Selective lesion of pain-transmitting axons provides lasting pain relief
Many pharmacologic pain management approaches are associated with substantial drawbacks, including short-term efficacy, intolerable side effects, and potential to develop dependence. Developing selective and persistent nerve-blocking approaches may improve outcomes in patients with chronic pain. Matthew Sapio, John Neubert, and coworkers looked in detail at the effects of resinife...ratoxin, which lesions a clinically important subpopulation of pain-sensing peripheral nerves by targeting the cation channel TRPV1. Resiniferatoxin injection produced long-lasting analgesia in rats, dogs, and a patient with cancer pain. In all three species, these effects appeared to be primarily exerted on the axonal compartment of TRPV1-expressing neurons, as perikarya displayed few transcriptomic or histologic changes. These insights support TRPV1-targeting approaches as a promising alternative to long-term pharmacological therapies in some patients with chronic pain. The accompanying image shows the preservation of cell bodies in sensory ganglia following intracisternal injection of resiniferatoxin.
Insulin-sensitive FoxO transcription factors regulate HDL cholesterol homeostasis
Insulin resistance often co-occurs with low HDL cholesterol levels, an association that may underlie increased incidence of cardiovascular disease in individuals with type II diabetes and metabolic syndrome. Noting the role of the FoxO family in hepatic glucose and lipid homeostasis, Samuel Lee, Markus Heine, and colleagues investigated whether expression of these insulin...-inactivated transcription factors influences HDL metabolism. In mice, combined loss of FoxO1, 3, and 4 in hepatocytes elevated plasma HDL but not LDL, an effect that was exacerbated by high-fat feeding. FoxO ablation also reduced expression of HDL-clearing proteins, which impaired hepatic clearance of HDL from the bloodstream. Restoring expression of the HDL-clearing protein SR-BI ameliorated cholesterol accumulation in FoxO-deficient mice. Taken together, these findings suggest that failure to suppress FoxO transcription factors may underlie low HDL cholesterol levels in insulin-resistant individuals.
In JCI Insight: Cirrhosis-related changes in gut microbial RNA and DNA
Alterations in patient microbiome have been reported with cirrhosis, though it is not clear if changes in the gut microbiota can be used to accurately assess disease severity, progression, or therapeutic response. Jasmohan Bajaj and colleagues analyzed microbial DNA, which captures live and dead bacterial taxa, and RNA, which likely represents the most metabolically active microbia...l taxa, in stool samples from patients presenting with a range of cirrhosis severity and from healthy volunteers. DNA and RNA analysis highlighted different bacterial taxa; however, both could be used to predict 90-day hospitalizations, and were markedly additive to the model for end stage liver disease (MELD) score. Together, these results demonstrate that microbial RNA and DNA are differentially altered in patients with cirrhosis and can be informative of disease severity and hospitalization risk.
Synthetic peptides mirror vaccine efficacy and enhance biological stability
Peptide vaccines may represent a lower-risk and lower-cost alternative to classical vaccines because their antigenic contents are limited to epitopes essential for eliciting protective immunity. However, poor biological stability limits practical use of these vaccines. More stable peptide design may be possible using hydrolysis-resistant D-amino acids (DAAs), stereoisomers of t...he L-amino acids that make up most natural proteins. In this issue, John Miles, Mai Ping Tan, Garry Dolton, and colleagues screened DAA peptide libraries to identify activators of influenza peptide-specific CD8+ T cell clones. While the DAA peptide they identified evoked weaker cytokine profiles than its natural counterpart, it expanded and mobilized CD8+ T cells with similar potency and resisted degradation in serum and gastric acid. In humanized mice, vaccination with DAA or influenza peptide prevented influenza fatality with equal efficacy. DAA peptide also stimulated immune responses when administered orally. These findings provide proof-of-concept that T cell ligands can be constructed from non-natural chemistries with improved stability over natural amino acid sequences.
Sepsis is a life-threatening complication of infection that results in over 250,000 deaths per year in the United States. There is a strong correlation between reduced levels of lymphocytes, such as CD8+ and CD4+ T cells, and increased mortality; therefore, strategies aimed to increase these cells have therapeutic potential. The cytokine IL-...7 prevents lymphocyte death, increases lymphocyte proliferation, and has been shown to improve intestinal lymphocyte counts in patients with HIV-1. In this episode, Richard Hotchkiss details the results from a prospective, randomized, double-blind, placebo-controlled trial of recombinant human IL-7 in patients with septic shock and severe lymphocytopenia. IL-7 reversed the loss of lymphocytes in septic patients, suggesting that this approach be further explored.
