Autophagy in herpesvirus immune control and immune escape

Autophagy delivers cytoplasmic constituents for lysosomal degradation, and thereby facilitates pathogen degradation and pathogen fragment loading onto MHC molecules for antigen presentation to T cells. Herpesviruses have been used to demonstrate these novel functions of autophagy, which previously has been primarily appreciated for its pro-survival role during starvation. In this review, we summarize recent findings how macroautophagy restricts herpesvirus infections directly, how macroautophagy and chaperone mediated autophagy contribute to herpesviral antigen presentation on MHC molecules, and which mechanisms herpesviruses have developed to interfere with these pathways. These studies suggest that herpesviruses significantly modulate autophagy to escape from its functions in innate and adaptive immunity

Human CD4+ T lymphocytes consistently respond to the latent Epstein- Barr virus nuclear antigen EBNA1

The Epstein-Barr virus (EBV)-encoded nuclear antigen EBNA1 is critical for the persistence of the viral episome in replicating EBV-transformed human B cells. Therefore, all EBV-induced tumors express this foreign antigen. However, EBNA1 is invisible to CD8+ cytotoxic T lymphocytes because its Gly/Ala repeat domain prevents proteasome-dependent processing for presentation on major histocompatibility complex (MHC) class I. We now describe that CD4+ T cells from healthy adults are primed to EBNA1. In fact, among latent EBV antigens that stimulate CD4+ T cells, EBNA1 is preferentially recognized. We present evidence that the CD4+ response may provide a protective role, including interferon γ secretion and direct cytolysis after encounter of transformed B lymphocyte cell lines (B-LCLs). Dendritic cells (DCs) process EBNA1 from purified protein and from MHC class II-mismatched, EBNA1-expressing cells including B-LCLs. In contrast, B-LCLs and Burkitt\u27s lymphoma lines likely present EBNA1 after endogenous processing, as their capacity to cross-present from exogenous sources is weak or undetectable. By limiting dilution, there is a tight correlation between the capacity of CD4+ T cell lines to recognize autologous B-LCL-expressing EBNA1 and DCs that have captured EBNA1. Therefore, CD4+ T cells can respond to the EBNA1 protein that is crucial for EBV persistence. We suggest that this immune response is initiated in vivo by DCs that present EBV-infected B cells, and that EBNA1-specific CD4+ T cell immunity be enhanced to prevent and treat EBV-associated malignancies

Instantaneous Bethe-Salpeter equation: utmost analytic approach

The Bethe-Salpeter formalism in the instantaneous approximation for the interaction kernel entering into the Bethe-Salpeter equation represents a reasonable framework for the description of bound states within relativistic quantum field theory. In contrast to its further simplifications (like, for instance, the so-called reduced Salpeter equation), it allows also the consideration of bound states composed of "light" constituents. Every eigenvalue equation with solutions in some linear space may be (approximately) solved by conversion into an equivalent matrix eigenvalue problem. We demonstrate that the matrices arising in these representations of the instantaneous Bethe-Salpeter equation may be found, at least for a wide class of interactions, in an entirely algebraic manner. The advantages of having the involved matrices explicitly, i.e., not "contaminated" by errors induced by numerical computations, at one's disposal are obvious: problems like, for instance, questions of the stability of eigenvalues may be analyzed more rigorously; furthermore, for small matrix sizes the eigenvalues may even be calculated analytically.Comment: LaTeX, 23 pages, 2 figures, version to appear in Phys. Rev.

Electromagnetic Meson Form Factors in the Salpeter Model

We present a covariant scheme to calculate mesonic transitions in the framework of the Salpeter equation for $q\bar{q}$-states. The full Bethe Salpeter amplitudes are reconstructed from equal time amplitudes which were obtained in a previous paper\cite{Mue} by solving the Salpeter equation for a confining plus an instanton induced interaction. This method is applied to calculate electromagnetic form factors and decay widths of low lying pseudoscalar and vector mesons including predictions for CEBAF experiments. We also describe the momentum transfer dependence for the processes $\pi^0,\eta,\eta'\rightarrow\gamma\gamma^*$.Comment: 22 pages including 10 figure

Robustness of Delayed Multistable Systems with Application to Droop-Controlled Inverter-Based Microgrids

Motivated by the problem of phase-locking in droop-controlled inverter-based microgrids with delays, the recently developed theory of input-to-state stability (ISS) for multistable systems is extended to the case of multistable systems with delayed dynamics. Sufficient conditions for ISS of delayed systems are presented using Lyapunov-Razumikhin functions. It is shown that ISS multistable systems are robust with respect to delays in a feedback. The derived theory is applied to two examples. First, the ISS property is established for the model of a nonlinear pendulum and delay-dependent robustness conditions are derived. Second, it is shown that, under certain assumptions, the problem of phase-locking analysis in droop-controlled inverter-based microgrids with delays can be reduced to the stability investigation of the nonlinear pendulum. For this case, corresponding delay-dependent conditions for asymptotic phase-locking are given

Monitoring Antigen Processing for MHC Presentation via Macroautophagy

Macroautophagy has recently emerged as an important catabolic process involved not only in innate immunity but also in adaptive immunity. Initially described to deliver intracellular antigens to MHC class II loading compartments, its molecular machinery has now also been described to impact the delivery of extracellular antigens to MHC class II loading compartments through the noncanonical use of the macroautophagy machinery during LC3-associated phagocytosis (LAP). Therefore, in pathological situations (viral or bacterial infections, tumorigenesis) the pathway might be involved in shaping CD4$^{+}$ T cell responses.In this chapter we describe three basic experiments for the monitoring and manipulation of macroautophagic antigen processing toward MHC class II presentation through the canonical pathway. Firstly, we will discuss how to monitor autophagic flux and autophagosome fusion with MHC class II loading compartments. Secondly, we will show how to target proteins to autophagosomes in order to monitor macroautophagy dependent antigen processing via their enhanced presentation on MHC class II molecules to CD4$^{+}$ T cells. And finally, we will describe how macroautophagy can be silenced in antigen presenting cells, like human monocyte-derived dendritic cells (DCs)

The stability of the spectator, Dirac, and Salpeter equations for mesons

Mesons are made of quark-antiquark pairs held together by the strong force. The one channel spectator, Dirac, and Salpeter equations can each be used to model this pairing. We look at cases where the relativistic kernel of these equations corresponds to a time-like vector exchange, a scalar exchange, or a linear combination of the two. Since the model used in this paper describes mesons which cannot decay physically, the equations must describe stable states. We find that this requirement is not always satisfied, and give a complete discussion of the conditions under which the various equations give unphysical, unstable solutions

Towards resolution of the scalar meson nonet enigma

By the application of a linear mass spectrum to a composite system of both the pseudoscalar and scalar meson nonets, we find three mass relations for the masses of the scalar states which suggest the $q\bar{q}$ assignment for the scalar meson nonet: $a_0(1320),$ $K_0^\ast (1430),$ $f_0(1500),$ $f_0'(980).$Comment: 16 pages, LaTe

Baryon spectra with instanton induced forces

Except the vibrational excitations of $K$ and $K^*$ mesons, the main features of spectra of mesons composed of quarks $u$, $d$, and $s$ can be quite well described by a semirelativistic potential model including instanton induced forces. The spectra of baryons composed of the same quarks is studied using the same model. The results and the limitations of this approach are described. Some possible improvements are suggested.Comment: 5 figure