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1.
Clin Transplant ; 38(5): e15339, 2024 May.
Article in English | MEDLINE | ID: mdl-38775413

ABSTRACT

Simultaneous pancreas-kidney transplantation (SPKT) is the best treatment for selected individuals with type 1 diabetes mellitus and end-stage renal disease. Despite advances in surgical techniques, donor and recipient selection, and immunosuppressive therapies, SPKT remains a complex procedure with associated surgical complications and adverse consequences. We conducted a retrospective study that included 263 SPKT procedures performed between May 2000, and December 2022. A total of 65 patients (25%) required at least one relaparotomy, resulting in an all-cause relaparotomy rate of 2.04 events per 100 in-hospital days. Lower donor body mass index was identified as an independent factor associated with reoperation (OR .815; 95% CI:  .725-.917, p = .001). Technical failure (TF) occurred in 9.9% of cases, primarily attributed to pancreas graft thrombosis, intra-abdominal infections, bleeding, and anastomotic leaks. Independent predictors of TF at 90 days included donor age above 36 years (HR 2.513; 95% CI 1.162-5.434), previous peritoneal dialysis (HR 2.503; 95% CI 1.149-5.451), and specific pancreas graft reinterventions. The findings highlight the importance of carefully considering donor and recipient factors in SPKT. The incidence of TF in our study population aligns with the recent series. Continuous efforts should focus on identifying and mitigating potential risk factors to enhance SPKT outcomes, thereby reducing post-transplant complications.


Subject(s)
Diabetes Mellitus, Type 1 , Graft Survival , Kidney Failure, Chronic , Kidney Transplantation , Pancreas Transplantation , Postoperative Complications , Humans , Female , Male , Pancreas Transplantation/adverse effects , Retrospective Studies , Kidney Transplantation/adverse effects , Adult , Postoperative Complications/etiology , Follow-Up Studies , Risk Factors , Kidney Failure, Chronic/surgery , Prognosis , Diabetes Mellitus, Type 1/surgery , Diabetes Mellitus, Type 1/complications , Graft Rejection/etiology , Middle Aged , Reoperation/statistics & numerical data , Kidney Function Tests , Survival Rate , Glomerular Filtration Rate
2.
Transplant Proc ; 2024 Feb 13.
Article in English | MEDLINE | ID: mdl-38355372

ABSTRACT

Transplant renal artery stenosis (TRAS) is a well-recognized vascular complication after kidney transplantation, with an incidence ranging from 1% to 23%. TRAS often presents with clinical features such as refractory hypertension, de novo hypertension, allograft dysfunction, and the presence of a bruit over the graft. A rare manifestation of TRAS is flash pulmonary edema. Here, we present a case of a 37-year-old male who received a living donor kidney. Four years after the transplant, he presented with acute kidney injury, hypertensive crisis, and flash pulmonary edema. Initially, methylprednisolone pulses were administered due to suspicion of acute rejection, which was later ruled out after a kidney graft biopsy. Computed tomography angiography showed findings suggesting stenosis or thrombus in the renal artery. The patient developed sudden acute pulmonary edema, requiring hemodialysis, with notable clinical improvement. Subsequently, stent placement was performed without complications, resulting in the complete recovery of renal function and effective blood pressure control. The incidence of renal artery stenosis is higher in living donor kidney transplantation, mainly due to technical complexities during surgery. Acute presentations, such as flash edema, are exceptionally rare but can occur years after transplantation. Prompt intervention can lead to favorable outcomes.

3.
Cureus ; 15(2): e35579, 2023 Feb.
Article in English | MEDLINE | ID: mdl-37007362

ABSTRACT

When the left cardinal vein fails to involute during fetal life, a persistent left superior vena cava (PLSVC) develops. PLSVC is a rare vascular anomaly, and the reported incidence is 0.3-0.5% in healthy individuals. It is usually asymptomatic and does not cause hemodynamic disturbances unless associated with cardiac malformations. If the PLSVC drains adequately into the right atrium and there are no cardiac abnormalities, catheterization of this vessel, including temporary and cuffed HD catheter insertion, is deemed safe. We present the case of a 70-year-old woman with acute kidney injury (AKI), in which the necessity to place an HD central venous catheter (CVC) through the left internal jugular vein led to the discovery of a PLSVC. Once it was shown that the vessel was adequately draining into the right atrium, this catheter was changed to a cuffed tunneled HD catheter, which was successfully utilized for HD sessions for three months and removed after the recuperation of renal function without complications.

