A noncanonical role for the engulfment gene ELMO1 in neutrophils that promotes inflammatory arthritis.

Rheumatoid arthritis is characterized by progressive joint inflammation and affects ~1% of the human population. We noted single-nucleotide polymorphisms (SNPs) in the apoptotic cell-engulfment genes ELMO1, DOCK2, and RAC1 linked to rheumatoid arthritis. As ELMO1 promotes cytoskeletal reorganization during engulfment, we hypothesized that ELMO1 loss would worsen inflammatory arthritis. Surprisingly, Elmo1-deficient mice showed reduced joint inflammation in acute and chronic arthritis models. Genetic and cell-biology studies revealed that ELMO1 associates with receptors linked to neutrophil function in arthritis and regulates activation and early neutrophil recruitment to the joints, without general inhibition of inflammatory responses. Further, neutrophils from the peripheral blood of human donors that carry the SNP in ELMO1 associated with arthritis display increased migratory capacity, whereas ELMO1 knockdown reduces human neutrophil migration to chemokines linked to arthritis. These data identify 'noncanonical' roles for ELMO1 as an important cytoplasmic regulator of specific neutrophil receptors and promoter of arthritis.

Neutrophil-Derived Tumor Necrosis Factor Drives Fungal Acute Lung Injury in Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) results from deficiency of nicotinamide adenine dinucleotide phosphate(NADPH) oxidase and impaired reactive oxygen species (ROS) generation. This leads to impaired killing of Aspergillus and, independently, a pathologic hyperinflammatory response to the organism. We hypothesized that neutrophil-derived ROS inhibit the inflammatory response to Aspergillus and that acute lung injury in CGD is due to failure of this regulation. Mice with gp91phox deficiency, the most common CGD mutation, had more severe lung injury, increased neutrophilinfiltration, and increased lung tumor necrosis factor (TNF) after Aspergillus challenge compared with wild-types. Neutrophils were surprisingly the predominant source of TNF in gp91phox-deficient lungs. TNF neutralization inhibited neutrophil recruitment in gp91phox-deficient mice and protected from lung injury. We propose that, in normal hosts, Aspergillus stimulates TNF-dependent neutrophil recruitment to the lungs and neutrophil-derived ROS limit inflammation. In CGD, in contrast, recruited neutrophils are the dominant source of TNF, promoting further neutrophil recruitment in a pathologic positive-feedback cycle, resulting in progressive lung injury.

Draft Genome Sequences of Phenotypically Distinct Janthinobacterium sp. Isolates Cultured from the Hudson Valley Watershed.

Investigation of the Hudson Valley watershed reveals many violacein-producing bacteria. These are of interest for their biotherapeutic potential in treating chytrid infections of amphibians. The draft whole-genome sequences for seven Janthinobacterium isolates with a variety of phenotypes are provided in this study.

Hepcidin-mediated iron sequestration protects against bacterial dissemination during pneumonia.

Gram-negative pneumonia is a dangerous illness, and bacterial dissemination to the bloodstream during the infection is strongly associated with death. Antibiotic resistance among the causative pathogens has resulted in diminishing treatment options against this infection. Hepcidin is the master regulator of extracellular iron availability in vertebrates, but its role in the context of host defense is undefined. We hypothesized that hepcidin-mediated depletion of extracellular iron during Gram-negative pneumonia protects the host by limiting dissemination of bacteria to the bloodstream. During experimental pneumonia, hepcidin was induced in the liver in an IL-6-dependent manner and mediated a rapid decline in plasma iron. In contrast, hepcidin-deficient mice developed a paradoxical increase in plasma iron during infection associated with profound susceptibility to bacteremia. Incubation of bacteria with iron-supplemented plasma enhanced bacterial growth in vitro, and systemic administration of iron to WT mice similarly promoted increased susceptibility to bloodstream infection. Finally, treatment with a hepcidin analogue restored hypoferremia in hepcidin-deficient hosts, mediated bacterial control, and improved outcomes. These data show hepcidin induction during pneumonia to be essential to preventing bacterial dissemination by limiting extracellular iron availability. Hepcidin agonists may represent an effective therapy for Gram-negative infections in patients with impaired hepcidin production or signaling.

A computational model of invasive aspergillosis in the lung and the role of iron.

BACKGROUND: Invasive aspergillosis is a severe infection of immunocompromised hosts, caused by the inhalation of the spores of the ubiquitous environmental molds of the Aspergillus genus. The innate immune response in this infection entails a series of complex and inter-related interactions between multiple recruited and resident cell populations with each other and with the fungal cell; in particular, iron is critical for fungal growth. RESULTS: A computational model of invasive aspergillosis is presented here; the model can be used as a rational hypothesis-generating tool to investigate host responses to this infection. Using a combination of laboratory data and published literature, an in silico model of a section of lung tissue was generated that includes an alveolar duct, adjacent capillaries, and surrounding lung parenchyma. The three-dimensional agent-based model integrates temporal events in fungal cells, epithelial cells, monocytes, and neutrophils after inhalation of spores with cellular dynamics at the tissue level, comprising part of the innate immune response. Iron levels in the blood and tissue play a key role in the fungus' ability to grow, and the model includes iron recruitment and consumption by the different types of cells included. Parameter sensitivity analysis suggests the model is robust with respect to unvalidated parameters, and thus is a viable tool for an in silico investigation of invasive aspergillosis. CONCLUSIONS: Using laboratory data from a mouse model of invasive aspergillosis in the context of transient neutropenia as validation, the model predicted qualitatively similar time course changes in fungal burden, monocyte and neutrophil populations, and tissue iron levels. This model lays the groundwork for a multi-scale dynamic mathematical model of the immune response to Aspergillus species.