Enteric coronavirus nsp2 is a virulence determinant that recruits NBR1 for autophagic targeting of TBK1 to diminish the innate immune response.

Non-structural protein 2 (nsp2) exists in all coronaviruses (CoVs), while its primary function in viral pathogenicity, is largely unclear. One such enteric CoV, porcine epidemic diarrhea virus (PEDV), causes high mortality in neonatal piglets worldwide. To determine the biological role of nsp2, we generated a PEDV mutant containing a complete nsp2 deletion (rPEDV-Δnsp2) from a highly pathogenic strain by reverse genetics, showing that nsp2 was dispensable for PEDV infection, while its deficiency reduced viral replication in vitro. Intriguingly, rPEDV-Δnsp2 was entirely avirulent in vivo, with significantly increased productions of IFNB (interferon beta) and IFN-stimulated genes (ISGs) in various intestinal tissues of challenged newborn piglets. Notably, nsp2 targets and degrades TBK1 (TANK binding kinase 1), the critical kinase in the innate immune response. Mechanistically, nsp2 induced the macroautophagy/autophagy process and recruited a selective autophagic receptor, NBR1 (NBR1 autophagy cargo receptor). NBR1 subsequently facilitated the K48-linked ubiquitination of TBK1 and delivered it for autophagosome-mediated degradation. Accordingly, the replication of rPEDV-Δnsp2 CoV was restrained by reduced autophagy and excess productions of type I IFNs and ISGs. Our data collectively define enteric CoV nsp2 as a novel virulence determinant, propose a crucial role of nsp2 in diminishing innate antiviral immunity by targeting TBK1 for NBR1-mediated selective autophagy, and pave the way to develop a new type of nsp2-based attenuated PEDV vaccine. The study also provides new insights into the prevention and treatment of other pathogenic CoVs.Abbreviations: 3-MA: 3-methyladenine; Baf A1: bafilomycin A1; CoV: coronavirus; CQ: chloroquine; dpi: days post-inoculation; DMVs: double-membrane vesicles; GABARAP: GABA type A receptor-associated protein; GFP: green fluorescent protein; GIGYF2: GRB10 interacting GYF protein 2; hpi: hours post-infection; IFA: immunofluorescence assay; IFIH1: interferon induced with helicase C domain 1; IFIT2: interferon induced protein with tetratricopeptide repeats 2; IFITM1: interferon induced transmembrane protein 1; IFNB: interferon beta; IRF3: interferon regulatory factor 3; ISGs: interferon-stimulated genes; mAb: monoclonal antibody; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; NBR1: NBR1 autophagy cargo receptor; nsp2: non-structural protein 2; OAS1: 2'-5'-oligoadenylate synthetase 1; PEDV: porcine epidemic diarrhea virus; PRRs: pattern recognition receptors; RIGI: RNA sensor RIG-I; RT-qPCR: reverse transcription quantitative polymerase chain reaction; SQSTM1: sequestosome 1; TBK1: TANK binding kinase 1; TCID50: 50% tissue culture infectious doses; VSV: vesicular stomatitis virus.

Cross-species transmission and animal infection model of hepatitis E virus.

Zoonotic hepatitis E virus (HEV) infection is an emerging global public health concern, and understanding the dynamics of HEV transmission between animals and humans is crucial for public health. Animal models are critical to advancing the understanding of HEV pathogenesis, drug screening, vaccine development, and other related areas. Here, we provide an overview of recent studies investigating the cross-species transmission of HEV, and also delve into the current research and application of animal HEV infection models including non-human primates, rodents, pigs, and chickens, offering a comprehensive assessment of the advantages and disadvantages of each model. This review highlights the findings related to viral replication, shedding patterns, and immune response in these animal models, and discusses the implications for our understanding of HEV transmission to humans. These advancements in the field enhance our understanding of the biological traits and pathogenic mechanisms of HEV, offering robust support for the development of highly effective and targeted prevention and treatment strategies.

Functional dissection of the spike glycoprotein S1 subunit and identification of cellular cofactors for regulation of swine acute diarrhea syndrome coronavirus entry.

