Efficacious control of cytomegalovirus infection after long-term depletion of CD8+ T lymphocytes

Although the relative contribution of different immune effector functions to clearing tissues of cytomegalovirus is controversial, the contribution of CD8+ T lymphocytes has generally been accepted as essential. In this report, we show that under certain conditions the CD8+ T-lymphocyte subset can be dispensable for clearance of cytomegalovirus. Mice depleted of the CD8+ T-lymphocyte subset eliminated infectious virus with a clearance kinetics similar to that of normal mice. Adoptive transfer studies revealed that the limitation of virus spread required the cooperation between the CD4+ subset and other cells. Comparison between protective functions generated in fully immunocompetent and in CD8- mice demonstrated that elimination of the CD8+ subset before infection altered the quality of the antiviral immune response. The compensatory protective activity gained by CD4+ cells in CD8- mice was absent in normal mice recovering from virus infection

Gamma interferon-dependent clearance of cytomegalovirus infection in salivary glands

Cytomegalovirus (CMV), similar to other members of the Herpesviridae family, can establish both persistent and latent infections. Each of the CMVs that are found in many animal species replicates in the salivary gland, and oral secretion represents a source of horizontal transmission. Locally restricted replication characterizes the immunocompetent individual, whereas in the immunocompromised host, protean disease manifestations occur due to virus dissemination. The virus is cleared by immune surveillance, and CD8+ T lymphocytes play a major role. Remarkably, certain cell types of salivary gland tissues are exempt from CD8+ T-lymphocyte control of murine CMV infection and require the activity of CD4+ T lymphocytes. The results presented here suggest that this activity is a function of Th1 cells. Neutralization of endogenous gamma interferon abrogated the antiviral activity of Th1 cells but not that of CD8+ T lymphocytes in other tissues. Neutralization of endogenous gamma interferon did not interfere with the induction of the cellular and humoral immune response but acted during the effector phase. Recombinant gamma interferon could not replace the function of Th1 cells in vivo and had limited direct antiviral activity in vitro. The results therefore suggest that gamma interferon represents one, but not the only, essential factor involved in salivary gland clearance, establishment of CMV latency, and, eventually, the control of horizontal transmission

Antibodies Are Not Essential for the Resolution of Primary Cytomegalovirus Infection but Limit Dissemination of Recurrent Virus

Virus shedding from the epithelial cells of the serous acini of salivary glands is a major source for the horizontal transmission of cytomegalovirus. These cells are, different to other tissues, exempt from CD8 T lymphocyte control. CD4 T lymphocytes are essential to terminate the productive infection. Here, we prove that T-B cooperation and the production of antibodies are not required for this process. For the infection with murine cytomegalovirus, mutant mice were used which do not produce antibodies because of a disrupted membrane exon of the immunoglobulin # chain gene. Also, in these mice the virus clearance from salivary glands is a function of CD4 T lymphocytes. However, these mice clear the virus and establish viral latency with a kinetics that is distinguishable from normal mice. Reactivation from virus latency is the only stage at which the absence of antibodies alters the phenotype of infection. In immunoglobulindeficient mice, virus recurrence results in higher virus titers. The adoptive serum transfer proved that antibody is the limited factor that prevents virus dissemination in the immunodeficient hos

The Conditions of Primary Infection Define the Load of Latent Viral Genome in Organs and the Risk of Recurrent Cytomegalovirus Disease

Recurrence of cytomegalovirus (CMV) from latency is a frequent cause of disease in immunocompromised patients. To date, there is no explanation for the diversity in the clinical manifestations. Primary infection can occur perinatally or later in life, and inevitably results in latent infection. Seropositivity for antibodies against CMV is indicative of latent infection, but is insufficient as a predictor for the risk of recurrence. As a model for this important medical problem, we compared the risks of murine CMV recurrence from latency established after neonatal primary infection and after infection at adult age. The risk of CMV recurrence was high only after neonatal infection. The copy number of latent viral genome in tissues was identified as the key parameter that determines the overall and organ-specific risks of recurrence. Latent CMV burden and risk of recurrence were related to the extent of virus multiplication during primary infection. The presence of latent CMV in multiple organs provides the molecular basis for stochastic events of recurrence in single organs or in any combination thereof. These findings are discussed as a concept of multifocal CMV latency and recurrence. It provides a rationale for the diversity in the clinical outcome of CMV disease

Participation of endogenous tumour necrosis factor α in host resistance to cytomegalovirus infection

