Ubiquitin in Influenza Virus Entry and Innate Immunity

Viruses are obligatory cellular parasites. Their mission is to enter a host cell, to transfer the viral genome, and to replicate progeny whilst diverting cellular immunity. The role of ubiquitin is to regulate fundamental cellular processes such as endocytosis, protein degradation, and immune signaling. Many viruses including influenza A virus (IAV) usurp ubiquitination and ubiquitin-like modifications to establish infection. In this focused review, we discuss how ubiquitin and unanchored ubiquitin regulate IAV host cell entry, and how histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase with ubiquitin-binding activity, mediates IAV capsid uncoating. We also discuss the roles of ubiquitin in innate immunity and its implications in the IAV life cycle

Microtubules in Influenza Virus Entry and Egress

Influenza viruses are respiratory pathogens that represent a significant threat to public health, despite the large-scale implementation of vaccination programs. It is necessary to understand the detailed and complex interactions between influenza virus and its host cells in order to identify successful strategies for therapeutic intervention. During viral entry, the cellular microenvironment presents invading pathogens with a series of obstacles that must be overcome to infect permissive cells. Influenza hijacks numerous host cell proteins and associated biological pathways during its journey into the cell, responding to environmental cues in order to successfully replicate. The cellular cytoskeleton and its constituent microtubules represent a heavily exploited network during viral infection. Cytoskeletal filaments provide a dynamic scaffold for subcellular viral trafficking, as well as virus-host interactions with cellular machineries that are essential for efficient uncoating, replication, and egress. In addition, influenza virus infection results in structural changes in the microtubule network, which itself has consequences for viral replication. Microtubules, their functional roles in normal cell biology, and their exploitation by influenza viruses will be the focus of this review.ISSN:1999-491

Kernel Rootkits Detection Method by Monitoring Branches Using Hardware Features

An operating system is an essential piece of software that manages hardware and software resources. Thus, attacks on an operating system kernel using kernel rootkits pose a particularly serious threat. Detecting an attack is difficult when the operating system kernel is infected with a kernel rootkit. For this reason, handling an attack will be delayed causing an increase in the amount of damage done to a computer system. In this paper, we propose Kernel Rootkits Guard (KRGuard), which is a new method to detect kernel rootkits that monitors branch records in the kernel space. Since many kernel rootkits make branches that differ from the usual branches in the kernel space, KRGuard can detect these differences by using the hardware features of commodity processors. Our evaluation shows that KRGuard can detect kernel rootkits that involve new branches in the system call handler processing with small overhead

KRGuard: Kernel Rootkits Detection Method by Monitoring Branches Using Hardware Features

Attacks on an operating system kernel using kernel rootkits pose a particularly serious threat. Detecting an attack is difficult when the operating system kernel is infected with a kernel rootkit. For this reason, handling an attack will be delayed causing an increase in the amount of damage done to a computer system. In this paper, we discuss KRGuard (Kernel Rootkits Guard), which is a new method to detect kernel rootkits that monitors branch records in the kernel space. Since many kernel rootkits make branches that differ from the usual branches in the kernel space, KRGuard can detect these differences by using hardware features of commodity processors. Our evaluation shows that KRGuard can detect kernel rootkits with small overhead

A widespread viral entry mechanism : The C-end Rule motif-neuropilin receptor interaction

Many phylogenetically distant animal viruses, including the new coronavirus severe acute respiratory syndrome coronavirus 2, have surface proteins with polybasic sites that are cleaved by host furin and furin-like proteases. Other than priming certain viral surface proteins for fusion, cleavage generates a carboxy-terminal RXXR sequence. This C-end Rule (CendR) motif is known to bind to neuropilin (NRP) receptors on the cell surface. NRPs are ubiquitously expressed, pleiotropic cell surface receptors with important roles in growth factor signaling, vascular biology, and neurobiology, as well as immune homeostasis and activation. The CendR-NRP receptor interaction promotes endocytic internalization and tissue spreading of different cargo, including viral particles. We propose that the interaction between viral surface proteins and NRPs plays an underappreciated and prevalent role in the transmission and pathogenesis of diverse viruses and represents a promising broad-spectrum antiviral target.Peer reviewe

High-content analysis of sequential events during the early phase of influenza A virus infection

Influenza A virus (IAV) represents a worldwide threat to public health by causing severe morbidity and mortality every year. Due to high mutation rate, new strains of IAV emerge frequently. These IAVs are often drug-resistant and require vaccine reformulation. A promising approach to circumvent this problem is to target host cell determinants crucial for IAV infection, but dispensable for the cell. Several RNAi-based screens have identified about one thousand cellular factors that promote IAV infection. However, systematic analyses to determine their specific functions are lacking. To address this issue, we developed quantitative, imaging-based assays to dissect seven consecutive steps in the early phases of IAV infection in tissue culture cells. The entry steps for which we developed the assays were: virus binding to the cell membrane, endocytosis, exposure to low pH in endocytic vacuoles, acid-activated fusion of viral envelope with the vacuolar membrane, nucleocapsid uncoating in the cytosol, nuclear import of viral ribonucleoproteins, and expression of the viral nucleoprotein. We adapted the assays to automated microscopy and optimized them for high-content screening. To quantify the image data, we performed both single and multi-parametric analyses, in combination with machine learning. By time-course experiments, we determined the optimal time points for each assay. Our quality control experiments showed that the assays were sufficiently robust for high-content analysis. The methods we describe in this study provide a powerful high-throughput platform to understand the host cell processes, which can eventually lead to the discovery of novel anti-pathogen strategies

Additional kernel observer: privilege escalation attack prevention mechanism focusing on system call privilege changes

Cyberattacks, especially attacks that exploit operating system vulnerabilities, have been increasing in recent years. In particular, if administrator privileges are acquired by an attacker through a privilege escalation attack, the attacker can operate the entire system and cause serious damage. In this paper, we propose an additional kernel observer (AKO) that prevents privilege escalation attacks that exploit operating system vulnerabilities. We focus on the fact that a process privilege can be changed only by specific system calls. AKO monitors privilege information changes during system call processing. If AKO detects a privilege change after system call processing, whereby the invoked system call does not originally change the process privilege, AKO regards the change as a privilege escalation attack and applies countermeasures against it. AKO can therefore prevent privilege escalation attacks. Introducing the proposed method in advance can prevent this type of attack by changing any process privilege that was not originally changed in a system call, regardless of the vulnerability type. In this paper, we describe the design and implementation of AKO for Linux x86 64-bit. Moreover, we show that AKO can be expanded to prevent the falsification of various data in the kernel space. Then, we present an expansion example that prevents the invalidation of Security-Enhanced Linux. Finally, our evaluation results show that AKO is effective against privilege escalation attacks, while maintaining low overhead