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel porcine enteric coronavirus, and the broad interspecies infection of SADS-CoV poses a potential threat to human health. This study provides experimental evidence to dissect the roles of distinct domains within the SADS-CoV spike S1 subunit in cellular entry. Specifically, we expressed the S1 and its subdomains, S1A and S1B. Cell binding and invasion inhibition assays revealed a preference for the S1B subdomain in binding to the receptors on the cell surface, and this unknown receptor is not utilized by the porcine epidemic diarrhea virus. Nanoparticle display demonstrated hemagglutination of erythrocytes from pigs, humans, and mice, linking the S1A subdomain to the binding of sialic acid (Sia) involved in virus attachment. We successfully rescued GFP-labeled SADS-CoV (rSADS-GFP) from a recombinant cDNA clone to track viral infection. Antisera raised against S1, S1A, or S1B contained highly potent neutralizing antibodies, with anti-S1B showing better efficiency in neutralizing rSADS-GFP infection compared to anti-S1A. Furthermore, depletion of heparan sulfate (HS) by heparinase treatment or pre-incubation of rSADS-GFP with HS or constituent monosaccharides could inhibit SADS-CoV entry. Finally, we demonstrated that active furin cleavage of S glycoprotein and the presence of type II transmembrane serine protease (TMPRSS2) are essential for SADS-CoV infection. These combined observations suggest that the wide cell tropism of SADS-CoV may be related to the distribution of Sia or HS on the cell surface, whereas the S1B contains the main protein receptor binding site. Specific host proteases also play important roles in facilitating SADS-CoV entry.IMPORTANCESwine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel pathogen infecting piglet, and its unique genetic evolution characteristics and broad species tropism suggest the potential for cross-species transmission. The virus enters cells through its spike (S) glycoprotein. In this study, we identify the receptor binding domain on the C-terminal part of the S1 subunit (S1B) of SADS-CoV, whereas the sugar-binding domain located at the S1 N-terminal part of S1 (S1A). Sialic acid, heparan sulfate, and specific host proteases play essential roles in viral attachment and entry. The dissection of SADS-CoV S1 subunit's functional domains and identification of cellular entry cofactors will help to explore the receptors used by SADS-CoV, which may contribute to exploring the mechanisms behind cross-species transmission and host tropism.

Fucoidan from Ascophyllum nodosum and Undaria pinnatifida attenuate SARS-CoV-2 infection in vitro and in vivo by suppressing ACE2 and alleviating inflammation.

The global healthcare challenge posed by COVID-19 necessitates the continuous exploration for novel antiviral agents. Fucoidans have demonstrated antiviral activity. However, the underlying structure-activity mechanism responsible for the inhibitory activity of fucoidans from Ascophyllum nodosum (FUCA) and Undaria pinnatifida (FUCU) against SARS-CoV-2 remains unclear. FUCA was characterized as a homopolymer with a backbone structure of repeating (1 â†’ 3) and (1 â†’ 4) linked α-l-fucopyranose residues, whereas FUCU was a heteropolysaccharide composed of Fuc1-3Gal1-6 repeats. Furthermore, FUCA demonstrated significantly higher anti-SARS-CoV-2 activity than FUCU (EC50: 48.66 vs 69.52 µg/mL), suggesting the degree of branching rather than sulfate content affected the antiviral activity. Additionally, FUCA exhibited a dose-dependent inhibitory effect on ACE2, surpassing the inhibitory activity of FUCU. In vitro, both FUCA and FUCU treatments downregulated the expression of pro-inflammatory cytokines (IL-6, IFN-α, IFN-γ, and TNF-α) and anti-inflammatory cytokines (IL-10 and IFN-ß) induced by viral infection. In hamsters, FUCA demonstrated greater effectiveness in attenuating lung and gastrointestinal injury and reducing ACE2 expression, compared to FUCU. Analysis of the 16S rRNA gene sequencing revealed that only FUCU partially alleviated the gut microbiota dysbiosis caused by SARS-CoV-2. Consequently, our study provides a scientific basis for considering fucoidans as poteintial prophylactic food components against SARS-CoV-2.