4.
Cureus ; 15(2): e35445, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36994281

ABSTRACT

Peritoneal dialysis-associated-peritonitis remains a major concern, increasing patient morbidity and mortality. Empirical antibiotics should be quickly started to allow a rapid resolution of symptoms and preservation of the peritoneal membrane. We report a case of peritoneal dialysis-associated-peritonitis due to Prevotella salivae and Corynebacterium jeikeium, in a 51-year-old male. Suspected peritonitis led to an immediate prescription of vancomycin and ceftazidime, with no clinical improvement. Prevotella is difficult to identify in culture since it's a gram-negative anaerobic bacterium, so metronidazole administration was delayed over days. New diagnostic techniques have been explored for the early diagnosis of peritonitis, including polymerase chain reaction (PCR) for bacterial DNA fragments. A multiplex PCR panel that includes Prevotella, already available for other applications, could be an advantage in cases like this.

5.
Cureus ; 14(10): e30800, 2022 Oct.
Article in English | MEDLINE | ID: mdl-36447734

ABSTRACT

Pneumatosis intestinalis (PI) and aeroportia have been rarely described in hemodialysis patients. We present a case of a 64-year-old woman on regular hemodialysis who presented with abdominal pain, vomiting, and diarrhea. Abdominal CT showed pneumatosis intestinalis and aeroportia suggestive of ischemic abnormalities. In this case, given the absence of transmural necrosis or bowel perforation, aeroportia seemed to be caused by nonocclusive mesenteric ischemia (NOMI), an increasingly recognized complication in hemodialysis patients. The patient was proposed for emergent exploratory laparotomy; however, she had a fatal outcome. Hemodialysis-dependent patients should be considered at risk of the "low-flow syndrome" of mesenteric arterial circulation. Prevention is crucial, and early detection of these entities is important for prompt diagnosis and management of mesenteric ischemia.

6.
Mol Cell Proteomics ; 21(3): 100208, 2022 03.
Article in English | MEDLINE | ID: mdl-35091090

ABSTRACT

In trypanosomatids, transcription is polycistronic and all mRNAs are processed by trans-splicing, with export mediated by noncanonical mechanisms. Although mRNA export is central to gene regulation and expression, few orthologs of proteins involved in mRNA export in higher eukaryotes are detectable in trypanosome genomes, necessitating direct identification of protein components. We previously described conserved mRNA export pathway components in Trypanosoma cruzi, including orthologs of Sub2, a component of the TREX complex, and eIF4AIII (previously Hel45), a core component of the exon junction complex (EJC). Here, we searched for protein interactors of both proteins using cryomilling and mass spectrometry. Significant overlap between TcSub2 and TceIF4AIII-interacting protein cohorts suggests that both proteins associate with similar machinery. We identified several interactions with conserved core components of the EJC and multiple additional complexes, together with proteins specific to trypanosomatids. Additional immunoisolations of kinetoplastid-specific proteins both validated and extended the superinteractome, which is capable of supporting RNA processing from splicing through to nuclear export and cytoplasmic events. We also suggest that only proteomics is powerful enough to uncover the high connectivity between multiple aspects of mRNA metabolism and to uncover kinetoplastid-specific components that create a unique amalgam to support trypanosome mRNA maturation.


