Genomic Characterization of Salmonella Typhimurium Isolated from Guinea Pigs with Salmonellosis in Lima, Peru.

Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) is one of the most important foodborne pathogens that infect humans globally. The gastrointestinal tracts of animals like pigs, poultry or cattle are the main reservoirs of Salmonella serotypes. Guinea pig meat is an important protein source for Andean countries, but this animal is commonly infected by S. Typhimurium, producing high mortality rates and generating economic losses. Despite its impact on human health, food security, and economy, there is no genomic information about the S. Typhimurium responsible for the guinea pig infections in Peru. Here, we sequence and characterize 11 S. Typhimurium genomes isolated from guinea pigs from four farms in Lima-Peru. We were able to identify two genetic clusters (HC100_9460 and HC100_9757) distinguishable at the H100 level of the Hierarchical Clustering of Core Genome Multi-Locus Sequence Typing (HierCC-cgMLST) scheme with an average of 608 SNPs of distance. All sequences belonged to sequence type 19 (ST19) and HC100_9460 isolates were typed in silico as monophasic variants (1,4,[5],12:i:-) lacking the fljA and fljB genes. Phylogenomic analysis showed that human isolates from Peru were located within the same genetic clusters as guinea pig isolates, suggesting that these lineages can infect both hosts. We identified a genetic antimicrobial resistance cassette carrying the ant(3)-Ia, dfrA15, qacE, and sul1 genes associated with transposons TnAs3 and IS21 within an IncI1 plasmid in one guinea pig isolate, while antimicrobial resistance genes (ARGs) for ß-lactam (blaCTX-M-65) and colistin (mcr-1) resistance were detected in Peruvian human-derived isolates. The presence of a virulence plasmid highly similar to the pSLT plasmid (LT2 reference strain) containing the spvRABCD operon was found in all guinea pig isolates. Finally, seven phage sequences (STGP_Φ1 to STGP_Φ7) were identified in guinea pig isolates, distributed according to the genetic lineage (H50 clusters level) and forming part of the specific gene content of each cluster. This study presents, for the first time, the genomic characteristics of S. Typhimurium isolated from guinea pigs in South America, showing particular diversity and genetic elements (plasmids and prophages) that require special attention and also broader studies in different periods of time and locations to determine their impact on human health.

Carnivore protoparvovirus 1 in Peruvian dogs: Temporal/geographical and evolutionary dynamics of virus.

Canine parvovirus (CPV) has been recognized all around the world as the causal agent of a contagious and highly mortal disease in domestic dogs. In Peru, the infection is endemic and unvaccinated animals and puppies are the most at risk. In order to analyze viral diversity and determine the evolutionary genetic relationships and transmission dynamic of Peruvian CPV-2, were collected during the period of 2016-2017 rectal swabs from puppies with parvovirosis compatible symptoms. Viral DNA was amplified by PCR using primers that flanked the ends of the viral genome and sequenced by Illumina Miseq platform. Twenty-six genomic sequences (NSP1-VP1) of CPV from several districts in Lima Metropolitan area were obtained. The VP2 gene analysis demonstrated the presence of the New CPV-2a, New CPV-2b and 2c variants. The phylodynamic analysis of the viral genomes determined that all Peruvian sequences were clustered into a big clade named South American clade that emerged from the west region of Europe (Italy). The Time to the Most Recent Common Ancestor (TMRCA) of the South American clade was dated to 1993. Peruvian sequences were distributed into three subclades, and the 92% of these sequences were related to Ecuadorian CPV-2. The results suggests that three independent introduction events of virus from other countries could have occurred, in two of these events, CPV-2 from Ecuador were introduced in Peru in 2003 and 2009, and another introduction event, in 2000, from Europe. Overall, these results indicate a viral genetic relationship between Peruvian with Ecuadorian and European virus, and the circulation of several viral subpopulations in Lima Metropolitan.

Role of Inflammasome Activation in Systemic Lupus Erythematosus: Are Innate Immune Cells Activated? / Rol de la activación del inflammasome en lupus eritematoso sistémico: están las células del sistema inmune innato activados?