Type-II IFN inhibits SARS-CoV-2 replication in human lung epithelial cells and ex vivo human lung tissues through indoleamine 2,3-dioxygenase-mediated pathways.

Interferons (IFNs) are critical for immune defense against pathogens. While type-I and -III IFNs have been reported to inhibit SARS-CoV-2 replication, the antiviral effect and mechanism of type-II IFN against SARS-CoV-2 remain largely unknown. Here, we evaluate the antiviral activity of type-II IFN (IFNγ) using human lung epithelial cells (Calu3) and ex vivo human lung tissues. In this study, we found that IFNγ suppresses SARS-CoV-2 replication in both Calu3 cells and ex vivo human lung tissues. Moreover, IFNγ treatment does not significantly modulate the expression of SARS-CoV-2 entry-related factors and induces a similar level of pro-inflammatory response in human lung tissues when compared with IFNß treatment. Mechanistically, we show that overexpression of indoleamine 2,3-dioxygenase 1 (IDO1), which is most profoundly induced by IFNγ, substantially restricts the replication of ancestral SARS-CoV-2 and the Alpha and Delta variants. Meanwhile, loss-of-function study reveals that IDO1 knockdown restores SARS-CoV-2 replication restricted by IFNγ in Calu3 cells. We further found that the treatment of l-tryptophan, a substrate of IDO1, partially rescues the IFNγ-mediated inhibitory effect on SARS-CoV-2 replication in both Calu3 cells and ex vivo human lung tissues. Collectively, these results suggest that type-II IFN potently inhibits SARS-CoV-2 replication through IDO1-mediated antiviral response.

Metasurface- and PCSEL-Based Structured Light for Monocular Depth Perception and Facial Recognition.

The novel depth-sensing system presented here revolutionizes structured light (SL) technology by employing metasurfaces and photonic crystal surface-emitting lasers (PCSELs) for efficient facial recognition in monocular depth-sensing. Unlike conventional dot projectors relying on diffractive optical elements (DOEs) and collimators, our system projects approximately 45,700 infrared dots from a compact 297-µm-dimention metasurface, drastically more spots (1.43 times) and smaller (233 times) than the DOE-based dot projector in an iPhone. With a measured field-of-view (FOV) of 158° and a 0.611° dot sampling angle, the system is lens-free and lightweight and boasts lower power consumption than vertical-cavity surface-emitting laser (VCSEL) arrays, resulting in a 5-10 times reduction in power. Utilizing a GaAs-based metasurface and a simplified optical architecture, this innovation not only addresses the drawbacks of traditional SL depth-sensing but also opens avenues for compact integration into wearable devices, offering remarkable advantages in size, power efficiency, and potential for widespread adoption.

Metasurface-driven polarization-division multiplexing of PCSEL for optical communications.

Free-space optical communications hold promising advantages, including a large bandwidth, access to license-free spectrum, high data rates, quick and simple deployment, low power consumption, and relaxed quality requirements. Nevertheless, key technical challenges remain, such as a higher transmission efficiency, a lower transmission loss, and a smaller form factor of optical systems. Here, we demonstrate the viability of circular-polarization-multiplexed multi-channel optical communication using metasurfaces alongside a photonic-crystal surface-emitting laser (PCSEL) light source at wavelength of 940 nm. Through the light manipulation with metasurface, we split the linearly polarized incidence into left and right circular polarizations with desired diffraction angles. Such orthogonal polarization states provide a paradigm of polarization division multiplexing technique for light communication. The PCSEL light source maintains a low divergence angle of about 0.373 degrees after passing through an ultra-thin metasurface without further bulky collimator or light guide, making end-to-end (E2E) and device-to-device (D2D) communications available in a compact form. Both light source and modulated polarized light exhibit a - 3 dB bandwidth over 500 MHz, with successful 1 Gbit/s transmission demonstrated in eye diagrams. Our results affirm that metasurface effectively boosts transmission capacity without compromising the light source's inherent properties. Future metasurface designs could expand channel capacity, and its integration with PCSEL monolithically holds promise for reducing interface losses, thereby enhancing efficiency.

Reverse genetics systems for SARS-CoV-2: Development and applications.

The recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused serious harm to human health and struck a blow to global economic development. Research on SARS-CoV-2 has greatly benefited from the use of reverse genetics systems, which have been established to artificially manipulate the viral genome, generating recombinant and reporter infectious viruses or biosafety level 2 (BSL-2)-adapted non-infectious replicons with desired modifications. These tools have been instrumental in studying the molecular biological characteristics of the virus, investigating antiviral therapeutics, and facilitating the development of attenuated vaccine candidates. Here, we review the construction strategies, development, and applications of reverse genetics systems for SARS-CoV-2, which may be applied to other CoVs as well.

Design of high-efficiency and large-angle homo-metagratings for light source integration.

Meta-optics integrated with light sources has gained significant attention. However, most focused on the efficiency of metasurfaces themselves, rather than the efficiency of integration. To design highly efficient beam deflection, we develop a scheme of homo-metagrating, involving the same material for meta-atoms, substrate, and top layer of the laser, to achieve near-unity power from light-emitting to metasurfaces. We utilize three degrees of freedom: overall add-on phase, parameters of meta-atoms in a period, and lattice arrangement. The overall efficiency of homo-metagratings is higher than that of hetero-metagratings. We believe our approach is capable of being implemented in various ultracompact optic systems.

Production of singlet oxygen from photosensitizer erythrosine for facile inactivation of coronavirus on mask.

The global health crisis caused by the COVID-19 pandemic has led to a surge in demand and use of personal protective equipment (PPE) such as masks, putting great pressure on social production and the environment.It is urgent to find an efficient and non-destructive disinfection method for the safe reuse of PPE. This study proposes a PPE disinfection method that uses erythrosine, a U.S. Food and Drug Administration-approved food dye, as photosensitizer to produce singlet oxygen for virus inactivation, and indicates the completion of disinfection by its photobleaching color change.After spraying 100 µL of 10 µM erythrosine on the surface of the mask for 3 times and light exposure for 25 min, the titer of coronavirus decreased by more than 99.999%, and the color of erythrosine on the mask surface disappeared. In addition, the structure of the mask was intact and the filtration efficiency was maintained at > 95% after 10 cycles of erythrosine treatment.Therefore, this disinfection method can provide at least 10 cycles of reuse with the advantages of high safety and convenient, and the completion of disinfection can be indicated by its photobleaching, which is suitable for hospitals and daily life to reduce the consumption of PPE.

Compact structured light generation based on meta-hologram PCSEL integration.

Metasurfaces, a catalog of optical components, offer numerous novel functions on demand. They have been integrated with vertical cavity surface-emitting lasers (VCSELs) in previous studies. However, the performance has been limited by the features of the VCSELs such as low output power and large divergence angle. Although the solution of the module of VCSEL array could solve these issues, the practical application is limited by extra lens and large size. In this study, we experimentally demonstrate reconstruction of a holographic images using a compact integration of a photonic crystal surface-emitting laser and metasurface holograms designed for structured light generation. This research showcases the flexible design capabilities of metasurfaces, high output power (on the order of milliwatts), and the ability to produce well-uniformed images with a wide field of view without the need for a collection lens, making it suitable for 3D imaging and sensing.

Heat shock protein 90 facilitates SARS-CoV-2 structural protein-mediated virion assembly and promotes virus-induced pyroptosis.

Inhibition of heat shock protein 90 (Hsp90), a prominent molecular chaperone, effectively limits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but little is known about any interaction between Hsp90 and SARS-CoV-2 proteins. Here, we systematically analyzed the effects of the chaperone isoforms Hsp90α and Hsp90ß on individual SARS-CoV-2 viral proteins. Five SARS-CoV-2 proteins, namely nucleocapsid (N), membrane (M), and accessory proteins Orf3, Orf7a, and Orf7b were found to be novel clients of Hsp90ß in particular. Pharmacological inhibition of Hsp90 with 17-DMAG results in N protein proteasome-dependent degradation. Hsp90 depletion-induced N protein degradation is independent of CHIP, a ubiquitin E3 ligase previously identified for Hsp90 client proteins, but alleviated by FBXO10, an E3 ligase identified by subsequent siRNA screening. We also provide evidence that Hsp90 depletion may suppress SARS-CoV-2 assembly partially through induced M or N degradation. Additionally, we found that GSDMD-mediated pyroptotic cell death triggered by SARS-CoV-2 was mitigated by inhibition of Hsp90. These findings collectively highlight a beneficial role for targeting of Hsp90 during SARS-CoV-2 infection, directly inhibiting virion production and reducing inflammatory injury by preventing the pyroptosis that contributes to severe SARS-CoV-2 disease.

