Epstein-Barr virus induces germinal center light zone chromatin architecture and promotes survival through enhancer looping at the BCL2A1 locus.

IMPORTANCE: Epstein-Barr virus has evolved with its human host leading to an intimate relationship where infection of antibody-producing B cells mimics the process by which these cells normally recognize foreign antigens and become activated. Virtually everyone in the world is infected by adulthood and controls this virus pushing it into life-long latency. However, immune-suppressed individuals are at high risk for EBV+ cancers. Here, we isolated B cells from tonsils and compare the underlying molecular genetic differences between these cells and those infected with EBV. We find similar regulatory mechanism for expression of an important cellular protein that enables B cells to survive in lymphoid tissue. These findings link an underlying relationship at the molecular level between EBV-infected B cells in vitro with normally activated B cells in vivo. Our studies also characterize the role of a key viral control mechanism for B cell survival involved in long-term infection.

Differential Requirement for IRGM Proteins during Tuberculosis Infection in Mice.

Mycobacterium tuberculosis (Mtb) is a bacterium that exclusively resides in human hosts and remains a dominant cause of morbidity and mortality among infectious diseases worldwide. Host protection against Mtb infection is dependent on the function of immunity-related GTPase clade M (IRGM) proteins. Polymorphisms in human IRGM associate with altered susceptibility to mycobacterial disease, and human IRGM promotes the delivery of Mtb into degradative autolysosomes. Among the three murine IRGM orthologs, Irgm1 has been singled out as essential for host protection during Mtb infections in cultured macrophages and in vivo. However, whether the paralogous murine Irgm genes, Irgm2 and Irgm3, play roles in host defense against Mtb or exhibit functional relationships with Irgm1 during Mtb infection remains undetermined. Here, we report that Irgm1-/- mice are indeed acutely susceptible to aerosol infection with Mtb, yet the additional deletion of the paralogous Irgm3 gene restores protective immunity to Mtb infections in Irgm1-deficient animals. Mice lacking all three Irgm genes (panIrgm-/-) are characterized by shifted lung cytokine profiles at 5 and 24 weeks postinfection, but control disease until the very late stages of the infection, when panIrgm-/- mice display increased mortality compared to wild-type mice. Collectively, our data demonstrate that disruptions in the balance between Irgm isoforms is more detrimental to the Mtb-infected host than total loss of Irgm-mediated host defense, a concept that also needs to be considered in the context of human Mtb susceptibility linked to IRGM polymorphisms.

Enteroviruses: The role of receptors in viral pathogenesis.

Enteroviruses are among the most common viral infectious agents of humans and cause a broad spectrum of illness, which can range from mild and self-limiting to severe. Severe outcomes of enteroviral infections can include aseptic meningitis, bronchitis, acute liver failure, hand-foot-mouth disease (HFMD), hemorrhagic conjunctivitis, or acute flaccid myelitis and other paralytic syndromes. Enteroviruses initiate their replicative life cycles by attaching to a broad range of cell surface receptors, which play direct roles in the clinical outcomes of enteroviral infections. In this chapter, we review the transmission and viral life cycle of enteroviruses and discuss the diverse cell surface receptors that facilitate enterovirus attachment, entry, or genome release.

Single-cell RNA-seq reveals transcriptomic heterogeneity mediated by host-pathogen dynamics in lymphoblastoid cell lines.

Lymphoblastoid cell lines (LCLs) are generated by transforming primary B cells with Epstein-Barr virus (EBV) and are used extensively as model systems in viral oncology, immunology, and human genetics research. In this study, we characterized single-cell transcriptomic profiles of five LCLs and present a simple discrete-time simulation to explore the influence of stochasticity on LCL clonal evolution. Single-cell RNA sequencing (scRNA-seq) revealed substantial phenotypic heterogeneity within and across LCLs with respect to immunoglobulin isotype; virus-modulated host pathways involved in survival, activation, and differentiation; viral replication state; and oxidative stress. This heterogeneity is likely attributable to intrinsic variance in primary B cells and host-pathogen dynamics. Stochastic simulations demonstrate that initial primary cell heterogeneity, random sampling, time in culture, and even mild differences in phenotype-specific fitness can contribute substantially to dynamic diversity in populations of nominally clonal cells.