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Autophagy is an evolutionarily conserved catabolic cellular process that exerts antiviral functions during a viral invasion. However, co-evolution and co-adaptation between viruses and autophagy have armed viruses with multiple strategies to subvert the autophagic machinery and counteract cellular antiviral responses. Specifically, the host cell quickly initiates the autophagy to degrade virus particles or virus components upon a viral infection, while cooperating with anti-viral interferon response to inhibit the virus replication. Degraded virus-derived antigens can be presented to T lymphocytes to orchestrate the adaptive immune response. Nevertheless, some viruses have evolved the ability to inhibit autophagy in order to evade degradation and immune responses. Others induce autophagy, but then hijack autophagosomes as a replication site, or hijack the secretion autophagy pathway to promote maturation and egress of virus particles, thereby increasing replication and transmission efficiency. Interestingly, different viruses have unique strategies to counteract different types of selective autophagy, such as exploiting autophagy to regulate organelle degradation, metabolic processes, and immune responses. In short, this review focuses on the interaction between autophagy and viruses, explaining how autophagy serves multiple roles in viral infection, with either proviral or antiviral functions. Highlights This review focuses on the interaction between autophagy and viruses, explaining how autophagy serves multiple roles in viral infection, with either proviral or antiviral functions. Based on different steps of autophagy and the regulation of immune responses by autophagy, this review oversees the role of autophagy in viral replication, maturation, egress and cell–cell spreading. This review provides an important foundation for the development of broad-spectrum antiviral treatment strategies and drugs based on the regulation of autophagy.

Ferroptosis is a novel form of cell death caused by the accumulation of lipid peroxides in an iron‐dependent manner. However, the precise mechanism underlying the exploitation of ferroptosis by influenza A viruses (IAV) remains unclear. The results demonstrate that IAV promotes its own replication through ferritinophagy by sensitizing cells to ferroptosis, with hemagglutinin identified as a key trigger in this process. Hemagglutinin interacts with autophagic receptors nuclear receptor coactivator 4 (NCOA4) and tax1‐binding protein 1 (TAX1BP1), facilitating the formation of ferritin‐NCOA4 condensates and inducing ferritinophagy. Further investigation shows that hemagglutinin‐induced ferritinophagy causes cellular lipid peroxidation, inhibits aggregation of mitochondrial antiviral signaling protein (MAVS), and suppresses the type I interferon response, thereby contributing to viral replication. Collectively, a novel mechanism by which IAV hemagglutinin induces ferritinophagy resulting in cellular lipid peroxidation, consequently impairing MAVS‐mediated antiviral immunity, is revealed. The precise relationship between influenza A virus (IAV) and ferroptosis remains unclear. In this study, IAV hemagglutinin is shown to support viral replication by inducing ferroptosis via ferritinophagy. Hemagglutinin interacts with the autophagic receptors NCOA4 and TAX1BP1, leading to ferritinophagy. This interaction results in cellular lipid peroxidation and inhibits mitochondrial antiviral signaling protein (MAVS) aggregation, thereby promoting viral replication.

The Eurasian avian-like (EA) H1N1 swine influenza virus (SIV) possesses the capacity to instigate the next influenza pandemic, owing to its heightened affinity for the human-type α-2,6 sialic acid (SA) receptor. Nevertheless, the molecular mechanisms underlying the switch in receptor binding preferences of EA H1N1 SIV remain elusive. In this study, we conduct a comprehensive genome-wide CRISPR/Cas9 knockout screen utilizing EA H1N1 SIV in porcine kidney cells. Knocking out the enzyme gamma glutamyl carboxylase (GGCX) reduces virus replication in vitro and in vivo by inhibiting the carboxylation modification of viral haemagglutinin (HA) and the adhesion of progeny viruses, ultimately impeding the replication of EA H1N1 SIV. Furthermore, GGCX is revealed to be the determinant of the D225E substitution of EA H1N1 SIV, and GGCX-medicated carboxylation modification of HA 225E contributes to the receptor binding adaption of EA H1N1 SIV to the α-2,6 SA receptor. Taken together, our CRISPR screen has elucidated a novel function of GGCX in the support of EA H1N1 SIV adaption for binding to α-2,6 SA receptor. Consequently, GGCX emerges as a prospective antiviral target against the infection and transmission of EA H1N1 SIV. The host factors that drive adaptive substitutions in the influenza virus remain poorly understood. Here, Zou et al. identify GGCX as a key determinant for the adaption of Eurasian avian-like H1N1 swine influenza virus to receptor binding.

