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Gallid alpha-herpesvirus 1, also known as avian infectious laryngotracheitis virus (ILTV), continues to cause huge economic losses to the poultry industry worldwide. Similar to that of other herpesvirus-encoded proteins, the expression of viral genes encoded by ILTV is regulated by a cascade, and the underlying regulatory mechanism remains largely unclear. The viral immediate-early (IE) gene ICP4 plays a prominent role in the initiation of the transcription of early and late genes during ILTV replication. In this study, we identified AP-1 as the key regulator of the transcription of ILTV genes by bioinformatics analysis of genome-wide transcriptome data. Subsequent functional studies of the key members of the AP-1 family revealed that Fos, but not Jun, regulates ILTV infection through AP-1 since knockdown of Fos, but not Jun, by gene silencing significantly reduced ICP4 transcription and subsequent viral genome replication and virion production. Using several approaches, we identified ICP4 as a bona fide target gene of Fos that regulated Fos and has Fos response elements within its promoter. Neither the physical binding of Jun to the promoter of ICP4 nor the transcriptional activity of Jun was observed. In addition, knockdown of Fos reduced the transcription of MDH1 and ATP5A1, genes encoding two host rate-limiting enzymes essential for the production of the TCA intermediates OAA and ATP. The biological significance of the transcriptional regulation of MDH1 and ATP5A1 by Fos in ILTV infection was supported by the fact that anaplerosis of OAA and ATP rescued both ICP4 transcription and virion production in infected cells under when Fos was silenced. Our study identified the transcription factor Fos as a key regulator of ILTV infection through its transcription factor function on both the virus and host sides, improving the current understanding of both avian herpesvirus–host interactions and the roles of AP-1 in viral infection.

Although therapeutics targeting viral metabolic processes have been considered as promising strategies to treat herpesvirus infection, the metabolic requirements of gallid alphaherpesvirus 1 (ILTV), which is economically important to the poultry industry worldwide, remain largely unknown. Using the ILTV-susceptible but nonpermissive chicken cell line DF-1 and the ILTV-permissive chicken cell line LMH as models, the present study explored the metabolic requirements of ILTV by global transcriptome analysis and metabolome assays of ILTV infected cell lines in combination with a set of functional validations. The extensive metabolic exploration demonstrated that ILTV infection tended to promote a metabolic shift from glycolysis to fatty acid (FA) and nucleotide biosynthesis and utilizes glutamine independently of glutaminolysis, without significant general effect on the TCA cycle. In addition, different metabolic pathways were found to be required for distinct stages of ILTV replication. Glucose and glutamine were required for the transcription of viral immediate early gene ICP4 and subsequent steps of viral replication. However, FA synthesis was essential for assembly but not required for other upstream steps of ILTV replication. Moreover, the metabolic requirements of ILTV infection revealed in chicken cell lines were further validated in chicken primary cells isolated from chicken embryo kidneys and chicken embryo livers. The present study, to the best of our knowledge, provides the first global metabolic profile of animal herpesviruses and illustrates the main characteristics of the metabolic program of ILTV., Author summary Virus-host metabolic interaction is a promising target for antiviral therapeutics. Explorations of viral-induced shifts of host metabolism could reveal substrates that are uniquely required at high levels for viral replication and have been conducted for many virus species in the last decade. Herpesviruses are commonly treated with nucleotide analogs in the clinic. However, recent metabolomics studies suggest that different herpesvirus species can execute distinct metabolic programs in host cells despite their high conservation of biological characteristics. To understand why herpesviruses have evolved to alter different metabolic processes in host cells and refine the antiviral treatments by targeting more species-specific metabolic requirements, metabolomic explorations of more herpesvirus species are needed. However, comprehensive exploration of virus-host metabolic interaction has only been limited to a few human herpesviruses. Gallid alphaherpesvirus 1 (ILTV), an economically important alphaherpesvirus to the poultry industry worldwide, is thought to be an ancient example of alphaherpesviruses. Here we reveal the global metabolic requirements of ILTV and highlight the common and unique metabolic characteristics of ILTV by comparing with the known global metabolic profiles of several human herpesviruses. Our study may increase current understanding of herpesvirus-host metabolic interplay and inspire further studies in this direction.

37662RM1 and 37662RM2 are two phenotypically different, carbapenem-resistant mutants of Acinetobacter baumannii 37662 isolate following selection with meropenem (MEM) at sub-inhibitory concentrations. 37662RM2 lacks capsule synthesis and shows dramatically increased biofilm formation, while 37662RM1 shows merely impaired capsule synthesis. Here we report that 37662RM1 and RM2 have transcription profiles that are different from those of their starting strain, 37662WT. There were far more differentially expressed genes in 37662RM2 than in 37662RM1. The capsule polysaccharide (CPS) synthesis-required genes (itrA2, gtr5, psaA, psaB, psaC, psaD, psaE, psaF, kpsS2, wzx, wzy, wza, wzb, and wzc) showed reduced transcription levels in 37662RM2, which may at least partially explain the loss of capsule synthesis. The csu operon genes responsible for pili assembly and their regulator genes bfmR-bfmS were over-expressed in 37662RM2. This result together with the established critical roles of these genes in biofilm formation provide solid evidence that up-regulation of csu and bfmR-bfmS should be considered responsible for the enhanced biofilm formation in 37662RM2. ISAba1 was found to insert into the intergenic region between the csu operon and the acrR gene and should be responsible for the significant up-regulation of acrR, which was proposed to be associated with biofilm formation. Genome sequencing revealed that the ISAba1 upstream bla OXA- 508 (a new member of bla OXA- 51-like) and acrR were duplicated, suggesting a replicative transposition event. Altogether, the phenotype divergence driven by MEM selection mainly occurs at the RNA level and the transposition of ISAba1 plays an important role in modulating gene expression to adapt to the environment.