A safe and reproducible strategy for evaluating human-to-mosquito malaria transmission
Anti-malarial strategies have substantially decreased worldwide mortality and morbidity due to malaria infection, but reducing transmission will be the key to eliminating this disease. The lack of a clinical model to reliably evaluate transmission-blocking therapies has stalled progress toward malaria eradication. Katharine Collins and colleagues developed a model of... controlled malaria infection in human participants that enables reproducible induction of gametocytemia – the transmissible form of the malaria parasite. The model uses intravenous inoculation of Plasmodium-infected erythrocytes to induce blood-stage malaria. As early as 20 days post-inoculation, participants’ gametocyte levels were sufficient to transmit malaria to mosquitoes via direct skin feeding or artificial membrane feeding. Importantly, the model proved to be safe and well-tolerated by all participants. An accompanying commentary from Kazutoyo Miura and Peter Crompton discusses this model of controlled human malaria infection as a potential method for evaluating transmission-blocking clinical interventions.
Complete melanoma remission after adoptive transfer of BRAFV600E-targeting T cells
Adoptive transfer of tumor-infiltrating lymphocytes (TILs) achieves impressive response rates in melanoma patients but is limited by its dependence on patient-specific neoantigens, which are often derived from random mutations. Broad-based treatments targeting common mutations, such as oncogenic drivers, could increase efficacy rates and reduce incidence of antigen-nega...tive escape variants. Unfortunately, driver-specific T cell responses are rarely observed. Joshua Veatch and coworkers report on the complete remission of stage IV melanoma in a patient who received TIL adoptive transfer. The BRAFV600E driver mutation, which occurs in 40% of melanoma cases, was one of a relatively low number of somatic mutations identified in tumor exome sequencing. Enrichment of a rare subset of BRAFV600E-reactive CD4+ T cells following TIL transfer suggests that driver-targeting TILs were responsible for the therapeutic response. Christian Hinrichs suggests that the BRAFV600E-specific T cell receptor is a potential source for engineering driver-targeting adoptive cell therapies in an accompanying commentary.
JCI Insight review: Host-survival strategies as therapeutic targets for Staphylococcus aureus
While Staphylococcus aureus can be part of the normal nasal microbiome, it is capable of infecting a variety of sites and can cause life-threatening bacteremia, pneumonia, endocarditis, and soft-tissue infections. Unfortunately, the prevalence of antibiotic resistance has been progressively increasing among S. aureus isolates, resulting in an impending need for additional therapeutic strategies for targeting this pathogen. In this issue, Isaac Thomsen and George Liu review recent advances in understanding mechanisms employed by S. aureus for surviving the hostile host environment. These nutritional, metabolic, and virulence pathways have potential to be exploited as antimicrobial targets for S. aureus intervention.
A new batch of articles is now available online at
In JCI Insight: Gene signature in infancy predicts type 1 diabetes autoantibodies
Type 1 diabetes (T1D) results from autoimmune-mediated destruction of insulin-producing pancreatic β cells. There is a genetic component to T1D and multiple islet autoantibodies predict childhood diabetes development; however, there is no reliable way to identify genetically at-risk individuals who will develop autoantibodies. A test would narrow down childhood screening ...to those at highest risk. Ahmed Mehdi and colleagues evaluated longitudinal transcriptomic data from 2 cohorts of children at high genetic risk of T1D that were followed for at least 10 years. The authors identified a 7-gene expression signature within the first year of life that when combined with HLA risk score was predictive of later seroconversion. Notably, differentially expressed genes and known T1D susceptibility genes were linked in a protein network involved in the ubiquitin-proteasome pathway. These results indicate that this gene expression signature can identify infants at highest risk of seroconversion and implicate alterations in ubiquitination in T1D progression.
Osteoclast-derived SLIT3 strikes a balance between bone resorption and formation
Osteoporosis and other metabolic bone disorders arise from imbalances between bone resorption and formation. Multiple studies indicate that signaling from bone-resorbing osteoclasts coordinates the performance of bone-forming osteoblasts, but the nature of this signaling is complex. Beom-Jun Kim, Young-Sun Lee, and coworkers identify the axon-guidance molecule SLIT3 as an ...osteoclast-derived regulator of bone remodeling. In mice, loss of SLIT3 led to reduced bone mass and thickness, which was attributed primarily to decreased formation and increased resorption. Further investigation revealed that SLIT3 acts as an autocrine signal, inhibiting osteoclast differentiation in addition to stimulating osteoblast migration and proliferation. Finally, elevated plasma concentrations of SLIT3 were positively linked with high bone mineral density in a large cohort of postmenopausal women. In the accompanying commentary, Iqbal et al. advocate for further investigation into the role of SLIT3 in human bone disorders and treatments.
