RESUMO
Scedosporium spp. is a fungal species documented as the cause of infections involving the lungs, brain, and other organ systems in both immunocompetent and immunocompromised individuals. Many cases of this type of fungal infection occurring in immunocompetent patients are subsequent to traumatic injury or drowning events in or near waters containing the fungi. Infection commonly involves the lungs. Rarely, it has been shown to cause disease in the endocardium, but there is even less documentation of the fungi invading the myocardium and causing myocarditis. In this report, we present a case of disseminated Scedosporium boydii infection in a 52-year-old male patient without any known risk factors. He presented with acute onset chest pain and dyspnea accompanied by bilateral lower extremity edema. He was found to have new onset heart failure with reduced ejection fraction, and his hospital course was complicated by pneumonia, disseminated intravascular coagulation (DIC), and brain abscess formation. Multiple blood cultures failed to reveal the source of the infection. At autopsy, septated branching hyphae were identified invading both the myocardium and the cortical brain tissue. DNA sequencing revealed the fungal organisms to be Scedosporium boydii. This case reinforces the importance of autopsies in the clinical setting. It not only established the definitive diagnosis of an unexpected fungal infection, but it also helped to recognize new clinical and pathologic features of this particular fungal organism.
Assuntos
Abscesso Encefálico , Miocardite , Scedosporium , Humanos , Masculino , Pessoa de Meia-Idade , Scedosporium/isolamento & purificação , Abscesso Encefálico/microbiologia , Abscesso Encefálico/diagnóstico , Miocardite/microbiologia , Miocardite/diagnóstico , Evolução Fatal , Micoses/diagnóstico , Micoses/microbiologiaRESUMO
SARS-CoV-2 is a novel zoonotic positive-sense RNA virus (ssRNA+) belonging to the genus beta coronaviruses (CoVs) in the Coronaviridae family. It is the causative agent for the outbreak of the disease, COVID-19. It is the third CoV causing pneumonia around the world in the past 2 decades. To date, it has caused significant deaths worldwide. Notably, the emergence of new genetic variants conferring efficient transmission and immune evasion remained a challenge, despite the reduction in the number of death cases, owing to effective vaccination regimen (boosting) and safety protocols. Thus, information harnessed from SARS-CoV-2 genomic organization is indispensable for seeking laboratory diagnosis and treatment options. Here in, we review previously circulating variants of SARS-CoV-2 designated variant of concern (VOC) including the Alpha (United Kingdom), Beta (South Africa), Gamma (Brazil), Delta (India), and recently circulating VOC, Omicron (South Africa) and its divergent subvariants (BA.1, BA.2, BA.3, BA.2.12.1, BA.4 and BA.5) with BA.5 currently becoming dominant and prolonging the COVID pandemic. In addition, we address the role of computational models for mutagenesis analysis which can predict important residues that contribute to transmissibility, virulence, immune evasion, and molecular detections of SARS-CoV-2. Concomitantly, the importance of harnessing the immunobiology of SARS-CoV-2 and host interaction for therapeutic purpose; and use of an in slilico based biocomputational approaches to achieve this purpose via predicting novel therapeutic agents targeting PRR such as toll like receptor, design of universal vaccine and chimeric antibodies tailored to the emergent variant have been highlighted.
RESUMO
Identifying factors that influence fetal growth in a sex-specific manner can help unravel mechanisms that explain sex differences in adverse neonatal outcomes and in-utero origins of cardiovascular disease disparities. Premature aging of the placenta, a tissue that supports fetal growth and exhibits sex-specific epigenetic changes, is associated with pregnancy complications. Using DNA methylation-based age estimator, we investigated the sex-specific relationship of placental epigenetic aging with fetal growth across 13-40 weeks gestation, neonatal size, and risk of low birth weight. Placental epigenetic age acceleration (PAA), the difference between DNA methylation age and gestational age, was associated with reduced fetal weight among males but with increased fetal weight among females. PAA was inversely associated with fetal weight, abdominal circumference, and biparietal diameter at 32-40 weeks among males but was positively associated with all growth measures among females across 13-40 weeks. A 1-week increase in PAA was associated with 2-fold (95% CI 1.2, 3.2) increased odds for low birth weight and 1.5-fold (95% CI 1.1, 2.0) increased odds for small-for-gestational age among males. In all, fetal growth was significantly reduced in males but not females exposed to a rapidly aging placenta. Epigenetic aging of the placenta may underlie sex differences in neonatal outcomes.
