Autophagy is a powerful tool that host cells use to defend against viral infection. Double-membrane vesicles, termed autophagosomes, deliver trapped viral cargo to the lysosome for degradation. Specifically, autophagy initiates an innate immune response by cooperating with pattern recognition receptor signalling to induce interferon production. It also selectively degrades immune components associated with viral particles. Following degradation, autophagy coordinates adaptive immunity by delivering virus-derived antigens for presentation to T lymphocytes. However, in an ongoing evolutionary arms race, viruses have acquired the potent ability to hijack and subvert autophagy for their benefit. In this Review, we focus on the key regulatory steps during viral infection in which autophagy is involved and discuss the specific molecular mechanisms that diverse viruses use to repurpose autophagy for their life cycle and pathogenesis.

Independent of its known role in NF-κB transcription, the HOIL-1L containing LUBAC is required for assembly and activation of the NLRP3 inflammasome via linear ubiquitination of ASC.

In this study we describe how to use a two-dimensional fast Fourier transform (2D FFT) approach to measure fiber alignment in electrospun materials. This image processing function can be coupled with a variety of imaging modalities to assign an objective numerical value to scaffold anisotropy. A data image of an electrospun scaffold is composed of pixels that depict the spatial organization of the constituent fibers. The 2D FFT function converts this spatial information into a mathematically defined frequency domain that maps the rate at which pixel intensities change across the original data image. This output image also contains quantitative information concerning the orientation of objects in a data image. We discuss the theory and practice of using the frequency plot of the 2D FFT function to measure relative scaffold anisotropy and identify the principal axis of fiber orientation. We note that specific degrees of scaffold anisotropy may represent a critical design feature in the fabrication of tissues that will be subjected to well-defined uniaxial mechanical loads. This structural property may also represent a source of guidance cues that can be exploited to regulate cell phenotype.

Blood CD14+ monocytes are the frontline immunomodulators categorized into classical, intermediate or non-classical subsets, subsequently differentiating into M1 pro- or M2 anti-inflammatory macrophages upon stimulation. While Zika virus (ZIKV) rapidly establishes viremia, the target cells and immune responses, particularly during pregnancy, remain elusive. Furthermore, it is unknown whether African- and Asian-lineage ZIKV have different phenotypic impacts on host immune responses. Using human blood infection, we identified CD14+ monocytes as the primary target for African- or Asian-lineage ZIKV infection. When immunoprofiles of human blood infected with ZIKV were compared, a classical/intermediate monocyte-mediated M1-skewed inflammation by African-lineage ZIKV infection was observed, in contrast to a non-classical monocyte-mediated M2-skewed immunosuppression by Asian-lineage ZIKV infection. Importantly, infection of pregnant women’s blood revealed enhanced susceptibility to ZIKV infection. Specifically, Asian-lineage ZIKV infection of pregnant women’s blood led to an exacerbated M2-skewed immunosuppression of non-classical monocytes in conjunction with global suppression of type I interferon-signaling pathway and an aberrant expression of host genes associated with pregnancy complications. 30 ZIKV+ sera from symptomatic pregnant patients also showed elevated levels of M2-skewed immunosuppressive cytokines and pregnancy complication-associated fibronectin-1. This study demonstrates the differential immunomodulatory responses of blood monocytes, particularly during pregnancy, upon infection with different lineages of ZIKV.

Many bacteria, including Legionella pneumophila, rely on the type IV secretion system to translocate a repertoire of effector proteins into the hosts for their survival and growth. Type IV coupling protein (T4CP) is a hexameric ATPase that links translocating substrates to the transenvelope secretion conduit. Yet, how a large number of effector proteins are selectively recruited and processed by T4CPs remains enigmatic. DotL, the T4CP of L. pneumophila, contains an ATPase domain and a C-terminal extension whose function is unknown. Unlike T4CPs involved in plasmid DNA translocation, DotL appeared to function by forming a multiprotein complex with four other proteins. Here, we show that the C-terminal extension of DotL interacts with DotN, IcmS, IcmW and an additionally identified subunit LvgA, and that this pentameric assembly binds Legionella effector proteins. We determined the crystal structure of this assembly and built an architecture of the T4CP holocomplex by combining a homology model of the ATPase domain of DotL. The holocomplex is a hexamer of a bipartite structure composed of a membrane-proximal ATPase domain and a membrane-distal substrate-recognition assembly. The presented information demonstrates the architecture and functional dissection of the multiprotein T4CP complexes and provides important insights into their substrate recruitment and processing.

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To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.

Foot compartment syndrome is a serious potential complication of foot crush injury, fractures, surgery, and vascular injury. The purpose of this article is to summarize and review the existing literature on this entity. Long-term sequelae of foot compartment syndrome (FCS) include contractures, deformity, weakness, paralysis, and sensory neuropathy. These complications are poorly tolerated, and often necessitate multiple procedures for rehabilitation. Therefore, the threshold for considering compartment syndrome and performing fasciotomy must be low to minimize such outcomes. The existence of nine foot compartments and frequent presence of complicating injuries necessitate multi-stick needle catheterization for direct measurement of compartment pressures. Fasciotomy is indicated when compartment pressure exceeds 30 mmHg, or if compartment pressure is greater than 10-30 mmHg below diastolic pressure. The approaches for compartment decompression generally include two dorsal incisions for access to forefoot compartments, and one medial incision for decompression of the calcaneal, medial, superficial, and lateral compartments.