The role of CC chemokine receptor 5 (CCR5) and RANTES/CCL5 during chronic fungal asthma in mice1

In the present study, we explored the role of CC chemokine receptor 5 (CCR5) in a murine model of chronic fungal asthma induced by an intrapulmonary challenge with Aspergillus fumigatus conidia (or spores). Airway hyperresponsiveness was significantly lower in A. fumigatus‐sensitized mice lacking CCR5 (CCR5‐/‐) compared with similarly sensitized wild‐type (CCR5+/+) control mice at days 2, 21, 30, and 40 after the conidia challenge. CCR5‐/‐ mice exhibited significantly less peribronchial T‐cell and eosinophil accumulation and airway‐remodeling features, such as goblet cell hyperplasia and peribronchial fibrosis, compared with CCR5+/+ mice at these times after conidia. However, both groups of mice exhibited similar allergic airway disease at day 12 after the conidia challenge. In CCR5‐/‐ mice at day 12, the allergic airway disease was associated with airway hyperresponsiveness, peribronchial allergic inflammation, and goblet cell hyperplasia. Immunoneutralization of RANTES/CCL5 in sensitized CCR5+/+ and CCR5‐/‐ mice for 12 days after the conidia challenge significantly reduced the peribronchial inflammation and airway hyperresponsiveness in comparison with control wild‐type and knockout mice at this time. These data demonstrate that functional CCR5 and RANTES/CCL5 are required for the persistence of chronic fungal asthma in mice.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154329/1/fsb2fj010528fje.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154329/2/fsb2fj010528fje-sup-0001.pd

Aspergillus niger: an unusual cause of invasive pulmonary aspergillosis

Infections due to Aspergillus species cause significant morbidity and mortality. Most are attributed to Aspergillus fumigatus, followed by Aspergillus flavus and Aspergillus terreus. Aspergillus niger is a mould that is rarely reported as a cause of pneumonia. A 72-year-old female with chronic obstructive pulmonary disease and temporal arteritis being treated with steroids long term presented with haemoptysis and pleuritic chest pain. Chest radiography revealed areas of heterogeneous consolidation with cavitation in the right upper lobe of the lung. Induced bacterial sputum cultures, and acid-fast smears and cultures were negative. Fungal sputum cultures grew A. niger. The patient clinically improved on a combination therapy of empiric antibacterials and voriconazole, followed by voriconazole monotherapy. After 4 weeks of voriconazole therapy, however, repeat chest computed tomography scanning showed a significant progression of the infection and near-complete necrosis of the right upper lobe of the lung. Serum voriconazole levels were low–normal (1.0 μg ml−1, normal range for the assay 0.5–6.0 μg ml−1). A. niger was again recovered from bronchoalveolar lavage specimens. A right upper lobectomy was performed, and lung tissue cultures grew A. niger. Furthermore, the lung histopathology showed acute and organizing pneumonia, fungal hyphae and oxalate crystallosis, confirming the diagnosis of invasive A. niger infection. A. niger, unlike A. fumigatus and A. flavus, is less commonly considered a cause of invasive aspergillosis (IA). The finding of calcium oxalate crystals in histopathology specimens is classic for A. niger infection and can be helpful in making a diagnosis even in the absence of conidia. Therapeutic drug monitoring may be useful in optimizing the treatment of IA given the wide variations in the oral bioavailability of voriconazole

The Role of Fibrocytes in Sickle Cell Lung Disease

<div><h3>Background</h3><p>Interstitial lung disease is a frequent complication in sickle cell disease and is characterized by vascular remodeling and interstitial fibrosis. Bone marrow-derived fibrocytes have been shown to contribute to the pathogenesis of other interstitial lung diseases. The goal of this study was to define the contribution of fibrocytes to the pathogenesis of sickle cell lung disease.</p> <h3>Methodology/Principal Findings</h3><p>Fibrocytes were quantified and characterized in subjects with sickle cell disease or healthy controls, and in a model of sickle cell disease, the NY1DD mouse. The role of the chemokine ligand CXCL12 in trafficking of fibrocytes and phenotype of lung disease was examined in the animal model. We found elevated concentration of activated fibrocytes in the peripheral blood of subjects with sickle cell disease, which increased further during vaso-occlusive crises. There was a similar elevations in the numbers and activation phenotype of fibrocytes in the bone marrow, blood, and lungs of the NY1DD mouse, both at baseline and under conditions of hypoxia/re-oxygenation. In both subjects with sickle cell disease and the mouse model, fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on most fibrocytes, and CCR2 and CCR7 expressed on a smaller subset of cells. Depletion of the CXCR4 ligand, CXCL12, in the mouse model resulted in a marked reduction of fibrocyte trafficking into the lungs, reduced lung collagen content and improved lung compliance and histology.</p> <h3>Conclusions</h3><p>These data support the notion that activated fibrocytes play a significant role in the pathogenesis of sickle cell lung disease.</p> </div

