Research articles

Recent studies have shown that neutrophil extracellular traps (NETs) can capture and kill bacteria but may also contribute to chronic inflammation. The mechanisms that trigger NET formation are not yet fully elucidated. Marcos et al. now report that stimulation of the chemokine receptor CXCR, induces NET formation and that NETs are present in airway fluids of individuals with cystic fibrosis. Blocking CXCR2 activation in the lung reduced NET formation and improved lung function in a mouse model of cystic fibrosis.

The rapid mutation rate of HIV-1 enables its escape from neutralizing antibodies (NAbs) in infected individuals. Bunnik et al. now show that the immune pressure exerted by NAbs has, over the course of the HIV epidemic, altered the HIV-1 envelope glycoprotein such that HIV-1 variants isolated from recently infected individuals are more resistant to NAbs, compared with viral variants isolated from individuals infected at the start of the epidemic. Their results suggest the need to carefully select the envelope gene used in today's vaccine efforts.

Standard methods of neutrophil isolation require skilled personnel, are time consuming and use large blood volumes. Kotz and his colleagues have developed a rapid microfluidic chip-based approach for rapidly isolating neutrophils directly from whole blood with 'on-chip' processing for mRNA and protein isolation. The device, which yields sufficient quantities and purities for downstream genomic or proteomic analysis, was validated in a multicenter clinical study of the immune response to severe trauma and burn injury.

Thyroid hormones are well known to regulate whole-body energy metabolism, which was believed to occur as a direct effect on individual cells in the periphery. But Antonio Vidal-Puig and his colleagues now show that these thyroid hormone effects on energy regulation are actually indirect, as they regulate AMPK activity in the hypothalamus and thus central signaling to brown adipose tissue in the periphery.

ALDH-2 inhibitors are a potential treatment for alcohol addiction. Now, Lina Yao et al. show that ALDH-2 inhibitors can reduce addiction to cocaine in rats by generating a dopamine metabolite called THP. THP inhibits an enzyme involved in dopamine synthesis, thereby blocking dopamine production in response to cocaine.

Mutations in the kinase LRRK2 have been linked to Parkinson's disease. Now, Ted Dawson and his colleagues have identified inhibitors of LRRK2 that can reduce LRRK2-induced neurotoxicity in cell culture and in mice.

Ebola and Marburg viruses cause lethal hemorrhagic fevers for which there are presently no licensed preventive or curative antiviral agents. In a new report, Warren et al. show that positively charged phosphorodiamidate morpholino oligomers administered shortly after viral infection can protect nonhuman primates from this frequently fatal disease.

One of the main shortcomings of cell therapy is the poor persistence and loss of functionality of donor cells after transfer. Using adjuvant drug–loaded nanoparticles conjugated directly to the surface of therapeutic donor cells, an approach designed to minimize the systemic side effects of adjuvant drugs, Matthias Stephan and his colleagues show enhanced functionality in a model of adoptive T cell therapy for cancer and of hematopoietic stem cell engraftment.

Our knowledge of the diversity of human T cell receptors (TCRs) is limited by tolerance mechanisms—most high-avidity autoreactive T cells are deleted. Li et al. have now transferred the entire TCR-αβ gene loci into mice, which will facilitate the study of T cell responses to human antigens.

Neutrophils release the serine proteases neutrophil elastase and cathepsin G, which have microbicidal activity and thereby contribute to the innate immune response. Steffen Massberg et al. now show that these neutrophil serine proteases, in association with extracellular nucleosomes, can also promote coagulation and thrombosis within large blood vessels. In a mouse model of systemic bacterial infection, these proteases spurred intravascular coagulation in the microcirculation of the liver, limiting bacterial tissue invasion. These findings point to a role for thrombosis in antimicrobial defense.

Sudarshan Anand et al. show that endothelial cell expression of the microRNA miR-132 targets a negative regulator of Ras pathway signaling and thereby releases a brake to new blood vessel formation. miR-132 expression is upregulated in the endothelium of human hemangioma and tumor samples, and an antagonist of miR-132, delivered specifically to tumor endothelium using an integrin-targeted nanoparticle, was able to inhibit tumor angiogenesis and growth in mice.

Ethylmalonic encephalopathy is a metabolic disease affecting many organ systems that is caused by the inability to metabolize sulfide. Now, Zeviani and colleagues have discovered a dual drug regimen that can ameliorate disease in affected children.

Excessive glutamate seen in multiple sclerosis leads to excitotoxicity and neuronal dysfunction. Fallarino et al. find that the clinical signs and neuroinflammation in experimental autoimmune encephalitis is worsened in mice deficient in the metabotropic glutamate receptor-4. Small molecules that enhance signaling through this receptor suppress neuroinflammation by promoting T regulatory cell development and suppressing T_H17 responses. This cross-talk between the nervous and immune system suggests an endogenous mechanism to suppress neuroinflammation in the context of multiple sclerosis.

Sullivan and his colleagues describe a novel microneedle patch-based system for vaccine delivery that targets the skin's antigen-presenting cells, providing improved immunogenicity and eliminating the hazards associated with using hypodermic needles. The group demonstrates the feasibility of this approach for influenza prophylaxis, whereby vaccine is encapsulated within microscopic polymeric needles that dissolve in the skin in minutes.

Increased levels of Ca²⁺ in cardiomyocytes promote cell growth that, under stressful conditions, such as those caused by hypertension, can contribute to heart remodeling and failure. Joerg Heineke et al. identify a new regulator of this type of maladaptive cardiac muscle growth in mice, the calcium-binding protein CIB1, which they show regulates the membrane-association of calcineurin and downstream signaling.

Tarik Massoud and colleagues offer a new, noninvasive molecular imaging technique based on split reporter complementation for quantifying and imaging protein-protein interactions—cytoplasmic and nuclear—in vivo using positron emission tomography. They use a split reporter system based on the enzyme herpes simplex virus type 1 thymidine kinase, an approach designed to significantly improve the sensitivity and dynamic range of imaging protein-protein interactions.

Harald Ott and his colleagues build on their earlier work, based on reconstruction of a decellularized heart, to develop a new way to bioengineer a functioning lung. Through a process of decellularization, seeding with endothelial and epithelial cells, and maturation in an innovative bioreactor system, followed by transplantation into rats of the regenerated lungs in orthotopic position, the group was able to demonstrate adequate ventilation, blood flow and gas exchange in vivo for short periods of time.

Dendritic cells in individuals with cancer and in mouse tumor models show an increase in triacylglycerides that seems to impair their antigen-processing capability and could thus contribute to tumor immune tolerance. This aberrant lipid load results from tumor-induced elevation of the scavenger receptor Msr1 on dendritic cells, and it can be targeted therapeutically to improve the efficiency of anticancer vaccines.

The authors uncover a new role for the RNA-binding protein Msi2 in the regulation of hematopoietic stem cell homeostasis and leukemogenesis. Msi2 is required for the maintenance of the balance between progenitor renewal and differentiation, and its overexpression cooperates with oncogenic events to induce aggressive leukemia. Msi2 expression is also elevated in human myeloid leukemias and may be a new prognostic marker and therapeutic target in acute myeloid leukemia.

Candida albicans is a fungal pathogen that causes serious systemic and mucosal infections in immunocompromised people. Blocking acetylation of histone H3 sensitizes C. albicans to antifungal agents, pointing to a new therapeutic strategy.