Subject(s)
Proteomics , Trypanosoma cruzi , Active Transport, Cell Nucleus , RNA , RNA Splicing , RNA Transport
7.
Article in English | MEDLINE | ID: mdl-32156011

ABSTRACT

Hydrocarbon bioremediation in anoxic sediment layers is still challenging not only because it involves metabolic pathways with lower energy yields but also because the production of biosurfactants that contribute to the dispersion of the pollutant is limited by oxygen availability. This work aims at screening populations of culturable hydrocarbonoclastic and biosurfactant (BSF) producing bacteria from deep sub-seafloor sediments (mud volcanos from Gulf of Cadiz) and estuarine sub-surface sediments (Ria de Aveiro) for strains with potential to operate in sub-oxic conditions. Isolates were retrieved from anaerobic selective cultures in which crude oil was provided as sole carbon source and different supplements were provided as electron acceptors. Twelve representative isolates were obtained from selective cultures with deep-sea and estuary sediments, six from each. These were identified by sequencing of 16S rRNA gene fragments belonging to Pseudomonas, Bacillus, Ochrobactrum, Brevundimonas, Psychrobacter, Staphylococcus, Marinobacter and Curtobacterium genera. BSF production by the isolates was tested by atomized oil assay, surface tension measurement and determination of the emulsification index. All isolates were able to produce BSFs under aerobic and anaerobic conditions, except for isolate DS27 which only produced BSF under aerobic conditions. These isolates presented potential to be applied in bioremediation or microbial enhanced oil recovery strategies under conditions of oxygen limitation. For the first time, members of Ochrobactrum, Brevundimonas, Psychrobacter, Staphylococcus, Marinobacter and Curtobacterium genera are described as anaerobic producers of BSFs.


Subject(s)
Hydrocarbons , Petroleum , Surface-Active Agents , Water Pollutants, Chemical , Bacteria , Biodegradation, Environmental , Geologic Sediments , RNA, Ribosomal, 16S
8.
Elife ; 82019 08 12.
Article in English | MEDLINE | ID: mdl-31403400

ABSTRACT

Knowledge of the host factors required for norovirus replication has been hindered by the challenges associated with culturing human noroviruses. We have combined proteomic analysis of the viral translation and replication complexes with a CRISPR screen, to identify host factors required for norovirus infection. The core stress granule component G3BP1 was identified as a host factor essential for efficient human and murine norovirus infection, demonstrating a conserved function across the Norovirus genus. Furthermore, we show that G3BP1 functions in the novel paradigm of viral VPg-dependent translation initiation, contributing to the assembly of translation complexes on the VPg-linked viral positive sense RNA genome by facilitating ribosome recruitment. Our data uncovers a novel function for G3BP1 in the life cycle of positive sense RNA viruses and identifies the first host factor with pan-norovirus pro-viral activity.


Subject(s)
DNA Helicases/metabolism , Host-Pathogen Interactions , Norovirus/growth & development , Poly-ADP-Ribose Binding Proteins/metabolism , Protein Biosynthesis , RNA Helicases/metabolism , RNA Recognition Motif Proteins/metabolism , Viral Proteins/biosynthesis , Animals , Caliciviridae Infections , Cell Line , Humans , Mice
9.
Nat Commun ; 10(1): 3396, 2019 07 30.
Article in English | MEDLINE | ID: mdl-31363119

ABSTRACT

Species' differences in cellular factors limit avian influenza A virus (IAV) zoonoses and human pandemics. The IAV polymerase, vPol, harbors evolutionary sites to overcome restriction and determines virulence. Here, we establish host ANP32A as a critical driver of selection, and identify host-specific ANP32A splicing landscapes that predict viral evolution. We find that avian species differentially express three ANP32A isoforms diverging in a vPol-promoting insert. ANP32As with shorter inserts interact poorly with vPol, are compromised in supporting avian-like IAV replication, and drive selection of mammalian-adaptive vPol sequences with distinct kinetics. By integrating selection data with multi-species ANP32A splice variant profiling, we develop a mathematical model to predict avian species potentially driving (swallow, magpie) or maintaining (goose, swan) mammalian-adaptive vPol signatures. Supporting these predictions, surveillance data confirm enrichment of several mammalian-adaptive vPol substitutions in magpie IAVs. Profiling host ANP32A splicing could enhance surveillance and eradication efforts against IAVs with pandemic potential.


