Viral tegument proteins restrict cGAS-DNA phase separation to mediate immune evasion.

DNA-induced liquid-liquid phase separation of cyclic GMP-AMP synthase (cGAS) triggers a potent response to detect pathogen infection and promote innate immune signaling. Whether and how pathogens manipulate cGAS-DNA condensation to mediate immune evasion is unknown. We report the identification of a structurally related viral tegument protein family, represented by ORF52 and VP22 from gamma- and alpha-herpesvirinae, respectively, that employs a conserved mechanism to restrict cGAS-DNA phase separation. ORF52/VP22 proteins accumulate into, and effectively disrupt, the pre-formed cGAS-DNA condensation both in vitro and in cells. The inhibition process is dependent on DNA-induced liquid-liquid phase separation of the viral protein rather than a direct interaction with cGAS. Moreover, highly abundant ORF52 proteins carried within viral particles are able to target cGAS-DNA phase separation in early infection stage. Our results define ORF52/VP22-type tegument proteins as a family of inhibitors targeting cGAS-DNA phase separation and demonstrate a mechanism for how viruses overcome innate immunity.

Structural Aspects of Betaherpesvirus-Encoded Proteins.

Betaherpesvirus possesses a large genome DNA with a lot of open reading frames, indicating abundance in the variety of viral protein factors. Because the complicated pathogenicity of herpesvirus reflects the combined functions of these factors, analyses of individual proteins are the fundamental steps to comprehensively understand about the viral life cycle and the pathogenicity. In this chapter, structural aspects of the betaherpesvirus-encoded proteins are introduced. Betaherpesvirus-encoded proteins of which structural information is available were summarized and subcategorized into capsid proteins, tegument proteins, nuclear egress complex proteins, envelope glycoproteins, enzymes, and immune-modulating factors. Structure of capsid proteins are analyzed in capsid by electron cryomicroscopy at quasi-atomic resolution. Structural information of teguments is limited, but a recent crystallographic analysis of an essential tegument protein of human herpesvirus 6B is introduced. As for the envelope glycoproteins, crystallographic analysis of glycoprotein gB has been done, revealing the fine-tuned structure and the distribution of its antigenic domains. gH/gL structure of betaherpesvirus is not available yet, but the overall shape and the spatial arrangement of the accessory proteins are analyzed by electron microscopy. Nuclear egress complex was analyzed from the structural perspective in 2015, with the structural analysis of cytomegalovirus UL50/UL53. The category "enzymes" includes the viral protease, DNA polymerase and terminase for which crystallographic analyses have been done. The immune-modulating factors are viral ligands or receptors for immune regulating factors of host immune cells, and their communications with host immune molecules are demonstrated in the aspect of molecular structure.

Alphaherpesvirinae and Gammaherpesvirinae glycoprotein L and CMV UL130 originate from chemokines.

Herpesviridae is a large family of DNA viruses divided into three subfamilies: Alpha-, Beta- and Gammaherpesvirinae. The process of herpesvirus transmission is mediated by a range of proteins, one of which is glycoprotein L (gL). Based on our analysis of the solved structures of HSV2 and EBV gH/gL complexes, we propose that Alphaherpesvirinae and Gammaherpesvirinae glycoprotein L and Betaherpesvirinae UL130 originate from chemokines. Herpes simplex virus type 2 gL and human cytomegalovirus homolog (UL130) adopt a novel C chemokine-like fold, while Epstein-Barr virus gL mimics a CC chemokine structure. Hence, it is possible that gL interface with specific chemokine receptors during the transmission of Herpesviridae. We conclude that the further understanding of the function of viral chemokine-like proteins in Herpesviridae infection may lead to development of novel prophylactic and therapeutic treatment.

Infección congénita por citomegalovirus

El citomegalovirus (CMV) se encuentra ampliamente distribuido en la población, es el responsable de graves infecciones especialmente congénitas y es considerado como un problema médico-biológico debido al poco conocimiento de la epidemiología de la infección latente (1-5). El CMV es un ADN virus miembro de la subfamilia Betaherpesvirinae, con una gran capacidad para adaptarse y permanecer latente y presentar reactivaciones en situaciones en que esté alterada la respuesta inmune, por lo que se ha considerado como un verdadero marcador de inmunodeficiencia (6-9). Su incidencia es variable, oscila entre 1 y 5 por ciento. La enfermedad por citomegalovirus es subclínica en un 90 por ciento de los casos y de éstos el 10 por ciento tienen secuelas neurológicas. El CMV ataca la matriz germinal ependimaria y la sustancia blanca produciendo lesiones de necrosis, calcificación, disgenesia cerebral, microcefalia, micropoligiria que se traduce en retardo mental, convulsiones, displejía espástica (5, 10-12). El diagnóstico no sólo es clínico, sino virológico inmunológico, histológico y escanográfico. El tratamiento es multidisciplinario y el pronóstico depende del compromiso neurológico (9, 13-15). Con el objeto de resaltar las manifestaciones neurológicas en los pacientes pediátricos infectado por el CMV, presentamos estas cuatro casos clínicos que consultaron el servicio de neurología infantil del Hospital Universitario de Cartagena.