Interferon gamma (IFN) represents an essential cytokine involved in murine cytomegalovirus (MCMV) clearance from the salivary gland and the control of horizontal transmission. Because IFN cannot be responsible for all cytokine effects during recovery from MCMV infection we have now tested the potential participation of tumour necrosis factor alpha (TNF) in the antiviral defence. Neutralization of endogenous TNF abolished the antiviral activity of CD4 T cells in immunocompetent as well as in CD8 subset-deficient mice. These data suggest that the antiviral effect of the CD4 subset requires the presence of at least two cytokines, namely IFN and TNF. Depletion of endogenous TNF in adoptive cell transfer recipients diminished the antiviral function of CD8 T lymphocytes suggesting that TNF also participates in CD8 T cell effector functions. Furthermore, endogenous cytokines were found to be required for survival after infection with lethal doses of MCMV, whereas immunotherapy with recombinant TNF and IFN could not limit virus replication in vivo. The results suggest that, similar to IFN, TNF is an integral part of the protective mechanisms involved in cytomegalovirus clearance

Determining residual deviation and analysis of the current use of the magnetic compass

The use of electronic compasses and satellite systems has led to the magnetic compass becoming a secondary means of navigation. Yet this means of navigating is not only not obsolete, it is a necessary backup device: the construction simplicity of the magnetic compass, without electrical windings, rotating elements, and control units, remains resistant to power losses, hardware malfunction, and thus is reliable under the harshest conditions. This durability, however, comes at some costthe magnetic compass is influenced by ships\u27 permanent and transient magnetism, cargo gears. For the proper use of a magnetic compass, it is necessary to perform an adjustment to determine the residual deviation at regular intervals. The paper analyses selected methods to manage this, and to identify the main features of classical methods. The research was supplemented by a study carried out during the practical compensations of the magnetic compass at sea and by a survey among navigation officers on its basic requirements for proper use. The results indicate insufficient inspection of the magnetic compass. Further, an investigation into the causes of deviation delivers information regarding the causes under varying conditions including type of ship and latitudinal circumstances. This paper presents findings and recommendations to improve the compensation and use of the ships magnetic compasses

AIS data vulnerability indicated by a spoofing case-study

This paper takes a close look at the landscape of the Automatic Identification System (AIS) as a major source of information for maritime situational awareness (MSA) and identifies its vulnerabilities and challenges for safe navigation and shipping. As an important subset of cyber threats affecting many maritime systems, the AIS is subject to problems of tampering and reliabilityindeed, the messages received may be inadvertently false, jammed, or intentionally spoofed. A systematic literature review was conducted for this article, complemented by a case study of a specific spoofing event near Elba in December 2019, which confirmed that the typical maritime AIS could be easily spoofed and generate erroneous position information. This intentional spoofing has affected navigation in international waters and passage through territorial waters. The maritime industry is neither immune to cyberattacks nor fully prepared for the risks associated with the use of modern digital systems. Maintaining seaworthiness in the face of the impact of digital technologies requires a robust cybersecurity framework

Assessing cyber challenges of maritime navigation

This paper provides a close investigation into the landscape of both cyber threats and actual incidents in the maritime sector, identifying the cyber trends and challenges as they relate to safe navigation and marine shipping. As an important subset of cyber threats that impact many maritime systems, the vulnerabilities of satellite navigation systems, in particular the Global Positioning System (GPS), receive special attention. For this article, a systematic literature review was conducted, complemented by the research and analysis of a specific spoofing event. Analyzing available resources, we might summarize that a shift in mind-set is essential to direct more attention and resources toward cybersecurity as well as the necessity for manufacturers to improve the cybersecurity of their products, as shipping systems currently remain vulnerable to cybercriminals. There is a need for multiple positioning, navigation, and timing (PNT) systems onboard maritime vessels to complement GPS-only navigation. The use of multiple satellite navigation constellations, public as well as private, in combination with the terrestrial components of an enhanced LOng-RAnge Navigation (eLoran) system and ports\u27 laser-based aid system for berthing and docking should provide the shipping industry with the direly needed increased protection from cyber-attackers for the foreseeable future

Assessing Cyber Challenges of Maritime Navigation

This paper provides a close investigation into the landscape of both cyber threats and actual incidents in the maritime sector, identifying the cyber trends and challenges as they relate to safe navigation and marine shipping. As an important subset of cyber threats that impact many maritime systems, the vulnerabilities of satellite navigation systems, in particular the Global Positioning System (GPS), receive special attention. For this article, a systematic literature review was conducted, complemented by the research and analysis of a specific spoofing event. Analyzing available resources, we might summarize that a shift in mind-set is essential to direct more attention and resources toward cybersecurity as well as the necessity for manufacturers to improve the cybersecurity of their products, as shipping systems currently remain vulnerable to cybercriminals. There is a need for multiple positioning, navigation, and timing (PNT) systems onboard maritime vessels to complement GPS-only navigation. The use of multiple satellite navigation constellations, public as well as private, in combination with the terrestrial components of an enhanced LOng-RAnge Navigation (eLoran) system and ports’ laser-based aid system for berthing and docking should provide the shipping industry with the direly needed increased protection from cyberattackers for the foreseeable future.JRC.E.7-Knowledge for Security and Migratio