Subject(s)
Influenza A virus/enzymology , Influenza in Birds/genetics , RNA Splicing , RNA-Binding Proteins/genetics , Viral Proteins/metabolism , Amino Acid Sequence , Animals , Birds , Chickens , Humans , Influenza A Virus, H1N1 Subtype , Influenza A virus/chemistry , Influenza A virus/genetics , Influenza A virus/physiology , Influenza in Birds/metabolism , Influenza in Birds/virology , Influenza, Human/genetics , Influenza, Human/metabolism , Influenza, Human/virology , Nuclear Proteins , Protein Binding , RNA-Binding Proteins/chemistry , RNA-Binding Proteins/metabolism , Viral Proteins/chemistry , Viral Proteins/genetics , Virus Replication
10.
Proc Natl Acad Sci U S A ; 116(35): 17399-17408, 2019 08 27.
Article in English | MEDLINE | ID: mdl-31391303

ABSTRACT

Dynamic small ubiquitin-like modifier (SUMO) linkages to diverse cellular protein groups are critical to orchestrate resolution of stresses such as genome damage, hypoxia, or proteotoxicity. Defense against pathogen insult (often reliant upon host recognition of "non-self" nucleic acids) is also modulated by SUMO, but the underlying mechanisms are incompletely understood. Here, we used quantitative SILAC-based proteomics to survey pan-viral host SUMOylation responses, creating a resource of almost 600 common and unique SUMO remodeling events that are mounted during influenza A and B virus infections, as well as during viral innate immune stimulation. Subsequent mechanistic profiling focused on a common infection-induced loss of the SUMO-modified form of TRIM28/KAP1, a host transcriptional repressor. By integrating knockout and reconstitution models with system-wide transcriptomics, we provide evidence that influenza virus-triggered loss of SUMO-modified TRIM28 leads to derepression of endogenous retroviral (ERV) elements, unmasking this cellular source of "self" double-stranded (ds)RNA. Consequently, loss of SUMO-modified TRIM28 potentiates canonical cytosolic dsRNA-activated IFN-mediated defenses that rely on RIG-I, MAVS, TBK1, and JAK1. Intriguingly, although wild-type influenza A virus robustly triggers this SUMO switch in TRIM28, the induction of IFN-stimulated genes is limited unless expression of the viral dsRNA-binding protein NS1 is abrogated. This may imply a viral strategy to antagonize such a host response by sequestration of induced immunostimulatory ERV dsRNAs. Overall, our data reveal that a key nuclear mechanism that normally prevents aberrant expression of ERV elements (ERVs) has been functionally co-opted via a stress-induced SUMO switch to augment antiviral immunity.


Subject(s)
Endogenous Retroviruses/immunology , Host-Pathogen Interactions , Influenza A virus/physiology , Influenza, Human/metabolism , Influenza, Human/virology , Microbial Interactions , SUMO-1 Protein/metabolism , Animals , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate/immunology , Models, Biological , RNA, Double-Stranded/metabolism , Sumoylation , Tripartite Motif-Containing Protein 28/metabolism , Virus Replication
11.
An Bras Dermatol ; 93(1): 148-150, 2018.
Article in English | MEDLINE | ID: mdl-29641722

ABSTRACT

Porphyria cutanea tarda has a complex etiology with genetic factors not completely elucidated. The miscegenation of the Brazilian population has important implications in the predisposition to diseases. There are no studies concerning the genetic ancestry of patients with porphyria cutanea tarda from a mixed population. Thirty patients living in Rio de Janeiro with sporadic porphyria cutanea tarda were studied for the genetic ancestry through informative markers - INDELS. There was a significant predominance of European ancestry across the sample of patients with porphyria cutanea tarda (70.2%), and a small contribution of African and Amerindian ancestry, 20.1% and 10.9%, respectively.


Subject(s)
Porphyria Cutanea Tarda/genetics , White People/genetics , Brazil/ethnology , Cross-Sectional Studies , Genetic Markers/genetics , Genotype , Humans
12.
An. bras. dermatol ; 93(1): 148-150, Jan.-Feb. 2018. tab, graf
Article in English | LILACS | ID: biblio-1038264

ABSTRACT

Abstract: Porphyria cutanea tarda has a complex etiology with genetic factors not completely elucidated. The miscegenation of the Brazilian population has important implications in the predisposition to diseases. There are no studies concerning the genetic ancestry of patients with porphyria cutanea tarda from a mixed population. Thirty patients living in Rio de Janeiro with sporadic porphyria cutanea tarda were studied for the genetic ancestry through informative markers - INDELS. There was a significant predominance of European ancestry across the sample of patients with porphyria cutanea tarda (70.2%), and a small contribution of African and Amerindian ancestry, 20.1% and 10.9%, respectively.