Assuntos
Epigênese Genética/fisiologia , Desenvolvimento Fetal/genética , Placentação/genética , Placentação/fisiologia , Adulto , Antropometria , Peso ao Nascer , Metilação de DNA , Feminino , Cabeça/anatomia & histologia , Cabeça/crescimento & desenvolvimento , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Masculino , Gravidez , Resultado da Gravidez , Caracteres SexuaisRESUMO
OBJECTIVES: To examine neonatal risk factors associated with recurrent Staphylococcus aureus colonization and to determine the genetic relatedness of S. aureus strains cultured from neonates before and after decolonization.Study designSingle-center retrospective cohort study of neonates admitted to the neonatal intensive care unit (NICU) from April 2013 to December 2015, during which weekly nasal cultures from hospitalized NICU patients were routinely obtained for S. aureus surveillance. SETTING: Johns Hopkins Hospital's 45-bed level IV NICU in Baltimore, Maryland. METHODS: Demographics and clinical data were collected on all neonates admitted to the NICU with S. aureus nasal colonization who underwent mupirocin-based decolonization during the study period. A decolonized neonate was defined as a neonate with ≥1 negative culture after intranasal mupirocin treatment. Pulsed-field gel electrophoresis was used for strain typing. RESULTS: Of 2,060 infants screened for S. aureus, 271 (13%) were colonized, and 203 of these 271 (75%) received intranasal mupirocin. Of those treated, 162 (80%) had follow-up surveillance cultures, and 63 of these 162 infants (39%) developed recurrent colonization after treatment. The S. aureus strains were often genetically similar before and after decolonization. The presence of an endotracheal tube or nasal cannula/mask was associated with an increased risk of recurrent S. aureus colonization (hazard ratio [HR], 2.65; 95% confidence interval [CI], 1.19-5.90; and HR, 2.21; 95% CI, 1.02-4.75, respectively). CONCLUSION: Strains identified before and after decolonization were often genetically similar, and the presence of invasive respiratory devices increased the risk of recurrent S. aureus nasal colonization in neonates. To improve decolonization efficacy, alternative strategies may be needed.
Assuntos
Antibacterianos/administração & dosagem , Infecção Hospitalar/epidemiologia , Mupirocina/administração & dosagem , Infecções Estafilocócicas/epidemiologia , Staphylococcus aureus/efeitos dos fármacos , Administração Intranasal , Baltimore/epidemiologia , Portador Sadio/microbiologia , Portador Sadio/prevenção & controle , Infecção Hospitalar/prevenção & controle , Desinfecção/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Masculino , Razão de Chances , Estudos Retrospectivos , Fatores de Risco , Infecções Estafilocócicas/prevenção & controle , Staphylococcus aureus/isolamento & purificaçãoRESUMO
Toxoplasma gondii is an intracellular parasite that infects a wide range of warm-blooded species. Rats vary in their susceptibility to this parasite. The Toxo1 locus conferring Toxoplasma resistance in rats was previously mapped to a region of chromosome 10 containing Nlrp1. This gene encodes an inflammasome sensor controlling macrophage sensitivity to anthrax lethal toxin (LT) induced rapid cell death (pyroptosis). We show here that rat strain differences in Toxoplasma infected macrophage sensitivity to pyroptosis, IL-1ß/IL-18 processing, and inhibition of parasite proliferation are perfectly correlated with NLRP1 sequence, while inversely correlated with sensitivity to anthrax LT-induced cell death. Using recombinant inbred rats, SNP analyses and whole transcriptome gene expression studies, we narrowed the candidate genes for control of Toxoplasma-mediated rat macrophage pyroptosis to four genes, one of which was Nlrp1. Knockdown of Nlrp1 in pyroptosis-sensitive macrophages resulted in higher parasite replication and protection from cell death. Reciprocally, overexpression of the NLRP1 variant from Toxoplasma-sensitive macrophages in pyroptosis-resistant cells led to sensitization of these resistant macrophages. Our findings reveal Toxoplasma as a novel activator of the NLRP1 inflammasome in rat macrophages.
