Letters in 2014

Kwangseog Ahn and colleagues show that the RNase activity of SAMHD1 accounts for its ability to limit HIV-1 replication by degrading HIV-1 RNA.

An orally available, highly selective agonist of Gpr120 is developed and tested.

Ribosomal protein deficiency in Diamond-Blackfan anemia impairs protein translation of the key erythroid transcription factor GATA1.

Activation of bone marrow hematopoietic stem cells by chronic stress raises circulating leukocyte levels and increases atherosclerotic plaque inflammation.

Treatment with exogenous leptin has been reported to improve hyperglycemia in mouse models of type 1 diabetes through lowering of glucagon signaling. Jerry Shulman and his colleagues now report that the more primary beneficial effect of leptin on hyperglycemia is by reducing the activity of the hypothalamic-pituitary-adrenal axis. These results give further credence to the possible use of leptin therapy for this form of diabetes.

Gustavo Turecki and colleagues report that miR-1202, a miRNA specific to primates, is decreased in individuals with depression and seems to be differentially regulated in individuals who will end up showing beneficial responses to antidepressant treatment compared to those who will not respond.

Antibodies capable of neutralizing a broad array of HIV-1 viral isolates from different clades have been isolated from some chronically infected individuals, but their development is thought to require several years. In this issue, Julie Overbaugh and her colleagues report that HIV-infected infants also develop broadly neutralizing antibodies—some at 1 year of age—and their occurrence early in life may shed light on HIV vaccine efforts to induce these antibodies.

Although neutrophils have crucial functions in microbial killing, they can also trigger tissue damage via the release of reactive oxygen species and proinflammatory mediators. Robert Zeiser and colleagues now report that neutrophils also contribute to the severity of graft-versus-host disease following translocation of bacteria in the gut induced by the conditioning regimen for allogeneic hematopoietic cell transplantation.

The immune system matures during the neonatal period and is influenced by environmental factors. Benjamin J. Marsland and his colleagues show that the lung is colonized by microbes early in life. Formation of the lung microbiota is associated with the induction of regulatory T cells and the development of tolerance to allergens. Absence of microbial colonization leads to allergic airway disease later in life, suggesting that the lung microbiota promotes immune tolerance.

Lower levels of ω–3 fatty acid–derived resolution mediators have been linked to insulin resistance in obese mice. André Marette and his colleagues now show that treatment of obese mice with a resolution mediator (protectin DX (PDX)) results in IL-6 release from muscle and subsequent improvement in insulin sensitivity. PDX may represent a new class of antidiabetes medication.

Aging is associated with cognitive impairment and degenerative processes in the brain. Here, Tony Wyss-Coray and colleagues report that exposure of aged mice to young blood improves learning and memory in aged mice. This effect is associated with structural improvements in dendritic spine density in the hippocampus and functionally with increased synaptic plasticity. These findings suggest that circulating factors in young blood can reverse impairments in learning, memory and synaptic plasticity in aged mice.

Osteogenesis imperfecta (OI) is a debilitating illness marked by brittle bones and fractures, as well as extraskeletal abnormalities. Now, Ingo Grafe and colleagues show that both the dominant and recessive forms of this disease are caused by excessive TGF-β signaling and that targeting this pathway improves bone health in mouse models of OI.

A potential treatment for Huntington's disease involves reducing expression of the mutant gene, but it is unclear to which part of the brain the treatment should be directed. Now, X. William Yang and colleagues show that reducing HTT expression in both the striatum and the cortex provides the most benefit for ameliorating disease in mice when compared with reducing expression in just one of the two brain structures.

Here, Hitesh S. Deshmukh et al. report that in neonates, establishment of the intestinal microbiota is associated with neutrophil development. Antibiotic-treated and germ-free mice have reduced numbers of neutrophils and are susceptible to Escherichia coli K1 and Klebsiella pneumoniae sepsis. Reconstitution of the intestinal microbiota promotes interleukin-17 production by innate lymphoid cells and increases plasma granulocyte colony–stimulating factor levels, granulocytosis and host resistance to sepsis.

Patients with cirrhosis are susceptible to infection, but the mechanisms underlying this immunosuppression remain unclear. Derek W. Gilroy and colleagues show that plasma prostaglandin E₂ (PGE₂) is elevated in these patients and in mouse models of liver injury and suppresses TNF-α release from macrophages. Albumin, which binds to PGE₂ and reduces its bioavailability, is reduced in the plasma of a subset of cirrhosis patients. Administration of albumin partially reverses the immunosuppression observed in vitro and restores bacterial killing in mouse models, suggesting that future studies are warranted on the use of albumin to prevent infection in a subset of patients with cirrhosis.

Chronic stress can lead to depression. Ronald Duman and his colleagues show that REDD1 expression is increased in the brain of patients with major depressive disorder and is upregulated in the brains of stressed mice. Mice lacking REDD1 were resistant to stress-induced depressive behaviors, and unstressed rats in which REDD1 was artificially increased exhibited depressive behaviors.

In Friedreich's ataxia, caused by mutation of the gene encoding the mitochondrial protein frataxin, the major cause of mortality is heart failure. Using mice lacking frataxin in the heart, Hélène Puccio and her colleagues demonstrate that frataxin gene therapy can correct mitochondrial metabolism and reverse heart damage, raising the possibility of a gene therapy treatment for this disease.

Latency-reversing agents (LRAs) have been tested in HIV-1–infected individuals in the hopes of activating the latent viral reservoir and contributing to efforts to eradicate the virus. Robert F. Siliciano and his colleagues now report that most individual LRAs fail to reactivate latent virus in cells from infected individuals and that in vitro models of latency do not adequately reflect the ability of these agents to induce latent virus ex vivo.

Rajasekhar Suragani et al. show that a modified activin receptor IIB ligand trap increases red blood cell numbers in mice, rats and monkeys and ameliorates anemia in mice and rats, including in a mouse model of myelodysplastic syndromes. The ligand trap binds to the cytokine GDF11 and acts by inhibiting Smad2/3 signaling, thereby reversing ineffective erythropoiesis. Also in this issue, Michael Dussiot et al. show related findings using a wild-type activin receptor IIA ligand trap.

Mammals respond to bacterial infection by inducing the expression of hepcidin, which restricts serum iron levels through its effects on macrophage iron export and thereby limits systemic bacterial growth. Kim et al. now report that the macrophage-tropic pathogen Salmonella typhimurium exploits this pathway by triggering the expression of estrogen-related receptor-γ (ERR-γ), which they show increases hepcidin expression and enhances S. typhimurium growth.