilariae in the eye. We have utilized a murine model of corneal inflammation (keratitis) to investigate the immune and inflammatory responses associated with river blindness. Soluble extracts of O. volvulus, a filarial species that contains the endosymbiont bacteria Wolbachia or Acanthocheilonema viteae (a nematode not naturally infected with the bacteria) were injected into mouse corneas. Inflammatory responses and corneal changes were measured. We demonstrated a major role for endosymbiont Wolbachia bacteria and Toll-like receptor 4 (TLR4) in the pathogenesis of ocular onchocerciasis.
Inflammasome and caspase-1 dependent cleavage of IL-1β to the mature, active form is the predomin... more Inflammasome and caspase-1 dependent cleavage of IL-1β to the mature, active form is the predominant, but not sole mechanism of IL-1β processing. To investigate the role of IL-1β, IPAF/NLRC4 inflammasome and caspase-1 in bacterial keratitis, which is an important worldwide cause of blindness, mouse corneas were infected with Pseudomonas aeruginosa invasive strain PAO1 (expressing ExoS, T and Y but not ExoU), and corneal inflammation and bacterial survival were examined. We found that IL-1β-/- mice had significantly fewer infiltrating neutrophils, and significantly higher CFU than C57BL/6 mice. In contrast, there was no difference in either corneal disease or bacterial survival between caspase-1-/-, IPAF1-/- and C57BL/6 mice. In all mouse strains, we found that neutrophils are the major producers of IL-1β during corneal infection, and that although IL-1β processing by macrophages was completely dependent on caspase-1, neutrophil mediated IL-1β processing in vivo was not impaired in caspase-1-/- or in IPAF1-/- mice. In vitro studies showed that inhibition of neutrophil elastase significantly inhibited IL-1β processing by human and mouse neutrophils. Taken together, these results demonstrate a novel caspase-1 independent mechanism of IL-1β processing by neutrophils during bacterial infection.
SEE PROFILE All in-text references underlined in blue are linked to publications on ResearchGate,... more SEE PROFILE All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately.
Jeffrey Tomalka1 and Amy G. Hise1,2,3,* 1Department of Pathology, Case Western Reserve University... more Jeffrey Tomalka1 and Amy G. Hise1,2,3,* 1Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA 2Geriatric Research Education and Clinical Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH 44106, USA 3Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA *Correspondence: amy.hise@case.eduhttp://dx.doi.org/10.1016/j.chom.2015.02.017
Disseminated infection by Candida species represents a common, often life-threatening condition. ... more Disseminated infection by Candida species represents a common, often life-threatening condition. Increased resistance to current antifungal drugs has led to an urgent need to develop new antifungal drugs to treat this pathogen. However, in vivo screening of candidate antifungal compounds requires large numbers of animals and using immunosuppressive agents to allow for fungal dissemination. To increase the efficiency of screening, to use fewer mice, and to remove the need for immunosuppressive agents, which may interfere with the drug candidates, we tested the potential for a novel approach using in vivo imaging of a fluorescent strain of Candida albicans, in a mouse strain deficient in the host defense peptide, murine β-defensin 1 (mBD-1). We developed a strain of C. albicans that expresses red fluorescent protein (RFP), which exhibits similar infectivity to the non-fluorescent parent strain. When this strain was injected into immunocompetent mBD-1-deficient mice, we observed a non-...
Background: Wolbachia are rickettsia-like endosymbionts of Wuchereria bancrofti and Brugia spp. i... more Background: Wolbachia are rickettsia-like endosymbionts of Wuchereria bancrofti and Brugia spp. implicated in the pathogenesis of lymphatic filariasis (LF). Wolbachia surface protein (wsp) has been shown to activate mammalian innate immune responses and elicit proinflammatory responses via toll-like receptors. We examined sera from Papua New Guineans living in a W. bancrofti endemic area for anti-Wolbachia antibodies in order to determine if there was a correlation between acute adenolymphangitis (ADL) defined by transient limb/genital swelling with fever and the titers of anti-Wolbachia antibody. Methods: Serum samples were collected from 20 individuals within a 30-day period before or after an episode of ADL and from 20 age- and sex-matched individuals without ADL. ELISA using recombinant wsp as the target antigen was used to measure anti-Wolbachia IgG antibody. Microfilaria burden was similar between the two groups; a higher proportion of individuals in the ADL group had pre-exis...
Intracellular inflammasome complexes regulate critical cytokine responses to infections. In this ... more Intracellular inflammasome complexes regulate critical cytokine responses to infections. In this issue of Cell Host & Microbe,Karki et al. (2015) show that protection against the fungus Aspergillus requires the combined efforts of the NLRP3 and AIM2 inflammasomes and involves both caspase-1 and caspase-8.