Assuntos
Inflamassomos/imunologia , Macrófagos/parasitologia , Proteínas do Tecido Nervoso/imunologia , Toxoplasmose/imunologia , Animais , Western Blotting , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Predisposição Genética para Doença/genética , Inflamassomos/genética , Macrófagos/imunologia , Proteínas do Tecido Nervoso/genética , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Ratos , Ratos Endogâmicos , Toxoplasmose/genética , TranscriptomaRESUMO
UNLABELLED: Induction of immunity that limits Toxoplasma gondii infection in mice is critically dependent on the activation of the innate immune response. In this study, we investigated the role of cytoplasmic nucleotide-binding domain and leucine-rich repeat containing a pyrin domain (NLRP) inflammasome sensors during acute toxoplasmosis in mice. We show that in vitro Toxoplasma infection of murine bone marrow-derived macrophages activates the NLRP3 inflammasome, resulting in the rapid production and cleavage of interleukin-1ß (IL-1ß), with no measurable cleavage of IL-18 and no pyroptosis. Paradoxically, Toxoplasma-infected mice produced large quantities of IL-18 but had no measurable IL-1ß in their serum. Infection of mice deficient in NLRP3, caspase-1/11, IL-1R, or the inflammasome adaptor protein ASC led to decreased levels of circulating IL-18, increased parasite replication, and death. Interestingly, mice deficient in NLRP1 also displayed increased parasite loads and acute mortality. Using mice deficient in IL-18 and IL-18R, we show that this cytokine plays an important role in limiting parasite replication to promote murine survival. Our findings reveal T. gondii as a novel activator of the NLRP1 and NLRP3 inflammasomes in vivo and establish a role for these sensors in host resistance to toxoplasmosis. IMPORTANCE: Inflammasomes are multiprotein complexes that are a major component of the innate immune system. They contain "sensor" proteins that are responsible for detecting various microbial and environmental danger signals and function by activating caspase-1, an enzyme that mediates cleavage and release of the proinflammatory cytokines interleukin-1ß (IL-1ß) and IL-18. Toxoplasma gondii is a highly successful protozoan parasite capable of infecting a wide range of host species that have variable levels of resistance. We report here that T. gondii is a novel activator of the NLRP1 and NLRP3 inflammasomes in vivo and establish a role for these sensors in host resistance to toxoplasmosis. Using mice deficient in IL-18 and IL-18R, we show that the IL-18 cytokine plays a pivotal role by limiting parasite replication to promote murine survival.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Proteínas de Transporte/imunologia , Resistência à Doença , Inflamassomos/imunologia , Toxoplasma/imunologia , Toxoplasmose Animal/imunologia , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Animais , Proteínas Reguladoras de Apoptose/deficiência , Proteínas de Transporte/genética , Feminino , Macrófagos/imunologia , Macrófagos/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Carga Parasitária , Análise de SobrevidaRESUMO
Lymphocyte recruitment to intestinal tissues depends on ß(7) integrins. In this study, we studied disease severity and lymphocyte recruitment into the small intestine in SAMP1/YitFc mice, which develop chronic ileitis with similarity to human Crohn's disease. To assess the role of ß(7) integrins in chronic ileitis, we generated SAMP1/YitFc lacking ß(7) integrins (SAMP1/YitFc Itgb7(-/-)) using a congenic strain developed via marker-assisted selection. We analyzed ileal inflammation in SAMP1/YitFc and SAMP1/YitFc Itgb7(-/-) mice by histopathology and the distribution of T and B lymphocytes in the mesenteric lymph nodes (MLNs) by flow cytometry. Short-term (18 h) adoptive transfer experiments were used to study the in vivo homing capacity of T and B lymphocytes. In both young (<20 wk) and old (20-50 wk) SAMP1/YitFc Itgb7(-/-) mice, ileitis was reduced by 30-50% compared with SAMP1/YitFc mice. SAMP1/YitFc Itgb7(-/-) mice showed a dramatic 67% reduction in the size of their MLNs, which was caused by a 85% reduction in lymphocyte numbers and reduced short-term B cell homing. Flow cytometric analysis revealed a highly significant decrease in the percentage of B cells in MLNs of SAMP1/YitFc Itgb7(-/-) mice. Cotransfer of SAMP1/YitFc MLN B cells but not SAMP1/YitFc Itgb7(-/-) MLN B cells along with CD4(+) T cells resulted in exacerbated ileitis severity in SCID mice. Our findings suggest that ß(7) integrins play an essential role in spontaneous chronic ileitis in vivo by promoting homing of disease-exacerbating B cells to MLNs and other intestinal tissues.
Assuntos
Linfócitos B/imunologia , Quimiotaxia de Leucócito/imunologia , Ileíte/patologia , Cadeias beta de Integrinas/imunologia , Animais , Linfócitos B/citologia , Doença Crônica , Citometria de Fluxo , Ileíte/imunologia , Ileíte/metabolismo , Cadeias beta de Integrinas/metabolismo , Intestino Delgado/imunologia , Intestino Delgado/patologia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/imunologiaRESUMO
During extravasation and within lymph nodes (LNs), blood lymphocytes interact with laminins (Lms), major components of vascular basement membranes (BMs) and of reticular fibers (RFs), a fibrillar extracellular matrix. However, the identity and role of these laminin isoform(s) are poorly known. By using confocal microscopy examination of human LNs, we show that BMs of high endothelial venules (HEVs) express laminin alpha3, alpha4, alpha5, beta1, beta2, and gamma1 chains and that the same chains, in addition to alpha2, are found in RFs. In functional studies with laminin isoforms covering all Lm alpha chains, alpha5-laminin (Lm-511) was the most adhesion- and migration-promoting isoform for human blood lymphocytes, followed by alpha3- (Lm-332) and alpha4- (Lm-411) laminins, and the lymphocytes used the alpha6beta1 integrin as the primary receptor for the alpha5-laminin. Moreover, Lm-511 strongly co-stimulated T cell proliferation, and blood lymphocytes were able to secrete alpha4- and alpha5-laminins following stimulation. The LN cell number in laminin alpha4-deficient mice compared with wild-type did not differ significantly. This study demonstrates a predominant role for alpha5-laminin(s) in blood lymphocyte biology and identifies LN laminins and their integrin receptors in blood lymphocytes.
