Four-way interaction screen gives clues to drug effects

Researchers at the Christian Albrechts University of Kiel and the MRC London Institute of Medical Science have developed a way to screen four-way interactions between genetically simple hosts, their microbiome, nutrients and drugs. Current research into extreme multifactorial aspects of physiology, including both nutrition and the microbiome, is largely confined to studies that are both oversimplified and correlative. The authors developed a high-throughput screen in E. coli and C. elegans that enabled them to identify mechanisms of cause and effect relationships of how gut microbes and metformin affected the effects of metformin depending on the genetics of the host. "Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies," the authors wrote. "Moving away from correlative descriptions to in-depth mechanistic studies that establish a causative role for microbiota and their metabolites on host physiology is a highly desirable aim of both fundamental and applied research with wider implications for personalized medicine." Their work appeared in the Aug. 29, 2019, issue of Cell.

ADC traffic rules revealed

With four approved agents and roughly 80 more in clinical trials, antibody drug conjugates (ADCs) are an emerging therapeutic class. In principle, they enable the targeted delivery of agents that would be far too toxic for systemic administration. However, the details of how ADCs are internalized and separated from their payloads are not fully understood, and the ADC receptor binding and trafficking of the ADC/receptor complex can differ from that of a receptor's natural ligand. Researchers from Stanford University have compared the trafficking patterns of antibodies with different payloads and thus gained new insights into ADC trafficking that collectively "reveal new regulators of endolysosomal trafficking, provide important insights for ADC design and identify candidate combination therapy targets." Their work appeared in the Aug. 26, 2019, online issue of Cell Chemical Biology.

HIV rebound shows diverse sources, identical virus

Scientists at the University of Ghent have conducted a large-scale sequencing study to identify the sources of HIV reservoir that fuel viral rebound in response to treatment interruption, and have found that there is no single source, instead finding "a remarkably heterogeneous source of viral rebound." Additionally, sequencing of different reservoir sites revealed that viral mixing appeared to occur between different reservoir sites, "indicating dynamic interchanges between compartments and little evidence for viral evolution or clustering by site." Rebound populations could come from different origins in different patients, but within a patient, rebound appeared to be driven by proliferating cells, as rebound virus was genetically identical. The authors concluded that their work "demonstrates the complexity of latency mechanisms and the challenges this brings about for strategies aimed at purging the reservoir ... Focusing on mechanisms that drive antigenic and homeostatic proliferation of immune cells will be crucial to achieve progress toward an HIV cure." They published their results in the Aug. 29, 2019, issue of Cell Host & Microbe.

Antimalarial kinase inhibitor

Scientists at the University of Glasgow have identified a novel antimalarial target that could be effective in targeting the malaria parasite Plasmodium falciparum across multiple stages of its lifecycle, blocking transmission as well as killing the parasite itself. The authors focused their search for new antimalarials on the parasite's kinases, as phosphorylation is a key regulatory mechanism, and showed that inhibiting the kinase PfCLK3 led to the downregulation of hundreds of essential genes. "Inhibition of PfCLK3 mediated rapid killing of asexual liver- and blood-stage P. falciparum and blockade of gametocyte development, thereby preventing transmission, and also showed parasiticidal activity against P. berghei and P. knowlesi," the authors wrote. "Hence, our data establish PfCLK3 as a target with the potential to deliver prophylactic and symptomatic treatment in addition to transmission blocking in malaria." Their work appeared in the Aug. 30, 2019, issue of Science.

CRISPR targets fat cells, improves metabolism

Investigators at Hanyang University's Institute for Bioengineering and Biopharmaceutical Research have developed a CRISPR system targeted to white fat cells that improved metabolic parameters in animal studies by silencing Fatty Acid-Binding Protein 4 (FABP4). "Targeted delivery of CRISPRi system against Fabp4 to white adipocytes... induced effective silencing of Fabp4, resulting in reduction of body weight, inflammation and restoration of hepatic steatosis in obese mice," the authors wrote. Adding that the platform "provides a simple and safe approach to regress and treat obesity and obesity-induced metabolic syndromes." They reported their findings in the Aug. 29, 2019, issue of Genome Research.