On the cover of JCI Insight: Characterization of thoracic aortic aneurysm and dissection-associated proteoglycans
Thoracic aortic aneurysm and dissection (TAAD) occurs as the result of weakening of the aortic wall in response to diverse disorders, typically of genetic origin, such as Marfan syndrome. Proteoglycan accumulation is a hallmark of TAAD; however, the precise molecular changes that precede TAAD and predispose to this catastrophic complication... are poorly understood. Using a mass spectrometry-based approach, Frank Cikach, Christopher Koch and colleagues characterized TAAD-associated alterations of aorta proteoglycan populations. The large aggregating proteoglycans aggrecan and versican were identified as part of the normal human aortic proteoglycanome and shown to accumulate in medial degeneration lesions in ascending TAAD. This increase in aggregating proteoglycans coincided with a decrease in expression of the proteoglycanase gene ADAMTS5. In a mouse model of Marfan syndrome, aggrecan, but not versican, dramatically increased within the aorta, especially in mice that rapidly progressed to ascending aortic dissection. These results indicate that aggrecan and versican accumulation is deleterious to aortic integrity and that these aggregating proteoglycans could potentially be exploited as biomarkers for stratifying those at risk of dissection. The cover image shows the severely disrupted architecture of the aorta of a patient with a type A dissection. Alterations include fragmentation of elastic fibers (black/brown), loss of vascular smooth muscle cells (red), disorganization of intra-lamellar collagen (yellow), and marked accumulation of proteoglycan (blue).
In JCI Insight: Talking TOR with Joe Heitman and Rao Movva
In 1991, a collaboration between Joe Heitman, Rao Movva, and Michael Hall identified two undescribed proteins in yeast as targets of the immunosuppressant rapamycin. Additional investigation revealed that these proteins, which they named TOR1 and TOR2, are highly-conserved regulators of cell growth and metabolism in all eukaryotic organisms. Today we study the role of TOR signaling in diseases ...ranging from cancer to neurodegeneration. Michael Hall’s work on TOR proteins was recognized with a Lasker Award in 2017 (see Ushma Neill’s interview with Hall for JCI here: https://buff.ly/2FeiSJb). For this issue of JCI Insight, editor Corinne Williams sat down with Joe Heitman and Rao Movva to learn more about the collaboration that led to the discovery of TOR proteins. (In the photo, from left to right: Hall, Heitman, and Movva at the 2017 Lasker Award Ceremony. Photo courtesy of Joe Heitman.)
Blocking immune resistance to oncolytic viruses improves antitumor response
Oncolytic therapies utilize a virus’s natural or engineered specificity for tumor cells to promote immunogenic cell death. Observations that tumor suppression persists after elimination of the infected tumor suggest that oncolytic viruses can also upregulate host antitumor immunity. Dmitriy Zamarin and coworkers evaluated responses affecting antitumor immunity in tumors infect...ed with Newcastle Disease virus (NDV). They observed that while NDV therapy initially increased immune infiltration and delayed growth of both injected and uninjected tumors, the effect was typically short-lived. Further investigation revealed that tumors in NDV-treated animals developed immunosuppressive adaptations to early-stage type I IFN responses and to late-stage immune infiltration by upregulating PD-L1 (see the accompanying image). Interventions combining NDV therapy with PD-1/PD-L1 blockade led to more durable antitumor responses. Praveen Bommareddy and Howard Kaufman’s commentary gives context to these mechanistic insights, which support the potential efficacy of clinical approaches combining checkpoint therapies with oncolytic viruses.
In JCI Insight: Lack of T cell population shift predicts preterm infant outcomes
Premature infants are at high risk of respiratory complications following viral infection compared to their full-term counterparts. The factors that underlie discrepant outcomes following infection are not fully understood; however, incomplete immune cell maturation has been proposed as a possible driver. Kristin Scheible and colleagues evaluated T cells from 157 infants b...orn between 23-42 weeks of gestation and identified gestational age-dependent differences in T cell populations. Moreover, these postnatal differences in T cell development were predictive of respiratory outcomes at 1-year of age. Specifically, naïve CD4+ T cells were shown to shift from CD31-TNF-α+ to predominantly CD31+IL-8+ mid-late gestation, and preterm infants with a CD31-TNF-α+CD4+ T cell bias were at much higher risk of respiratory complications. This work lays the foundation for future studies to elucidate how this population arises and may be enhanced in preterm infants.