Summary Pathogenic Yersinia, including Y. pestis, the agent of plague in humans, and Y. pseudotuberculosis, the related enteric pathogen, deliver virulence effectors into host cells via a prototypical type III secretion system to promote pathogenesis. These effectors, termed Yersinia outer proteins (Yops), modulate multiple host signaling responses. Studies in Y. pestis and Y. pseudotuberculosis have shown that YopM suppresses infection-induced inflammasome activation, however the underlying molecular mechanism is largely unknown. Here we show that YopM specifically restricts the pyrin inflammasome, which is triggered by the RhoA-inactivating enzymatic activities of YopE and YopT, in Y. pseudotuberculosis-infected macrophages. The attenuation of a yopM mutant is fully reversed in pyrin knock-out mice, demonstrating that YopM inhibits pyrin to promote virulence. Mechanistically, YopM recruits and activates the host kinases PRK1 and PRK2 to negatively regulate pyrin by phosphorylation. These results show how a virulence factor can hijack host kinases to inhibit effector-triggered pyrin inflammasome activation.
Interferons (IFNs) are cytokines that have pleiotropic effects and play important roles in innate and adaptive immunity. IFNs have broad antiviral properties and function by different mechanisms. IFNs fail to inhibit wild-type Adenovirus (Ad) replication in established cancer cell lines. In this study, we analyzed the effects of IFNs on Ad replication in normal human cells. Our data demonstrate that both IFNα and IFNγ blocked wild-type Ad5 replication in primary human bronchial epithelial cells (NHBEC) and TERT-immortalized normal human diploid fibroblasts (HDF-TERT). IFNs inhibited the replication of divergent adenoviruses. The inhibition of Ad5 replication by IFNα and IFNγ is the consequence of repression of transcription of the E1A immediate early gene product. Both IFNα and IFNγ impede the association of the transactivator GABP with the E1A enhancer region during the early phase of infection. The repression of E1A expression by IFNs requires a conserved E2F binding site in the E1A enhancer, and IFNs increased the enrichment of the E2F-associated pocket proteins, Rb and p107, at the E1A enhancer in vivo. PD0332991 (Pabociclib), a specific CDK4/6 inhibitor, dephosphoryles pocket proteins to promote their interaction with E2Fs and inhibited wild-type Ad5 replication dependent on the conserved E2F binding site. Consistent with this result, expression of the small E1A oncoprotein, which abrogates E2F/pocket protein interactions, rescued Ad replication in the presence of IFNα or IFNγ. Finally, we established a persistent Ad infection model in vitro and demonstrated that IFNγ suppresses productive Ad replication in a manner dependent on the E2F binding site in the E1A enhancer. This is the first study that probes the molecular basis of persistent adenovirus infection and reveals a novel mechanism by which adenoviruses utilize IFN signaling to suppress lytic virus replication and to promote persistent infection.
The Adenovirus (Ad) genome within the capsid is tightly associated with a virus-encoded, histone-like core protein—protein VII. Two other Ad core proteins, V and X/μ, also are located within the virion and are loosely associated with viral DNA. Core protein VII remains associated with the Ad genome during the early phase of infection. It is not known if naked Ad DNA is packaged into the capsid, as with dsDNA bacteriophage and herpesviruses, followed by the encapsidation of viral core proteins, or if a unique packaging mechanism exists with Ad where a DNA-protein complex is simultaneously packaged into the virion. The latter model would require an entirely new molecular mechanism for packaging compared to known viral packaging motors. We characterized a virus with a conditional knockout of core protein VII. Remarkably, virus particles were assembled efficiently in the absence of protein VII. No changes in protein composition were evident with VII−virus particles, including the abundance of core protein V, but changes in the proteolytic processing of some capsid proteins were evident. Virus particles that lack protein VII enter the cell, but incoming virions did not escape efficiently from endosomes. This greatly diminished all subsequent aspects of the infectious cycle. These results reveal that the Ad major core protein VII is not required to condense viral DNA within the capsid, but rather plays an unexpected role during virus maturation and the early stages of infection. These results establish a new paradigm pertaining to the Ad assembly mechanism and reveal a new and important role of protein VII in early stages of infection.