Altered monocyte and fibrocyte phenotype and function in scleroderma interstitial lung disease: reversal by caveolin-1 scaffolding domain peptide

Interstitial lung disease (ILD) is a major cause of morbidity and mortality in scleroderma (systemic sclerosis, or SSc). Fibrocytes are a monocyte-derived cell population implicated in the pathogenesis of fibrosing disorders. Given the recently recognized importance of caveolin-1 in regulating function and signaling in SSc monocytes, in the present study we examined the role of caveolin-1 in the migration and/or trafficking and phenotype of monocytes and fibrocytes in fibrotic lung disease in human patients and an animal model. These studies fill a gap in our understanding of how monocytes and fibrocytes contribute to SSc-ILD pathology. We found that C-X-C chemokine receptor type 4-positive (CXCR4+)/collagen I-positive (ColI+), CD34+/ColI+ and CD45+/ColI+ cells are present in SSc-ILD lungs, but not in control lungs, with CXCR4+ cells being most prevalent. Expression of CXCR4 and its ligand, stromal cell-derived factor 1 (CXCL12), are also highly upregulated in SSc-ILD lung tissue. SSc monocytes, which lack caveolin-1 and therefore overexpress CXCR4, exhibit almost sevenfold increased migration toward CXCL12 compared to control monocytes. Restoration of caveolin-1 function by administering the caveolin scaffolding domain (CSD) peptide reverses this hypermigration. Similarly, transforming growth factor β-treated normal monocytes lose caveolin-1, overexpress CXCR4 and exhibit 15-fold increased monocyte migration that is CSD peptide-sensitive. SSc monocytes exhibit a different phenotype than normal monocytes, expressing high levels of ColI, CD14 and CD34. Because ColI+/CD14+ cells are prevalent in SSc blood, we looked for such cells in lung tissue and confirmed their presence in SSc-ILD lungs but not in normal lungs. Finally, in the bleomycin model of lung fibrosis, we show that CSD peptide diminishes fibrocyte accumulation in the lungs. Our results suggest that low caveolin-1 in SSc monocytes contributes to ILD via effects on cell migration and phenotype and that the hyperaccumulation of fibrocytes in SSc-ILD may result from the altered phenotype and migratory activity of their monocyte precursors

Airway hyperresponsiveness, but not airway remodeling, is attenuated during chronic pulmonary allergic responses to Aspergillus in CCR4‐/‐ mice

The role of CC chemokine receptor 4 (CCR4) during the development and maintenance of Th2type allergic airway disease is controversial. In this study, we examined the role of CCR4 in the chronic allergic airway response to live Aspergillus fumigatus spores, or conidia, in A. fumigatussensitized mice. After the conidia challenge, mice lacking CCR4 (CCR4‐/‐ mice) exhibited significantly increased numbers of airway neutrophils and macrophages, and conidia were more rapidly eliminated from these mice compared with control CCR4 wild‐type (CCR4+/+) mice. Significant airway hyperresponsiveness to intravenous methacholine was observed at day 3 in CCR4‐/‐ mice, whereas at days 7 and 30, airway hyperresponsiveness was attenuated in these mice compared with control mice. A major reduction in peribronchial and airway eosinophilia was observed in CCR4‐/‐ mice at all times after conidia challenge in contrast to CCR4+/+ mice. Further, whole lung levels of interleukin (IL) 4 and IL‐5 were significantly increased in CCR4‐/‐ mice at day 3, whereas these Th2 cytokines and IL‐13 were significantly decreased at day 30 in CCR4‐/‐ mice compared with their wild‐type counterparts. Peribronchial fibrosis and goblet cell hyperplasia were similar in both groups of mice throughout the course of this model. In summary, CCR4 modulates both innate and acquired immune responses associated with chronic fungal asthma.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154441/1/fsb2fasebj16100193-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154441/2/fsb2fasebj16100193.pd

Functional diversity of chemokines and chemokine receptors in response to viral infection of the central nervous system.