Apoptosis is a common innate defense mechanism of host cells against viral infection and is therefore suppressed by many viruses, including herpes simplex virus (HSV), via various strategies. A recent in vivo study reported the apoptosis of remote uninfected cells during Gallid herpesvirus 1 (GaHV-1) infection, yet little is known about this previously unknown aspect of herpesvirus-host interactions. The aim of the present study was to investigate the apoptosis of uninfected host cells during GaHV-1 infection. The present study used in vitro and in ovo models, which avoided potential interference by host antiviral immunity, and demonstrated that this GaHV-1–host interaction is independent of host immune responses and important for both the pathological effect of viral infection and early viral dissemination from the primary infection site to distant tissues. Further, we revealed that GaHV-1 infection triggers this process in a paracrine-regulated manner. Using genome-wide transcriptome analyses in combination with a set of functional studies, we found that this paracrine-regulated effect requires the repression of p53 activity in uninfected cells. In contrast, the activation of p53 not only prevented the apoptosis of remote uninfected cells and subsequent pathological damage induced by GaHV-1 infection but also delayed viral dissemination significantly. Moreover, p53 activation repressed viral replication both in vitro and in ovo, suggesting that dual cell-intrinsic mechanisms underlie the suppression of GaHV-1 infection by p53 activation. This study uncovers the mechanism underlying the herpesvirus-triggered apoptosis of remote host cells and extends our understanding of both herpesvirus-host interactions and the roles of p53 in viral infection. IMPORTANCE It is well accepted that herpesviruses suppress the apoptosis of host cells via various strategies to ensure sustained viral replication during infection. However, a recent in vivo study reported the apoptosis of remote uninfected cells during GaHV-1 infection. The mechanism and the biological meaning of this unexpected herpesvirus-host interaction are unclear. This study uncovers the mechanisms of herpesvirus-triggered apoptosis in uninfected cells and may also contribute to a mechanistic illustration of paracrine-regulated apoptosis induced by other viruses in uninfected host cells.

Homografts and synthetic grafts are used in surgery for congenital heart disease (CHD). Determining these materials' mechanical properties will aid in understanding tissue behavior when subjected to abnormal CHD hemodynamics. Homograft tissue samples from anterior/posterior aspects, of ascending/descending aorta (AA, DA), innominate artery (IA), left subclavian artery (LScA), left common carotid artery (LCCA), main/left/right pulmonary artery (MPA, LPA, RPA), and synthetic vascular grafts, were obtained in three orientations: circumferential, diagonal (45 deg relative to circumferential direction), and longitudinal. Samples were subjected to uniaxial tensile testing (UTT). True strain-Cauchy stress curves were individually fitted for each orientation to calibrate Fung model. Then, they were used to calibrate anisotropic Holzapfel–Gasser model (R2 > 0.95). Most samples demonstrated a nonlinear hyperelastic strain–stress response to UTT. Stiffness (measured by tangent modulus at different strains) in all orientations were compared and shown as contour plots. For each vessel segment at all strain levels, stiffness was not significantly different among aspects and orientations. For synthetic grafts, stiffness was significantly different among orientations (p

Genome-wide comparisons across 10 species from algae Guillardia theta to mammal human indicated that Caenorhabditis elegans and Caenorhabditis briggsae were highly enriched for glycine-rich secreted peptides (GRSPs) (110 GRSPs in C. elegans and 93 in C. briggsae) in this study. Chromosomal mapping showed that most GRSPs were clustered on the two nematode genomes [103 (93.64%) in C. elegans and 82 (88.17%) in C. briggsae], which could be divided into 18 cluster units in C. elegans and 13 in C. briggsae, respectively. Except for four C. elegans GRSPs clusters without matching clusters in C. briggsae, all other GRSPs clusters had paired synteny block between the two nematode genomes. Analyzing transcriptome datasets quantified by microarray indicated extensive genome-wide co-expression of GRSPs clusters after C. elegans infections. Highly homologous coding sequences and conserved exon-intron structures indicated that GRSPs tight clusters were likely derived from local DNA duplications. Phylogenetic conservation of synteny blocks between their genomes, co-expression of GRSPs clusters after C. elegans infections, and strong purifying selections of coding sequences may indicate evolutionary constraints acting on C. elegans to guarantee that C. elegans could mount rapid systematic responses to infections by co-expression, co-regulation, and co-functionality of GRSPs clusters.