Comparative analysis of newly identified rodent arteriviruses and porcine reproductive and respiratory syndrome virus to characterize their evolutionary relationships.

Porcine reproductive and respiratory syndrome virus (PRRSV) has caused huge economic losses for the global pig industry, but its origins and evolution remain a mystery. In 2018, the genome sequences of seven arteriviruses isolated from rodents were determined, and here we publish new analysis showing that they may be ancestors of PRRSV. The sequence similarity of these viruses to PRRSV was ~60%, with shared genome organization and other characteristics, such as slippery sequences and C-rich motifs in nsp2, and a transactivated protein sequence in nsp1ß. Codon usage basis analysis showed that PRRSV was closer to these rodent arteriviruses than lactate dehydrogenase-elevating virus (LDV) and they were both under pressure of natural selection. Evolutionary analysis revealed that four of the rodent arteriviruses shared the same genus with PRRSV, and were more closely related to PRRSV-2 than PRRSV-1. In addition to this, they all appeared earlier than PRRSV according to evolutionary modeling, and we speculate that they represent an intermediate step in the origin of PRRSV by arterivirus transmission from rodents to swine. Our in-depth analysis furthers our understanding of arteriviruses, and will serve as the basis for subsequent exploration of the evolution of PRRSV and other arteriviruses.

The origin and evolution of emerged swine acute diarrhea syndrome coronavirus with zoonotic potential.

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a newly discovered alphacoronavirus with zoonotic potential that causes diarrhea and vomiting mainly in piglets. Having emerged suddenly in 2017, the prevailing opinion is that the virus originated from HKU2, an alphacoronavirus whose primary host is bats, and at some unknown point achieved interspecies transmission via some intermediate. Here, we further explore the evolutionary history and possible cross-species transmission event for SADS-CoV. Coevolutionary analysis demonstrated that HKU2 may have achieved host switch via SADS-related (SADSr)-CoV, which was isolated from the genus Rhinolophus in 2017. SADS-CoV, HKU2, and SADSr-CoV share similar codon usage patterns and showed a lower tendency to use CpG, which may reflect a method of immune escape. The analyses of virus-host coevolution and recombination support SADSr-CoV is the direct source of SADS-CoV that may have undergone recombination events during its formation. Structure-based spike glycoprotein variance analysis revealed a more nuanced evolutionary pathway to receptor recognition for host switch. We did not find a possible positive selection site, and the dN/dS of the S gene was only 0.29, which indicates that the current SADS-CoV is slowly evolving. These results provide new insights that may help predict future cross-species transmission, and possibly surveil future zoonotic outbreaks and associated public health emergencies.

Role of heat shock protein 90 as an antiviral target for swine enteric coronaviruses.

A variety of swine enteric coronaviruses (SECoVs) have emerged and are prevalent in pig populations, including porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), porcine deltacoronavirus (PDCoV), and swine acute diarrhea syndrome (SADS)-CoV, a newly identified bat-origin CoV with zoonotic potential. Unfortunately, available traditional, inactivated and attenuated SECoV vaccines are of limited efficacy against the variants currently circulating in most pig populations. In this study, we evaluated the role of host factor heat shock protein 90 (Hsp90) as an antiviral target against SECoVs, exemplified by SADS-CoV. Pharmacological inhibition of Hsp90 diminished SADS-CoV replication significantly in porcine and human cell lines, and also decreased replication of SADS-CoV in a porcine intestinal enteroid model. Further mechanistic experiments revealed that both porcine and human isoforms of Hsp90 interact with the SADS-CoV nucleocapsid (N) protein, and inhibition of Hsp90 resulted in autophagic degradation of N protein. Moreover, we linked Hsp90 to virus-induced cellular pyroptosis, as SADS-CoV was found to trigger caspase-1/gasdermin-d-mediated pyroptotic cell death, which was mitigated by inhibition of Hsp90. Finally, we demonstrated that Hsp90 also associated with N proteins and was involved in propagation of PEDV, PDCoV and TGEV. This study thus extends our understanding of immune responses to SADS-CoV infection and offers a new potential therapeutic option against four SECoVs.