Encounters with neurotropic viruses result in varied outcomes ranging from encephalitis, paralytic poliomyelitis or other serious consequences to relatively benign infection. One of the principal factors that control the outcome of infection is the localized tissue response and subsequent immune response directed against the invading toxic agent. It is the role of the immune system to contain and control the spread of virus infection in the central nervous system (CNS), and paradoxically, this response may also be pathologic. Chemokines are potent proinflammatory molecules whose expression within virally infected tissues is often associated with protection and/or pathology which correlates with migration and accumulation of immune cells. Indeed, studies with a neurotropic murine coronavirus, mouse hepatitis virus (MHV), have provided important insight into the functional roles of chemokines and chemokine receptors in participating in various aspects of host defense as well as disease development within the CNS. This chapter will highlight recent discoveries that have provided insight into the diverse biologic roles of chemokines and their receptors in coordinating immune responses following viral infection of the CNS

Infection-mediated priming of phagocytes protects against lethal secondary Aspergillus fumigatus challenge

Phagocytes restrict the germination of Aspergillus fumigatus conidia and prevent the establishment of invasive pulmonary aspergillosis in immunecompetent mice. Here we report that immunecompetent mice recovering from a primary A. fumigatus challenge are protected against a secondary lethal challenge. Using RAGγc knock-out mice we show that this protection is independent of T, B and NK cells. In protected mice, lung phagocytes are recruited more rapidly and are more efficient in conidial phagocytosis and killing. Protection was also associated with an enhanced expression of CXCR2 and Dectin-1 on bone marrow phagocytes. We also show that protective lung cytokine and chemokine responses are induced more rapidly and with enhanced dynamics in protected mice. Our findings support the hypothesis that following a first encounter with a non-lethal dose of A. fumigatus conidia, the innate immune system is primed and can mediate protection against a secondary lethal infection

Impact Factor: outdated artefact or stepping-stone to journal certification?

A review of Garfield's journal impact factor and its specific implementation as the Thomson Reuters Impact Factor reveals several weaknesses in this commonly-used indicator of journal standing. Key limitations include the mismatch between citing and cited documents, the deceptive display of three decimals that belies the real precision, and the absence of confidence intervals. These are minor issues that are easily amended and should be corrected, but more substantive improvements are needed. There are indications that the scientific community seeks and needs better certification of journal procedures to improve the quality of published science. Comprehensive certification of editorial and review procedures could help ensure adequate procedures to detect duplicate and fraudulent submissions.Comment: 25 pages, 12 figures, 6 table

Mannose‐binding lectin deficiency alters the development of fungal asthma: effects on airway response, inflammation, and cytokine profile

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142115/1/jlb0805.pd

Measuring and modelling the response of Klebsiella pneumoniae KPC prey to Bdellovibrio bacteriovorus predation, in human serum and defined buffer

In worldwide conditions of increasingly antibiotic-resistant hospital infections, it is important to research alternative therapies. Bdellovibrio bacteriovorus bacteria naturally prey on Gram-negative pathogens, including antibiotic-resistant strains and so B. bacteriovorus have been proposed as "living antibiotics" to combat antimicrobially-resistant pathogens. Predator-prey interactions are complex and can be altered by environmental components. To be effective B. bacteriovorus predation needs to work in human body fluids such as serum where predation dynamics may differ to that studied in laboratory media. Here we combine mathematical modelling and lab experimentation to investigate the predation of an important carbapenem-resistant human pathogen, Klebsiella pneumoniae, by B. bacteriovorus in human serum versus buffer. We show experimentally that B. bacteriovorus is able to reduce prey numbers in each environment, on different timescales. Our mathematical model captures the underlying dynamics of the experimentation, including an initial predation-delay at the predator-prey-serum interface. Our research shows differences between predation in buffer and serum and highlights both the potential and limitations of B. bacteriovorus acting therapeutically against K. pneumoniae in serum, informing future research into the medicinal behaviours and dosing of this living antibacterial