Infection of cells with DNA viruses triggers innate immune responses mediated by DNA sensors. cGMP-AMP synthase (cGAS) is a key DNA sensor that produces the cyclic dinucleotide cGMP-AMP (cGAMP) upon activation, which binds to and activates stimulator of interferon genes (STING), leading to IFN production and an antiviral response. Kaposi's sarcoma-associated herpesvirus (KSHV) is a DNA virus that is linked to several human malignancies. We report that KSHV infection activates the cGAS-STING pathway, and that cGAS and STING also play an important role in regulating KSHV reactivation from latency. We screened KSHV proteins for their ability to inhibit this pathway and identified six viral proteins that block IFN-β activation through this pathway. This study is the first report identifying multiple viral proteins encoded by a human DNA virus that inhibit the cGAS-STING DNA sensing pathway. One such protein, viral interferon regulatory factor 1 (vIRF1), targets STING by preventing it from interacting with TANK binding kinase 1 (TBK1), thereby inhibiting STING's phosphorylation and concomitant activation, resulting in an inhibition of the DNA sensing pathway. Our data provide a unique mechanism for the negative regulation of STING-mediated DNA sensing. Moreover, the depletion of vIRF1 in the context of KSHV infection prevented efficient viral reactivation and replication, and increased the host IFN response to KSHV. The vIRF1-expressing cells also inhibited IFN-β production following infection with DNA pathogens. Collectively, our results demonstrate that gammaherpesviruses encode inhibitors that block cGAS-STING-mediated antiviral immunity, and that modulation of this pathway is important for viral transmission and the lifelong persistence of herpesviruses in the human population.aposi's sarcoma-associated herpesvirus (KSHV/HHV8) is the etiological agent of several human malignancies, including Kaposi's sarcoma (KS), multicentric Castleman's disease, and primary effusion lymphoma (1, 2). Evasion of the host innate immune response is essential for viral infection, replication, latency, transmission, and lifelong persistence.A member of the gammaherpesvirus subfamily, KSHV contains a large dsDNA genome that encodes for more than 80 ORFs. Different pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), nucleotide-binding domain leucine-rich repeat-containing (NLR) proteins, and retinoic acid-inducible gene-I-like receptors (RLRs), are activated upon KSHV infection in different cell types (3-5). As is the case with many pathogens, multiple PRRs can detect an incoming pathogen in the cell. Depending on the cell type, detection of viral DNA may take place in the nucleus (6) or in the cytoplasm due to premature release of the herpesviral DNA into the cytoplasm (7). It is plausible that defective herpesvirus virions release their genomic contents into the cytoplasm rather than the nucleus and that this viral DNA triggers cytosolic DNA sensors to be activated. Additionally, HSV-1 infection induces mitochon...
The innate immune system is important for control of infections, including herpesvirus infections. Intracellular DNA potently stimulates antiviral IFN responses. It is known that plasmacytoid dendritic cells sense herpesvirus DNA in endosomes via TLR9, and that non-immune tissue cells can sense herpesvirus DNA in the nucleus. However, it remains unknown how and where myeloid cells, like macrophages and conventional dendritic cells, detect infections with herpesviruses. Here we demonstrate that the HSV-1 capsid was ubiquitinated in the cytosol and degraded by the proteasome, hence releasing genomic DNA into the cytoplasm for detection by DNA sensors. In this context, the DNA sensor IFI16 is important for induction of IFN-β in human macrophages after infection with HSV-1 and CMV. Viral DNA localized to the same cytoplasmic regions as IFI16, with DNA sensing being independent of viral nuclear entry. Thus, proteasomal degradation of herpesvirus capsids releases DNA to the cytoplasm for recognition by DNA sensors.
Immunotherapy with T cells expressing the chimeric antigen receptor (CAR) specific for the CD19 antigen (CD19.CAR-Ts) is a very effective treatment in B cell lymphoid malignancies. However, B cell aplasia and cytokine release syndrome (CRS) secondary to the infusion of CD19.CAR-Ts remain significant drawbacks. The inclusion of safety switches into the vector encoding the CAR is seen as the safest method to terminate the effects of CD19.CAR-Ts in case of severe toxicities or after achieving long-term sustained remissions. By contrast, the complete elimination of CD19.CAR-Ts when CRS occurs may jeopardize clinical responses as CRS and antitumor activity seem to concur. We have demonstrated, in a humanized mouse model, that the inducible caspase-9 (iC9) safety switch can eliminate CD19.CAR-Ts in a dose-dependent manner, allowing either a selective containment of CD19.CAR-T expansion in case of CRS or complete deletion on demand granting normal B cell reconstitution.
The nucleotide-binding and oligomerization, leucine-rich repeat (NLR) family of proteins sense microbial infections and activate the inflammasome, a multi-protein complex that promotes microbial clearance. Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to several human malignancies. We report that KSHV Orf63 is a viral homolog of human NLRP1. Orf63 blocked NLRP1-dependent innate immune responses, including caspase-1 activation and processing of interleukin (IL)-1β and IL-18. KSHV Orf63 interacted with NLRP1, NLRP3, and NOD2. Inhibition of Orf63 expression resulted in increased expression of IL-1β during the KSHV lifecycle. Furthermore, inhibition of NLRP1 was necessary for efficient reactivation and generation of progeny virus. The viral homolog subverts the function of cellular NLRs, which suggests that modulation of NLR-mediated innate immunity is important for the life-long persistence of herpesviruses.
Red algae of the Bostrychia radicans/B. moritziana complex are common in warm temperate areas of North America. Phylogenetic analysis of both plastid and mitochondrial DNA sequence data revealed seven distinct evolutionary lineages among worldwide samples. Although only two haplotypes (plastid and mitochondrial) were found in Pacific Mexico, four plastid and 11 mitochondrial haplotypes were found in a similar latitudinal spread along the Atlantic coast of the United States. On the U.S. Atlantic coast only one plastid haplotype was found in northern samples (Connecticut to North Carolina), whereas further south several plastid haplotypes were found. Phylogenetic analyses suggested that this single plastid haplotype found among northern samples could be the result of a northward range expansion possibly since the last glacial maximum. Crossing data of samples within the same evolutionary lineage showed that samples with the same plastid haplotypes were generally sexually compatible; samples with different plastid haplotypes were reproductively isolated. Samples from Pacific Mexico were partially reproductively compatible with some samples from the Atlantic USA (plastid haplotype C) and were more closely related to these samples than these U.S. samples were to other U.S. Atlantic samples. Compatible solute types mirrored the plastid haplotype, with plastid haplotype B having only sorbitol, whereas all other haplotypes also contained dulcitol. Samples from Atlantic USA, with different plastid haplotypes (e.g. B vs. C), but within the same evolutionary lineage, were reproductively isolated from each other. Data indicate that reproductive isolation occurs between and within supported evolutionary lineages and that the number of cryptic species is high.
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