Mosquito-borne Rift Valley fever virus (RVFV) causes acute, often severe, disease in livestock an... more Mosquito-borne Rift Valley fever virus (RVFV) causes acute, often severe, disease in livestock and humans. To determine the exposure factors and range of symptoms associated with human RVF, we performed a population-based cross-sectional survey in six villages across a 40 km transect in northeastern Kenya. A systematic survey of the total populations of six Northeastern Kenyan villages was performed. Among 1082 residents tested via anti-RVFV IgG ELISA, seroprevalence was 15% (CI95%, 13-17%). Prevalence did not vary significantly among villages. Subject age was a significant factor, with 31% (154/498) of adults seropositive vs. only 2% of children ≤15 years (12/583). Seroprevalence was higher among men (18%) than women (13%). Factors associated with seropositivity included a history of animal exposure, non-focal fever symptoms, symptoms related to meningoencephalitis, and eye symptoms. Using cluster analysis in RVFV positive participants, a more severe symptom phenotype was empirical...
Journal of immunology (Baltimore, Md. : 1950), Jan 16, 2015
Candida is an opportunistic fungal pathogen that colonizes the mucosal tract of humans. Pathogeni... more Candida is an opportunistic fungal pathogen that colonizes the mucosal tract of humans. Pathogenic infection occurs in the presence of conditions causing perturbations to the commensal microbiota or host immunity. Early innate immune responses by the epithelium, including antimicrobial peptides (AMPs) and cytokines, are critical for protection against overgrowth. Reduced salivary AMP levels are associated with oral Candida infection, and certain AMPs, including human β-defensins 1-3, have direct fungicidal activity. In this study, we demonstrate that murine β-defensin 1 (mBD1) is important for control of early mucosal Candida infection and plays a critical role in the induction of innate inflammatory mediators. Mice deficient in mBD1, as compared with wild-type mice, exhibit elevated oral and systemic fungal burdens. Neutrophil infiltration to the sites of mucosal Candida invasion, an important step in limiting fungal infection, is significantly reduced in mBD1-deficient mice. These...
MyD88-dependent GM-CSF production by endothelial cells plays a role in the initiation of obesity-... more MyD88-dependent GM-CSF production by endothelial cells plays a role in the initiation of obesity-associated inflammation by promoting adipose macrophage recruitment and M1-like polarization.
Infection with the parasitic nematode Onchocerca volvulus is associated with inflammation of the ... more Infection with the parasitic nematode Onchocerca volvulus is associated with inflammation of the skin and cornea that can lead to blindness. Corneal damage is thought to occur as a result of the host inflammatory responses to degenerating microfilariae in the eye. We have utilized a murine model of corneal inflammation (keratitis) to investigate the immune and inflammatory responses associated with river blindness. Soluble extracts of O. volvulus, a filarial species that contains the endosymbiont bacteria Wolbachia or Acanthocheilonema viteae (a nematode not naturally infected with the bacteria) were injected into mouse corneas. Inflammatory responses and corneal changes were measured. We demonstrated a major role for endosymbiont Wolbachia bacteria and Toll-like receptor 4 (TLR4) in the pathogenesis of ocular onchocerciasis.
Inflammasome and caspase-1 dependent cleavage of IL-1β to the mature, active form is the predomin... more Inflammasome and caspase-1 dependent cleavage of IL-1β to the mature, active form is the predominant, but not sole mechanism of IL-1β processing. To investigate the role of IL-1β, IPAF/NLRC4 inflammasome and caspase-1 in bacterial keratitis, which is an important worldwide cause of blindness, mouse corneas were infected with Pseudomonas aeruginosa invasive strain PAO1 (expressing ExoS, T and Y but not ExoU), and corneal inflammation and bacterial survival were examined. We found that IL-1β-/- mice had significantly fewer infiltrating neutrophils, and significantly higher CFU than C57BL/6 mice. In contrast, there was no difference in either corneal disease or bacterial survival between caspase-1-/-, IPAF1-/- and C57BL/6 mice. In all mouse strains, we found that neutrophils are the major producers of IL-1β during corneal infection, and that although IL-1β processing by macrophages was completely dependent on caspase-1, neutrophil mediated IL-1β processing in vivo was not impaired in caspase-1-/- or in IPAF1-/- mice. In vitro studies showed that inhibition of neutrophil elastase significantly inhibited IL-1β processing by human and mouse neutrophils. Taken together, these results demonstrate a novel caspase-1 independent mechanism of IL-1β processing by neutrophils during bacterial infection.
SEE PROFILE All in-text references underlined in blue are linked to publications on ResearchGate,... more SEE PROFILE All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately.