Chicken or Porcine Aminopeptidase N Mediates Cellular Entry of Pseudoviruses Carrying Spike Glycoprotein from the Avian Deltacoronaviruses HKU11, HKU13, and HKU17.

Members of deltacoronavirus (DCoV) have mostly been identified in diverse avian species as natural reservoirs, though the porcine DCoV (PDCoV) is a major swine enteropathogenic virus with global spread. The important role of aminopeptidase N (APN) orthologues from various mammalian and avian species in PDCoV cellular entry and interspecies transmission has been revealed recently. In this study, comparative analysis indicated that three avian DCoVs, bulbul DCoV HKU11, munia DCoV HKU13, and sparrow DCoV HKU17 (Chinese strain), and PDCoV in the subgenera Buldecovirus are grouped together at whole-genome levels; however, the spike (S) glycoprotein and its S1 subunit of HKU17 are more closely related to night heron DCoV HKU19 in Herdecovirus. Nevertheless, the S1 protein of HKU11, HKU13, or HKU17 bound to or interacted with chicken APN (chAPN) or porcine APN (pAPN) by flow cytometry analysis of cell surface expression of APN and by coimmunoprecipitation in APN-overexpressing cells. Expression of chAPN or pAPN allowed entry of pseudotyped lentiviruses with the S proteins from HKU11, HKU13 and HKU17 into nonsusceptible cells and natural avian and porcine cells, which could be inhibited by the antibody against APN or anti-PDCoV-S1. APN knockdown by siRNA or knockout by CRISPR/Cas9 in chicken or swine cell lines significantly or almost completely blocked infection of these pseudoviruses. Hence, we demonstrate that HKU11, HKU13, and HKU17 with divergent S genes likely engage chAPN or pAPN to enter the cells, suggesting a potential interspecies transmission from wild birds to poultry and from birds to mammals by certain avian DCoVs. IMPORTANCE The receptor usage of avian deltacoronaviruses (DCoVs) has not been investigated thus far, though porcine deltacoronavirus (PDCoV) has been shown to utilize aminopeptidase N (APN) as a cell receptor. We report here that chicken or porcine APN also mediates cellular entry by three avian DCoV (HKU11, HKU13, and HKU17) spike pseudoviruses, and the S1 subunit of three avian DCoVs binds to APN in vitro and in the surface of avian and porcine cells. The results fill the gaps in knowledge about the avian DCoV receptor and elucidate important insights for the monitoring and prevention of potential interspecies transmission of certain avian DCoVs. In view of the diversity of DCoVs, whether this coronavirus genus will cause novel virus to emerge in other mammals from birds, are worthy of further surveillance and investigation.

Targeting proteostasis of the HEV replicase to combat infection in preclinical models.