Subject(s)
Humans , Porphyria Cutanea Tarda/genetics , White People/genetics , Brazil/ethnology , Genetic Markers/genetics , Cross-Sectional Studies , Genotype
13.
Int J Legal Med ; 132(5): 1313-1315, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29356946

ABSTRACT

In this work, the YfilerPlus kit was used to investigate a sample of 258 males from Rio de Janeiro. In addition, the previous database of 760 Yfiler profiles deposited in the YHRD was updated to 1610. YfilerPlus markers showed a high haplotype diversity (0.99997), with only one haplotype shared by two individuals. When only considering the Yfiler markers, the haplotype diversity was slightly lower (0.99976), with 5 haplotypes shared by two individuals and 1 haplotype shared by three individuals. Low genetic distances were found between the Rio de Janeiro and European populations as well as the European/Hispanic American samples.


Subject(s)
Chromosomes, Human, Y/genetics , Ethnicity/genetics , Genetic Variation , Genetics, Population , Microsatellite Repeats , DNA Fingerprinting , Haplotypes , Humans , Male , White People
14.
Cell Rep ; 20(11): 2538-2546, 2017 Sep 12.
Article in English | MEDLINE | ID: mdl-28903035

ABSTRACT

Host restriction of influenza A virus limits pandemic emergence. The viral RNA polymerase (vPol) is an essential enzyme that must adapt for avian viruses to replicate in humans. Species differences in host ANP32A dictate adaptation: human ANP32A lacks an uncharacterized 33 amino-acid insertion that is present in avian ANP32A. Here, we uncover important contributions of host SUMOylation to vPol activity, including avANP32A function. We also identify a hydrophobic SUMO interaction motif (SIM)-like sequence unique to avANP32A that critically supports avian-signature vPol. Unrelated SIM sequences partially recapitulate this function when introduced into huANP32A. By investigating ANP32A-vPol interactions, we find that huANP32A interacts weakly with both human- and avian-signature vPols, while the hydrophobic motif of avANP32A promotes stronger interactions. Furthermore, we identify a highly acidic stretch in avANP32A that constitutes a major site of vPol interaction. Our data suggest compensatory mechanisms underlying vPol adaptation to host ANP32A independent of species-specific interactions.


Subject(s)
DNA-Directed RNA Polymerases/metabolism , Influenza A virus/enzymology , Intracellular Signaling Peptides and Proteins/metabolism , Amino Acid Sequence , Animals , Chickens , Humans , Intracellular Signaling Peptides and Proteins/chemistry , Nuclear Proteins , RNA-Binding Proteins , Sumoylation
15.
J Virol ; 91(21)2017 11 01.
Article in English | MEDLINE | ID: mdl-28814525