Assuntos
Adesão Celular/fisiologia , Movimento Celular/fisiologia , Laminina/metabolismo , Linfonodos/metabolismo , Linfócitos/fisiologia , Animais , Membrana Basal/metabolismo , Proliferação de Células , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Citometria de Fluxo , Imunofluorescência , Humanos , Immunoblotting , Integrina alfa6beta1/genética , Integrina alfa6beta1/metabolismo , Laminina/fisiologia , Camundongos , Camundongos Knockout , Microscopia Confocal , Isoformas de Proteínas/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/citologia , Linfócitos T/metabolismoRESUMO
The dysregulated recruitment of leukocytes into the intestine is required for the initiation and maintenance of inflammatory bowel disease (IBD). Several families of molecules regulate the influx of these cells into sites of inflammation. Interference with some of these molecules has already shown efficacy in the clinics and antibodies that target the molecules involved have been approved by the FDA for use in Crohn's disease (CD), multiple sclerosis (i.e., natalizumab), and psoriasis (i.e., efalizumab). Here, we discuss basic aspects of the different families of relevant molecules and compile a large body of preclinical studies that supported the targeting of specific steps of the leukocyte adhesion cascade for therapeutic purposes in colitis and in novel models of CD-like ileitis.
Assuntos
Moléculas de Adesão Celular/fisiologia , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais/imunologia , Animais , Adesão Celular/imunologia , Leucócitos/imunologiaRESUMO
Following vascular injury, basement membrane (BM) components of the blood vessels are exposed to circulating cells and may contribute to hemostasis and/or thrombosis. Laminins 8 (LN-8) (alpha4beta1gamma1) and 10 (LN-10) (alpha5beta1gamma1) are major laminin isoforms of the endothelial BM, and LN-8 is also secreted by activated platelets. In the present study, we demonstrate synthesis of alpha5-laminins LN-10 and LN-11 (alpha5beta2gamma1) by megakaryocytic cells, and intracellular expression of these laminin isoforms in blood platelets. In contrast to platelet LN alpha4 chain that had an apparent molecular weight of 180 kDa and associated mostly to LNbeta1 chain, platelet LNalpha5 consisted of 300/350 kDa polypeptides and associated mainly to LNbeta2. Both alpha4- and alpha5-laminins were secreted by platelets following stimulation. When compared to recombinant human (rh) LN-8, rhLN-10 was much more adhesive to platelets, though adhesion to both proteins was largely mediated via alpha6beta1 integrin. In spite of their adhesive properties, rhLN-8 and rhLN-10 induced neither P-selectin expression nor cell aggregation, two signs of platelet activation. This study demonstrates synthesis/expression of heterotrimeric alpha5-laminins in hematopoietic/blood cells, and provides evidence for the adhesive, but not activating, role of endothelial laminin isoforms in platelet biology.
Assuntos
Plaquetas/metabolismo , Laminina/metabolismo , Megacariócitos/metabolismo , Plaquetas/efeitos dos fármacos , Adesão Celular , Linhagem Celular Tumoral , Humanos , Laminina/química , Laminina/genética , Laminina/farmacologia , Peso Molecular , Estrutura Quaternária de Proteína , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologiaRESUMO
Laminins, a family of large heterotrimeric (alphabetagamma) proteins, are major components of basement membranes implicated in a variety of cellular functions. Different commercial laminin preparations isolated from human placenta have been widely used in functional studies but their molecular properties are poorly known. In the present study, we characterized several of these preparations by ELISA, silver staining and Western blotting, in comparison to mouse laminin 1 (alpha1beta1gamma1), and recombinant human laminins 2 (alpha2beta1gamma1), 8 (alpha4beta1gamma1) and 10 (alpha5beta1gamma1). The cell migration-promoting activity of different batches was also tested. The placenta laminin preparations differed from one another and consisted of highly fragmented proteins, a mixture of laminin isoforms, and/or contaminating fibronectin. Major functional differences between batches were also observed, reflecting molecular heterogeneity. Previous data obtained in functional studies using these preparations need to be interpreted with caution and may require revision, and future functional studies demand prior molecular characterization of the laminins, particularly their alpha-chain.