The molecular mechanisms underlying the transport of influenza A virus (IAV) membrane proteins to the cell surface remain largely unclear. In this study, siRNA screening identifies Rab27a as a critical host factor regulating this transport process. GTP-bound Rab27a operates via its effectors, synaptotagmin-like protein 1 (SYTL1) and SYTL4, to facilitate the transport of vesicles carrying viral membrane proteins to the plasma membrane. Absence of Rab27a or SYTL4 does not block the early stages of the IAV life cycle but restricts viral assembly and budding. Notably, silencing SYTL4 provides superior protection in the female mouse IAV infection model. This investigation elucidates the molecular mechanism by which Rab27a and its effectors modulate the transport of IAV membrane proteins, thereby bridging a critical gap in IAV life cycle research and presenting a potential target for the development of antiviral drugs. Using siRNA screening, Chen et al demonstrate that Rab27a and its effector SYTL4 mediate the transport of influenza viral membrane proteins to the plasma membrane, highlighting their role in virion assembly and identifying SYTL4 as a potential therapeutic target for antiviral drug development.

Actin‐ and microtubule‐based transport systems are essential for the trafficking of endocytic viruses and cargoes. Microtubules facilitate long‐distance transport; however, the precise role of actin dynamics and its regulators during virus entry, particularly in the transit process, remains elusive. Here, Adducin‐1 (ADD1) is identified as a key regulator of actin dynamics, as demonstrated by real‐time monitoring of quantum dot (QD)‐labeled influenza A virus (IAV) movement. ADD1 deletion increases actin density around endocytic vesicles, disrupting general vesicular trafficking and inhibiting the replication of diverse endocytic viruses. Mechanistically, endocytic viruses or cargoes trigger the phosphorylation of ADD1 at Ser726, which reduces the density of actin branches for effective transport. Additionally, the physical force required for IAV capsid dissociation is influenced by ADD1. Collectively, the study identifies a basic actin dynamics event with broad relevance to endocytic viruses or cargo trafficking and represents ADD1 as a potential target for developing broad‐spectrum antiviral strategies. In this study, a novel mechanism is unveiled by which ADD1, acting as a molecular switch, coordinates actin branch dynamics and the transport of endocytic viruses and cargoes. Phosphorylation of ADD1 at Ser726 reduces actin branch density, enhancing endosome fusion and attachment to microtubules. EG‐011 treatment and ADD1 knockdown reduced influenza virus replication in vivo and in vitro.

H9N2 avian influenza viruses (AIVs) are widely distributed, causing continuous outbreaks in poultry and sporadic infections in humans. Vaccination is the primary method used to prevent and control H9N2 AIV infection. However, the ongoing evolution and mutation of AIVs often result in limited protection effects from vaccines. Therapeutic monoclonal antibodies (mAbs) targeting influenza viruses offer a promising alternative. In this study, we immunized mice with inactivated H9N2-W1 virus, and we screened and acquired five mAbs, namely 4D12, F4, 5C8, 2G8 and A11. We showed that all five mAbs specifically targeted the HA protein of various H9N2 AIV strains. In vitro neutralization tests demonstrated that all five mAbs exhibited neutralization activity against H9N2 AIVs, with mAb F4 displaying the most potent neutralization effect. The F4 mAb exhibited dose-dependent preventive and therapeutic effects against lethal H9N2-115 infection, and the administration of F4 at a dose of 3 μg/g provided complete protection in vivo. Our study presents an alternative approach for preventing and controlling H9N2 AIV infection. Furthermore, the identified F4 mAb holds promise as a solution to potential pandemics in humans caused by H9N2 AIVs.