ABSTRACT

Rational characterization of virulence and host-adaptive markers in the multifunctional influenza A virus NS1 protein is hindered by a lack of comprehensive knowledge about NS1-host protein protein interfaces. Here, we surveyed the impact of amino acid variation in NS1 at its structurally defined binding site for host p85ß, a regulator of phosphoinositide 3-kinase (PI3K) signaling. Structure-guided alanine scanning of all viral residues at this interface defined 10 positions contributing to the interaction, with residues 89, 95, 98, 133, 145, and 162 being the most important. A bioinformatic study of >24,000 publicly available NS1 sequences derived from viruses infecting different hosts highlighted several prevalent amino acid variants at the p85ß interface that either enhanced (I95) or weakened (N135, T145, L161, Y161, S164) p85ß binding. Interestingly, analysis of viruses circulating in humans since the 1918 pandemic revealed the temporal acquisition of functionally relevant variants at this interface. I95 (which enhanced p85ß binding) quickly became prevalent in the 1940s and experimentally conferred a fitness advantage to a recombinant 1930s-based H1N1 virus in human lung epithelial cells. Surprisingly, H1N1 and H3N2 viruses recently acquired T145 or N135, respectively, which diminished p85ß binding but apparently not the overall fitness in the human population. Evolutionary analyses revealed covariation of the NS1-p85ß binding phenotype in humans with functional changes at multiple residues in other viral proteins, suggesting an unexplored compensatory or synergistic interplay between phenotypes in vivo Overall, our data provide a resource to understand the consequences of the NS1-p85ß binding spectrum of different influenza viruses and highlight the dynamic evolution of this property in viruses circulating in humans.IMPORTANCE In humans, influenza A viruses are responsible for causing seasonal epidemics and occasional pandemics. These viruses also circulate and evolve in other animal species, creating a reservoir from which novel viruses with distinct properties can emerge. The viral nonstructural protein NS1 is an important host range determinant and virulence factor that exhibits strain-specific interactions with several host factors, although few have been characterized extensively. In the study described here, we comprehensively surveyed the impact of natural and unnatural NS1 variations on the binding of NS1 to host p85ß, a subunit of phosphoinositide 3-kinase that regulates intracellular metabolism and contributes to virus replication and virulence. We define the p85ß-binding site on NS1 and provide a predictive resource to assess this ability of NS1 in viruses from different hosts. Strikingly, we uncover a spectrum of p85ß binding by different NS1 proteins and reveal that viruses evolving in humans have undergone dynamic changes in this NS1 function over the last century.


Subject(s)
Class Ia Phosphatidylinositol 3-Kinase/metabolism , Influenza A Virus, H1N1 Subtype/pathogenicity , Influenza A Virus, H3N2 Subtype/pathogenicity , Influenza, Human/metabolism , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Amino Acid Sequence , Binding Sites , Evolution, Molecular , HEK293 Cells , Humans , Influenza A Virus, H1N1 Subtype/isolation & purification , Influenza A Virus, H3N2 Subtype/isolation & purification , Influenza, Human/blood , Influenza, Human/virology , Protein Binding , Protein Conformation , Signal Transduction , Viral Nonstructural Proteins/genetics , Virulence , Virus Replication
16.
Cancer Res ; 77(11): 2914-2926, 2017 06 01.
Article in English | MEDLINE | ID: mdl-28377454

ABSTRACT

Aneuploidy is a hallmark of most human tumors, but the molecular physiology of aneuploid cells is not well characterized. In this study, we screened cell surface biomarkers of approximately 300 proteins by multiparameter flow cytometry using multiple aneuploid model systems such as cell lines, patient samples, and mouse models. Several new biomarkers were identified with altered expression in aneuploid cells, including overexpression of the cellular prion protein CD230/PrPC and the immunosuppressive cell surface enzyme ecto-5'-nucleotidase CD73. Functional analyses associated these alterations with increased cellular stress. An increased number of CD73+ cells was observed in confluent cultures in aneuploid cells relative to their diploid counterparts. An elevated expression in CD230/PrPC was observed in serum-deprived cells in association with increased generation of reactive oxygen species. Overall, our work identified biomarkers of aneuploid karyotypes, which suggest insights into the underlying molecular physiology of aneuploid cells. Cancer Res; 77(11); 2914-26. ©2017 AACR.


Subject(s)
5'-Nucleotidase/metabolism , Aneuploidy , Prion Proteins/metabolism , Stress, Physiological/physiology , 5'-Nucleotidase/biosynthesis , Animals , Cell Line, Tumor , Disease Models, Animal , Humans , Mice , Signal Transduction
17.
Sci Rep ; 6: 35272, 2016 10 20.
Article in English | MEDLINE | ID: mdl-27762306

ABSTRACT

The present study assesses the diversity and composition of sediment bacterial and microeukaryotic communities from deep-sea mud volcanoes (MVs) associated with strike-slip faults in the South-West Iberian Margin (SWIM). We used a 16S/18S rRNA gene based pyrosequencing approach to characterize and correlate the sediment bacterial and microeukaryotic communities from MVs with differing gas seep regimes and from an additional site with no apparent seeping activity. In general, our results showed significant compositional changes of bacterial and microeukaryotic communities in sampling sites with different seepage regimes. Sediment bacterial communities were enriched with Methylococcales (putative methanotrophs) but had lower abundances of Rhodospirillales, Nitrospirales and SAR202 in the more active MVs. Within microeukaryotic communities, members of the Lobosa (lobose amoebae) were enriched in more active MVs. We also showed a strong correlation between Methylococcales populations and lobose amoeba in active MVs. This study provides baseline information on the diversity and composition of bacterial and microeukaryotic communities in deep-sea MVs associated with strike-slip faults.