Vulnerable brains can be steered toward healthy development

A team at the Friedrich Miescher Institute has shown that in a mouse model of schizophrenia, drug treatment during late adolescence or genetic activation of parvalbumin-expressing neurons could permanently prevent the transition to overt symptoms. Schizophrenia becomes symptomatic in late adolescence, but predisposing factors occur much earlier, in some cases prenatally. Abnormal local circuits in several brain areas, as well as abnormal synchronization between those local circuits, is hypothesized to contribute to the development of overt schizophrenia. The researchers showed that repeated treatment during late adolescence targeting either the ventral hippocampus or the medial prefrontal cortex, two brain areas that are dysfunctional in schizophrenia, led to "complete and long-lasting rescue" of network abnormalities and cognitive dysfunctions. The authors concluded that "long-lasting rescue might involve suppression of dysfunction during a critical time window long enough for transition to apparently normal adult brain function in spite of a strongly predisposing genetic background" in their mouse model. They reported their findings in the Aug. 29, 2019, issue of Cell.

TREM2 correlates with slow decline in AD

The Alzheimer's Disease Neuroimaging Initiative has shown that variants in triggering receptor expressed on myeloid cells 2 (TREM2) influence the risk of Alzheimer's disease (AD) more strongly than any other gene besides APOE, which has set off a correspondingly large effort to understand how, and the functions of TREM2 more generally. The researchers analyzed the levels of soluble TREM2 (sTREM2) in the cerebrospinal fluid of elderly patients with mild cognitive impairment, and showed that higher levels of sTREM2, which are indicative of more microglial activity, were correlated with a slower decline in memory and cognitive function. Despite the fact that the current study is observational in nature and therefore cause-effect conclusions cannot be drawn, our results support the notion that the modification of TREM2 function is a valuable target in AD," the authors wrote. "Furthermore, our data indicate that the early symptomatic disease stage of AD is a preferred time window for therapeutic microglial modulation." They published their results in the Aug. 28, 2019, issue of Science Translational Medicine.

New mouse models for human lung infections

Investigators at the University of North Carolina have developed two separate mouse models of human lung tissue, one that contained lung tissue only, and one that also had a humanized immune system. Many clinically important pathogens are human-specific, and even pathogens that infect both mice and humans can act differently in the two species. The authors subcutaneously implanted human lung tissue, which expanded and developed vasculature, though it was subcutaneous and did not breathe. In addition to demonstrating that their mice could be studied to study pathogens including Middle East Respiratory Syndrome coronavirus (MERS-CoV), Zika virus, respiratory syncytial virus and cytomegalovirus, "our results also suggest that developing additional in vivo humanized mouse models for human pathogens with tropism for other tissues might be possible and might enhance the precision of humanized mouse models for biomedical research." Their work appeared in the Aug. 26, 2019, issue of Nature Biotechnology.

Dystrophy mutation protects cells from HIV infection

Investigators at the Instituto de Salud Carlos III's National Center of Microbiology have demonstrated that a mutation in the gene for Transportin 3 (TNPO3) that is an autosomal dominant cause of limb girdle muscular dystrophy 1F protected cells from HIV infection. HIV requires multiple cellular proteins throughout its life cycle, and previous work had shown that Transportin 3, which transports proteins into the nucleus, affected HIV's ability to replicate. In the current study, the team looked at cultured cells from 23 related individuals with limb girdle dystrophy 1F, and showed that they were completely resistant to HIV infection. "TNPO3 mutation represents a natural model to understand the pathogenesis of both diseases. Cells from LGMD1F patients can be used to understand the mechanisms of action of TNPO3 in HIV infection and to design new therapeutic strategies for the treatment of both diseases, the authors wrote. "The use of HIV-1 as a methodological tool will permit a better understanding of the physiopathological mechanisms derived from the mutation in TNPO3 that causes the muscle disease." They reported their results in the Aug. 20, 2019, issue of PLoS Pathogens.

An organoid model for prenatal brain development

Researchers at the University of California at San Diego have demonstrated that cortical organoids showed a fixed developmental pattern in their synchronized electrical activity as they matured. While the brain follows fixed developmental programs in its structure and gene expression during prenatal development, whether the same is true for its electrical activity has been hard to assess experimentally due to the challenges of recording from prenatal brains. In their work, the authors used cortical organoids to look at the development of brain activity over several months of maturation instead. They showed that cell populations "exhibited consistent increases in electrical activity over the span of several months... Oscillatory activity transitioned to more spatiotemporally irregular patterns, and synchronous network events resembled features similar to those observed in preterm human electroencephalography. These results show that the development of structured network activity in a human neocortex model may follow stable genetic programming." Their work appeared in the Aug. 29, 2019, online issue of Cell Stem Cell.

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