Pigeon paramyxovirus type 1 (PPMV-1) poses significant economic challenges to the pigeon industry in China. However, information about the prevalence, genetic diversity, and epidemiology of PPMV-1 in China is still lacking. In this study, we isolated six strains of PPMV-1 from Hubei and Zhejiang provinces in 2022. All six isolates were found to belong to subgenotype VI.2.1.1.2.2. Five of them were identified as mesogenic and one as lentogenic. Multiple mutations were observed in the F and HN proteins of these isolates. Comprehensive analysis of global PPMV-1 strains highlighted the dominance of genotype VI, showing that VI.2.1.1.2.2 has been the dominant subgenotype since 2011. We also identified 36 host-specific amino acid substitutions that are unique to PPMV-1 in comparison to chicken-origin NDVs. The data reported here contribute to our understanding of the epidemiology, genetic diversity, and prevalence of PPMV-1 and serve as a valuable reference for the prevention and control of PPMV-1.

Classified as a class B infectious disease by the World Organization for Animal Health (OIE), bovine viral diarrhea/mucosal disease is an acute, highly contagious disease caused by the bovine viral diarrhea virus (BVDV). Sporadic endemics of BVDV often lead to huge economic losses to the dairy and beef industries. To shed light on the prevention and control of BVDV, we developed two novel subunit vaccines by expressing bovine viral diarrhea virus E2 fusion recombinant proteins (E2Fc and E2Ft) through suspended HEK293 cells. We also evaluated the immune effects of the vaccines. The results showed that both subunit vaccines induced an intense mucosal immune response in calves. Mechanistically, E2Fc bonded to the Fc γ receptor (FcγRI) on antigen-presenting cells (APCs) and promoted IgA secretion, leading to a stronger T-cell immune response (Th1 type). The neutralizing antibody titer stimulated by the mucosal-immunized E2Fc subunit vaccine reached 1:64, which was higher than that of the E2Ft subunit vaccine and that of the intramuscular inactivated vaccine. The two novel subunit vaccines for mucosal immunity developed in this study, E2Fc and E2Ft, can be further used as new strategies to control BVDV by enhancing cellular and humoral immunity.

Innate immunity serves as a crucial defense mechanism against invading pathogens, yet its negative regulatory network remains under explored. In this study, we identify BEN domain-containing protein 6 (BEND6) as a novel negative regulator of innate immunity through a genome-scale CRISPR knockout screen for host factors essential for viral replication. We show that BEND6 exhibits characteristics of an interferon-stimulated gene (ISG), with its mRNA and protein levels upregulated by RNA virus-induced IFN-β. BEND6 targets IRF3 and inhibits its recruitment by TBK1, thus preventing IRF3 phosphorylation and dimerization. Additionally, BEND6 directly binds to ISRE, thereby hindering the DNA binding activity of IRF3 and blocking the subsequent activation of IFN-β transcription. Taken together, our study reveals the mechanism of BEND6 in promoting the replication of various RNA viruses and provides a potential therapeutic target for RNA virus infection.

Our analysis of recent Internet traces shows that up to 71% of flows contain suspicious behaviors indicative of low-volume network attacks such as port scans. However, distinguishing anomalous traffic in real time is challenging as each attack flow may comprise only a few packets. We extend prior work that tracks heavy hitter flows to also detect low-volume and slow attacks by combining the capabilities of both switches and SmartNICs. We flip the usual design approach by proposing an efficient filter data structure used to quickly route traffic marked as benign towards destination end-systems. We make careful use of limited programmable switch memory and pipeline stages, and complement them with SmartNIC resources to analyze the remaining traffic that may be anomalous. Using machine learning classifiers and intrusion detection rules deployed on the SmartNIC, we identify malicious source IPs, which then undergo more detailed forensics for attack mitigation. Finally, we develop a dataplane based protocol to rapidly coordinate data structure updates between these devices. We implement immUNITY in a testbed with Tofino v1 switch and Bluefield 3 SmartNIC, demonstrating its high accuracy, while minimizing traffic that's analyzed outside the switch.