Subject(s)
Archaea/classification , Bacteria/classification , Geologic Sediments/microbiology , Lobosea/classification , Microbiota/genetics , RNA, Ribosomal, 16S/genetics , Archaea/genetics , Atlantic Ocean , Bacteria/genetics , Biodiversity , Lobosea/genetics , Phylogeny , Seawater/microbiology , Volcanic Eruptions/analysis
18.
J Virol ; 90(9): 4807-4826, 2016 May.
Article in English | MEDLINE | ID: mdl-26937035

ABSTRACT

UNLABELLED: Small ubiquitin-like modifier (SUMO) is used by the intrinsic antiviral immune response to restrict viral pathogens, such as herpes simplex virus 1 (HSV-1). Despite characterization of the host factors that rely on SUMOylation to exert their antiviral effects, the enzymes that mediate these SUMOylation events remain to be defined. We show that unconjugated SUMO levels are largely maintained throughout infection regardless of the presence of ICP0, the HSV-1 SUMO-targeted ubiquitin ligase. Moreover, in the absence of ICP0, high-molecular-weight SUMO-conjugated proteins do not accumulate if HSV-1 DNA does not replicate. These data highlight the continued importance for SUMO signaling throughout infection. We show that the SUMO ligase protein inhibitor of activated STAT 4 (PIAS4) is upregulated during HSV-1 infection and localizes to nuclear domains that contain viral DNA. PIAS4 is recruited to sites associated with HSV-1 genome entry through SUMO interaction motif (SIM)-dependent mechanisms that are destabilized by ICP0. In contrast, PIAS4 accumulates in replication compartments through SIM-independent mechanisms irrespective of ICP0 expression. Depletion of PIAS4 enhances the replication of ICP0-null mutant HSV-1, which is susceptible to restriction by the intrinsic antiviral immune response. The mechanisms of PIAS4-mediated restriction are synergistic with the restriction mechanisms of a characterized intrinsic antiviral factor, promyelocytic leukemia protein, and are antagonized by ICP0. We provide the first evidence that PIAS4 is an intrinsic antiviral factor. This novel role for PIAS4 in intrinsic antiviral immunity contrasts with the known roles of PIAS proteins as suppressors of innate immunity. IMPORTANCE: Posttranslational modifications with small ubiquitin-like modifier (SUMO) proteins regulate multiple aspects of host immunity and viral replication. The protein inhibitor of activated STAT (PIAS) family of SUMO ligases is predominantly associated with the suppression of innate immune signaling. We now identify a unique and contrasting role for PIAS proteins as positive regulators of the intrinsic antiviral immune response to herpes simplex virus 1 (HSV-1) infection. We show that PIAS4 relocalizes to nuclear domains that contain viral DNA throughout infection. Depletion of PIAS4, either alone or in combination with the intrinsic antiviral factor promyelocytic leukemia protein, significantly impairs the intrinsic antiviral immune response to HSV-1 infection. Our data reveal a novel and dynamic role for PIAS4 in the cellular-mediated restriction of herpesviruses and establish a new functional role for the PIAS family of SUMO ligases in the intrinsic antiviral immune response to DNA virus infection.