Jeffrey Tomalka1 and Amy G. Hise1,2,3,* 1Department of Pathology, Case Western Reserve University... more Jeffrey Tomalka1 and Amy G. Hise1,2,3,* 1Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA 2Geriatric Research Education and Clinical Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH 44106, USA 3Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA *Correspondence: amy.hise@case.eduhttp://dx.doi.org/10.1016/j.chom.2015.02.017
Disseminated infection by Candida species represents a common, often life-threatening condition. ... more Disseminated infection by Candida species represents a common, often life-threatening condition. Increased resistance to current antifungal drugs has led to an urgent need to develop new antifungal drugs to treat this pathogen. However, in vivo screening of candidate antifungal compounds requires large numbers of animals and using immunosuppressive agents to allow for fungal dissemination. To increase the efficiency of screening, to use fewer mice, and to remove the need for immunosuppressive agents, which may interfere with the drug candidates, we tested the potential for a novel approach using in vivo imaging of a fluorescent strain of Candida albicans, in a mouse strain deficient in the host defense peptide, murine β-defensin 1 (mBD-1). We developed a strain of C. albicans that expresses red fluorescent protein (RFP), which exhibits similar infectivity to the non-fluorescent parent strain. When this strain was injected into immunocompetent mBD-1-deficient mice, we observed a non-...
Background: Wolbachia are rickettsia-like endosymbionts of Wuchereria bancrofti and Brugia spp. i... more Background: Wolbachia are rickettsia-like endosymbionts of Wuchereria bancrofti and Brugia spp. implicated in the pathogenesis of lymphatic filariasis (LF). Wolbachia surface protein (wsp) has been shown to activate mammalian innate immune responses and elicit proinflammatory responses via toll-like receptors. We examined sera from Papua New Guineans living in a W. bancrofti endemic area for anti-Wolbachia antibodies in order to determine if there was a correlation between acute adenolymphangitis (ADL) defined by transient limb/genital swelling with fever and the titers of anti-Wolbachia antibody. Methods: Serum samples were collected from 20 individuals within a 30-day period before or after an episode of ADL and from 20 age- and sex-matched individuals without ADL. ELISA using recombinant wsp as the target antigen was used to measure anti-Wolbachia IgG antibody. Microfilaria burden was similar between the two groups; a higher proportion of individuals in the ADL group had pre-exis...
Intracellular inflammasome complexes regulate critical cytokine responses to infections. In this ... more Intracellular inflammasome complexes regulate critical cytokine responses to infections. In this issue of Cell Host & Microbe,Karki et al. (2015) show that protection against the fungus Aspergillus requires the combined efforts of the NLRP3 and AIM2 inflammasomes and involves both caspase-1 and caspase-8.
Mosquito-borne Rift Valley fever virus (RVFV) causes acute, often severe, disease in livestock an... more Mosquito-borne Rift Valley fever virus (RVFV) causes acute, often severe, disease in livestock and humans. To determine the exposure factors and range of symptoms associated with human RVF, we performed a population-based cross-sectional survey in six villages across a 40 km transect in northeastern Kenya. A systematic survey of the total populations of six Northeastern Kenyan villages was performed. Among 1082 residents tested via anti-RVFV IgG ELISA, seroprevalence was 15% (CI95%, 13-17%). Prevalence did not vary significantly among villages. Subject age was a significant factor, with 31% (154/498) of adults seropositive vs. only 2% of children ≤15 years (12/583). Seroprevalence was higher among men (18%) than women (13%). Factors associated with seropositivity included a history of animal exposure, non-focal fever symptoms, symptoms related to meningoencephalitis, and eye symptoms. Using cluster analysis in RVFV positive participants, a more severe symptom phenotype was empirical...
Journal of immunology (Baltimore, Md. : 1950), Jan 16, 2015
Candida is an opportunistic fungal pathogen that colonizes the mucosal tract of humans. Pathogeni... more Candida is an opportunistic fungal pathogen that colonizes the mucosal tract of humans. Pathogenic infection occurs in the presence of conditions causing perturbations to the commensal microbiota or host immunity. Early innate immune responses by the epithelium, including antimicrobial peptides (AMPs) and cytokines, are critical for protection against overgrowth. Reduced salivary AMP levels are associated with oral Candida infection, and certain AMPs, including human β-defensins 1-3, have direct fungicidal activity. In this study, we demonstrate that murine β-defensin 1 (mBD1) is important for control of early mucosal Candida infection and plays a critical role in the induction of innate inflammatory mediators. Mice deficient in mBD1, as compared with wild-type mice, exhibit elevated oral and systemic fungal burdens. Neutrophil infiltration to the sites of mucosal Candida invasion, an important step in limiting fungal infection, is significantly reduced in mBD1-deficient mice. These...
MyD88-dependent GM-CSF production by endothelial cells plays a role in the initiation of obesity-... more MyD88-dependent GM-CSF production by endothelial cells plays a role in the initiation of obesity-associated inflammation by promoting adipose macrophage recruitment and M1-like polarization.
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