cWe applied a custom tiled microarray to examine murine gammaherpesvirus 68 (MHV68) polyadenylated transcript expression in a time course of de novo infection of fibroblast cells and following phorbol ester-mediated reactivation from a latently infected B cell line. During de novo infection, all open reading frames (ORFs) were transcribed and clustered into four major temporal groups that were overlapping yet distinct from clusters based on the phorbol ester-stimulated B cell reactivation time course. High-density transcript analysis at 2-h intervals during de novo infection mapped gene boundaries with a 20-nucleotide resolution, including a previously undefined ORF73 transcript and the MHV68 ORF63 homolog of Kaposi's sarcoma-associated herpesvirus vNLRP1. ORF6 transcript initiation was mapped by tiled array and confirmed by 5= rapid amplification of cDNA ends. The ϳ1.3-kb region upstream of ORF6 was responsive to lytic infection and MHV68 RTA, identifying a novel RTA-responsive promoter. Transcription in intergenic regions consistent with the previously defined expressed genomic regions was detected during both types of productive infection. We conclude that the MHV68 transcriptome is dynamic and distinct during de novo fibroblast infection and upon phorbol ester-stimulated B cell reactivation, highlighting the need to evaluate further transcript structure and the context-dependent molecular events that govern viral gene expression during chronic infection. Murine gammaherpesvirus 68 (MHV68; also known as ␥HV68 or murid herpesvirus 4) infection of mice is a model pathogenesis system for gammaherpesviruses such as Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/ HHV-8) and Epstein-Barr virus (EBV) (5, 20). The life cycles of these lymphotropic and transforming viruses in the host involve the initial transit across a mucosal barrier to gain access to and establish latency in a leukocyte reservoir, followed by intermittent reactivation and dissemination to the mucosal surfaces for spread to new hosts (32,74,77,82).Replication at the site of primary infection impacts MHV68 dissemination and latency establishment in secondary lymphoid tissues of mice. The absence of proteins essential for lytic replication, such as the viral transactivator ORF50/mRTA (61) and the ORF6/single-stranded DNA-binding protein (ssDBP) (49), or the inhibition of viral DNA replication by the administration of cidofovir (62) impairs the establishment of latency in the splenic B cell compartment. In addition, virus replication at the mucosa triggers the innate and adaptive immune responses critical for host control (6,45,72,73). These responses might play a critical role in the recruitment and activation of target cells such as dendritic cells that precede dissemination to distal reservoirs, such as splenic B cells and peritoneal macrophages (5, 25). Thus, the lytic gene expression program in newly infected cells that are permissive for productive infection is an important aspect of pathogenesis.Reactivation from latency is a...
Mare Moscoviense (148°E, 27°N) is one of the few large maria on the lunar farside, with the thinnest crust and a positive gravity anomaly. In this paper, the Chang’E-2 Microwave Sounder (CELMS) data was employed to study the microwave thermal emission features of mare basalts in Moscoviense Basin. The time angle and linear interpolation method are used to generate the brightness temperature (TB) maps at noon and night, as well as the TB difference (dTB) map. The obtained important results are as follows. (1) A new geologic map is generated with the TB and dTB maps using the maximum likelihood method, which gives a new expression about the basaltic units in Mare Moscoviense compared to the optical results; (2) the substrate temperature of Moscoviense Basin is likely warmer than what we know; (3) unit Ihtm (a Late (?) Imbrian, mid- to high-Ti, high-Fe basalt) is re-understood as two independent volcanic features with their own fissures; (4) the dTB maps firstly indicate that the depth lunar regolith is homogeneous in the highlands surrounding Mare Moscoviense, at least in the microwave domain, and secondly that there exists a special material bringing about the low dTB anomaly in the shallow layer of the east highlands. The results will be of great significance to better understand the basaltic volcanism of the Moon.
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