Subject(s)
Herpes Simplex/genetics , Herpes Simplex/immunology , Herpesvirus 1, Human/physiology , Host-Pathogen Interactions , Immunity, Innate/genetics , Protein Inhibitors of Activated STAT/genetics , Amino Acid Motifs , Amino Acid Sequence , Cell Line , DNA Replication , DNA, Viral , Disease Progression , Gene Expression , Genome, Viral , Herpes Simplex/metabolism , Herpes Simplex/virology , Humans , Immediate-Early Proteins/metabolism , Mutation , Nuclear Proteins/metabolism , Promyelocytic Leukemia Protein , Protein Binding , Protein Inhibitors of Activated STAT/chemistry , Protein Interaction Domains and Motifs , Protein Transport , Recombinant Fusion Proteins , SUMO-1 Protein/metabolism , Sumoylation , Transcription Factors/metabolism , Tumor Suppressor Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Virus Replication
19.
Brain Behav Immun ; 53: 1-15, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26216710

ABSTRACT

Tumor-infiltrating immune cells are part of a complex microenvironment that promotes and/or regulates tumor development and growth. Depending on the type of cells and their functional interactions, immune cells may play a key role in suppressing the tumor or in providing support for tumor growth, with relevant effects on patient behavior. In recent years, important advances have been achieved in the characterization of immune cell infiltrates in central nervous system (CNS) tumors, but their role in tumorigenesis and patient behavior still remain poorly understood. Overall, these studies have shown significant but variable levels of infiltration of CNS tumors by macrophage/microglial cells (TAM) and to a less extent also lymphocytes (particularly T-cells and NK cells, and less frequently also B-cells). Of note, TAM infiltrate gliomas at moderate numbers where they frequently show an immune suppressive phenotype and functional behavior; in contrast, infiltration by TAM may be very pronounced in meningiomas, particularly in cases that carry isolated monosomy 22, where the immune infiltrates also contain greater numbers of cytotoxic T and NK-cells associated with an enhanced anti-tumoral immune response. In line with this, the presence of regulatory T cells, is usually limited to a small fraction of all meningiomas, while frequently found in gliomas. Despite these differences between gliomas and meningiomas, both tumors show heterogeneous levels of infiltration by immune cells with variable functionality. In this review we summarize current knowledge about tumor-infiltrating immune cells in the two most common types of CNS tumors-gliomas and meningiomas-, as well as the role that such immune cells may play in the tumor microenvironment in controlling and/or promoting tumor development, growth and control.


Subject(s)
Brain Neoplasms/immunology , Glioma/immunology , Meningeal Neoplasms/immunology , Meningioma/immunology , Animals , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Brain Neoplasms/pathology , Flow Cytometry , Glioma/metabolism , Glioma/pathology , Humans , Lymphocytes/immunology , Lymphocytes/pathology , Macrophages/immunology , Macrophages/pathology , Meningeal Neoplasms/metabolism , Meningioma/metabolism , Meningioma/pathology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/pathology
20.
Cell Rep ; 13(7): 1467-1480, 2015 Nov 17.
Article in English | MEDLINE | ID: mdl-26549460

ABSTRACT

Dynamic nuclear SUMO modifications play essential roles in orchestrating cellular responses to proteotoxic stress, DNA damage, and DNA virus infection. Here, we describe a non-canonical host SUMOylation response to the nuclear-replicating RNA pathogen, influenza virus, and identify viral RNA polymerase activity as a major contributor to SUMO proteome remodeling. Using quantitative proteomics to compare stress-induced SUMOylation responses, we reveal that influenza virus infection triggers unique re-targeting of SUMO to 63 host proteins involved in transcription, mRNA processing, RNA quality control, and DNA damage repair. This is paralleled by widespread host deSUMOylation. Depletion screening identified ten virus-induced SUMO targets as potential antiviral factors, including C18orf25 and the SMC5/6 and PAF1 complexes. Mechanistic studies further uncovered a role for SUMOylation of the PAF1 complex component, parafibromin (CDC73), in potentiating antiviral gene expression. Our global characterization of influenza virus-triggered SUMO redistribution provides a proteomic resource to understand host nuclear SUMOylation responses to infection.


Subject(s)
Influenza A virus/physiology , Sumoylation , Animals , Cell Line, Tumor , Chlorocebus aethiops , Dogs , HEK293 Cells , Host-Pathogen Interactions , Humans , Madin Darby Canine Kidney Cells , Protein Transport , Proteome/metabolism , RNA, Viral/physiology , Transcriptional Activation , Tumor Suppressor Proteins/metabolism , Vero Cells
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