Type I interferon regulation by USP18 is a key vulnerability in cancer

Precise regulation of Type I interferon signaling is crucial for combating infection and cancer while avoiding autoimmunity. Type I interferon signaling is negatively regulated by USP18. USP18 cleaves ISG15, an interferon-induced ubiquitin-like modification, via its canonical catalytic function, and inhibits Type I interferon receptor activity through its scaffold role. USP18 loss-of-function dramatically impacts immune regulation, pathogen susceptibility, and tumor growth. However, prior studies have reached conflicting conclusions regarding the relative importance of catalytic versus scaffold function. Here, we develop biochemical and cellular methods to systematically define the physiological role of USP18. By comparing a patient-derived mutation impairing scaffold function (I60N) to a mutation disrupting catalytic activity (C64S), we demonstrate that scaffold function is critical for cancer cell vulnerability to Type I interferon. Surprisingly, we discovered that human USP18 exhibits minimal catalytic activity, in stark contrast to mouse USP18. These findings resolve human USP18's mechanism-of-action and enable USP18-targeted therapeutics

Transmission of Yellow Fever Vaccine Virus Through Blood Transfusion and Organ Transplantation in the USA in 2021: Report of an Investigation

BACKGROUND: In 2021, four patients who had received solid organ transplants in the USA developed encephalitis beginning 2-6 weeks after transplantation from a common organ donor. We describe an investigation into the cause of encephalitis in these patients. METHODS: From Nov 7, 2021, to Feb 24, 2022, we conducted a public health investigation involving 15 agencies and medical centres in the USA. We tested various specimens (blood, cerebrospinal fluid, intraocular fluid, serum, and tissues) from the organ donor and recipients by serology, RT-PCR, immunohistochemistry, metagenomic next-generation sequencing, and host gene expression, and conducted a traceback of blood transfusions received by the organ donor. FINDINGS: We identified one read from yellow fever virus in cerebrospinal fluid from the recipient of a kidney using metagenomic next-generation sequencing. Recent infection with yellow fever virus was confirmed in all four organ recipients by identification of yellow fever virus RNA consistent with the 17D vaccine strain in brain tissue from one recipient and seroconversion after transplantation in three recipients. Two patients recovered and two patients had no neurological recovery and died. 3 days before organ procurement, the organ donor received a blood transfusion from a donor who had received a yellow fever vaccine 6 days before blood donation. INTERPRETATION: This investigation substantiates the use of metagenomic next-generation sequencing for the broad-based detection of rare or unexpected pathogens. Health-care workers providing vaccinations should inform patients of the need to defer blood donation for at least 2 weeks after receiving a yellow fever vaccine. Despite mitigation strategies and safety interventions, a low risk of transfusion-transmitted infections remains. FUNDING: US Centers for Disease Control and Prevention (CDC), the Biomedical Advanced Research and Development Authority, and the CDC Epidemiology and Laboratory Capacity Cooperative Agreement for Infectious Diseases

Spatial heterogeneity of denitrification genes in a highly homogenous urban stream

Human modification of natural streams by urbanization has led to more homogeneous channel surfaces; however, the influence of channel simplification on in situ microbial distribution and function is poorly characterized. For example, denitrification, a microbial process that reduces soluble nitrogen (N) levels, requires peripheral anoxic zones that might be lost in artificial channels such as those with a concrete lining. To examine how microbial function might be influenced by channel simplification, we quantified denitrification rates and conditions in microbial mats within an urban concrete channel. We quantified spatial and diurnal patterns of nitrate uptake, diurnal dissolved oxygen (DO) levels, and nutrient conditions, along with the spatial distribution of DO, solids, chlorophyll a, and genes associated with denitrification (nirS and nirK), ammonia-oxidizing bacteria (AOB), cyanobacteria, and algal chloroplasts. Despite the channel being superficially homogeneous, nir genes were distributed in a patchy manner. Two types of gene patches were observed: one associated with nirK, which had diurnally variable DO levels and high nocturnal nitrate uptake rates, and the other associated with nirS, which had elevated AOB genes, thicker layers of mud, and an apparent 24 h nitrate uptake. All active nir patches had elevated microbial photosynthetic genes. Results imply that even artificial channels, with reduced macroscale heterogeneity, can sustain significant rates of denitrification, although the responsible communities vary with space and time. This patchiness has significant implications to extending local data to landscape level predictions and field sampling strategies but also suggests alternate channel designs to increase N retention rate