BACKGROUND & AIMS: Appropriate treatment options are lacking for hepatitis E virus (HEV)-infected pregnant women and immunocompromised individuals. Thus, we aimed to identify efficient anti-HEV drugs through high-throughput screening, validate them in vitro and in vivo (in a preclinical animal study), and elucidate their underlying antiviral mechanism of action. METHODS: Using appropriate cellular and rodent HEV infection models, we studied a critical pathway for host-HEV interactions and performed a preclinical study of the corresponding antivirals, which target proteostasis of the HEV replicase. RESULTS: We found 17 inhibitors that target HEV-HSP90 interactions by unbiased compound library screening on human hepatocytes harboring an HEV replicon. Inhibitors of HSP90 (iHSP90) markedly suppressed HEV replication with efficacy exceeding that of conventional antivirals (IFNα and ribavirin) in vitro. Mechanistically, iHSP90 treatment released the viral replicase ORF1 protein from the ORF1-HSP90 complex and triggered rapid ubiquitin/proteasome-mediated degradation of ORF1, resulting in abrogated HEV replication. Furthermore, a preclinical trial in a Mongolian gerbil HEV infection model showed this novel anti-HEV strategy to be safe, efficient, and able to prevent HEV-induced liver damage. CONCLUSIONS: In this study, we uncover a proteostatic pathway that is critical for host-HEV interactions and we provide a foundation from which to translate this new understanding of the HEV life cycle into clinically promising antivirals. IMPACT AND IMPLICATIONS: Appropriate treatment options for hepatitis E virus (HEV)-infected pregnant women and immunocompromised patients are lacking; hence, there is an urgent need for safe and effective HEV-specific therapies. This study identified new antivirals (inhibitors of HSP90) that significantly limit HEV infection by targeting the viral replicase for degradation. Moreover, these anti-HEV drugs were validated in an HEV rodent model and were found to be safe and efficient for prevention of HEV-induced liver injury in preclinical experiments. Our findings substantially promote the understanding of HEV pathobiology and pave the way for antiviral development.

AMPK directly phosphorylates TBK1 to integrate glucose sensing into innate immunity.

Nutrient sensing and damage sensing are two fundamental processes in living organisms. While hyperglycemia is frequently linked to diabetes-related vulnerability to microbial infection, how body glucose levels affect innate immune responses to microbial invasion is not fully understood. Here, we surprisingly found that viral infection led to a rapid and dramatic decrease in blood glucose levels in rodents, leading to robust AMPK activation. AMPK, once activated, directly phosphorylates TBK1 at S511, which triggers IRF3 recruitment and the assembly of MAVS or STING signalosomes. Consistently, ablation or inhibition of AMPK, knockin of TBK1-S511A, or increased glucose levels compromised nucleic acid sensing, while boosting AMPK-TBK1 cascade by AICAR or TBK1-S511E knockin improves antiviral immunity substantially in various animal models. Thus, we identify TBK1 as an AMPK substrate, reveal the molecular mechanism coupling a dual sensing of glucose and nuclei acids, and report its physiological necessity in antiviral defense.

A Wireless Soil pH and Conductance Monitoring Chip Powered by Soil Microbial and Photovoltaic Energy Cells.

This paper presents an energy-autonomous wireless soil pH and electrical conductance measurement IC powered by soil microbial and photovoltaic energy. The chip integrates highly efficient dual-input, dual-output power management units, sensor readout circuits, a wireless receiver, and a transmitter. The design scavenges ambient energy with a maximal power point tracking mechanism while achieving a peak efficiency of 81.3% and the efficiency is more than 50% over the 0.05-14 mW load range. The sensor readout IC achieves a sensitivity of -8.8 kHz/pH and 6 kHz·m/S, a noise floor of 0.92 x 10-3 pH value, and 1.4 mS/m conductance. To avoid interference, a 433 MHz transceiver incorporates chirp modulation and on-off keying (OOK) modulation for data uplink and downlink communication. The receiver sensitivity is -80 dBm, and the output transmission power is -4 dBm. The uplink data rate is 100 kb/s using burst chirp modulation and gated Class E PA, while the downlink data rate is 10 kb/s with a self-frequency tracking mixer-first receiver.

Metasurface-based bijective illumination collection imaging provides high-resolution tomography in three dimensions.

Microscopic imaging in three dimensions enables numerous biological and clinical applications. However, high-resolution optical imaging preserved in a relatively large depth range is hampered by the rapid spread of tightly confined light due to diffraction. Here, we show that a particular disposition of light illumination and collection paths liberates optical imaging from the restrictions imposed by diffraction. This arrangement, realized by metasurfaces, decouples lateral resolution from depth-of-focus by establishing a one-to-one correspondence (bijection) along a focal line between the incident and collected light. Implementing this approach in optical coherence tomography, we demonstrate tissue imaging at 1.3 µm wavelength with ~ 3.2 µm lateral resolution, maintained nearly intact over 1.25 mm depth-of-focus, with no additional acquisition or computation burden. This method, termed bijective illumination collection imaging, is general and might be adapted across various existing imaging modalities.