Background: Systemic lupus erythematosus (SLE) is characterized by a wide spectrum of clinical and immunological abnormalities. New data have emerged about the role of inflammasomes in autoimmune diseases. We aimed to investigate whether basal inflammasome activation occurs in SLE patients, and whether a relationship between inflammasome-related-cytokines and disease activity exists. Methods: Fourteen (14) consecutive SLE patients and 13 healthy individuals, matched by sex, age and ethnicity, were included. Demographics, laboratory and clinical data were recorded. Peripheral blood mononuclear cells (PBMCs) from patients and controls were obtained and monocytes were isolated by negative selection. Purified monocytes were stimulated with LPS in the presence or absence of Caspase-1 inhibitor. CD14 and Caspase-1 expression were analyzed by flow cytometry. Cytokine levels were determined in plasma and culture supernatants by ELISA. Student's t test and Mann–Whitney tests were used for statistical analysis. Results: The percentage of CD14+/Caspase-1+ was significantly higher in monocytes from SLE patients compared to normal controls (p<0.01). These findings paralleled with higher plasma levels of IL-1β (p<0.05) and IL-18 (p<0.01) in those patients. Purified monocytes from SLE patients displayed a robust inflammatory response after LPS stimulation where Caspase-1, IL-1β and IL-18 were highly expressed. Plasma levels of IL-18 were also significantly higher in SLE patients with active disease (p<0.05). In addition, the production of IL-18 was reduced by 3 fold when Caspase-1 inhibitor was added to the cultures. Conclusions: Monocytes from SLE patients exhibited increased inflammasome activation, characterized by high expression of Caspase-1, IL-1β and IL-18. Caspase-1 specific inhibitor decreased inflammasome activation (in vitro) by suppressing the production of IL-18.(AU)

Introducción: El lupus eritematoso sistémico (LES) se caracteriza por presentar diversas anormalidades clínicas e inmunológicas. El ensamblaje de los componentes del inflamasoma da lugar a la activación de caspasa-1, generando la liberación de citoquinas pro-inflamatorias IL-1β e IL-18. Objetivos: Evaluar si existe una activación basal del inflamasoma en pacientes con LES y determinar la asociación de las citoquinas IL-1β e IL-18 con la actividad de la enfermedad. Materiales y métodos: Se incluyeron 14 (n=14) pacientes consecutivos con LES y 13 (n=13) controles, pareados por edad, sexo y raza. Se recogieron datos clínicos, demográficos y de laboratorio. Los monocitos fueron aislados a partir de células mononucleares de sangre periférica obtenidas de pacientes y controles. Los monocitos purificados fueron estimulados con LPS, en presencia y ausencia de inhibidor de caspasa-1. La expresión de CD14 y caspasa-1 fueron determinados por citometría de flujo. Niveles de citoquinas fueron determinadas en plasma y en sobrenadantes de cultivos mediante técnica de ELISA. Test de Student y Mann-Whitney fueron usados para el análisis estadístico. Resultados: El porcentaje de CD14+/caspasa-1+ fue significativamente superior en monocitos de pacientes con LES vs. controles (p<0,01). En forma paralela, se encontraron niveles plasmáticos significativamente superiores de IL-1β (p<0,05) y de IL-18 (p<0,01) en pacientes con LES. Monocitos purificados de pacientes lúpicos presentaron una robusta respuesta inflamatoria luego de ser estimulados con LPS, donde caspasa-1, IL-1β e IL-18 fueron altamente expresados. Niveles plasmáticos de IL-18 fueron significativamente mayores en pacientes con LES y enfermedad activa (p<0,05). Por otro lado, la producción de IL-18 se redujo casi 3 veces cuando se agregó inhibidor de caspasa-1 en cultivos.(AU)

Role of Inflammasome Activation in Systemic Lupus Erythematosus: Are Innate Immune Cells Activated?

BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by a wide spectrum of clinical and immunological abnormalities. New data have emerged about the role of inflammasomes in autoimmune diseases. We aimed to investigate whether basal inflammasome activation occurs in SLE patients, and whether a relationship between inflammasome-related-cytokines and disease activity exists. METHODS: Fourteen (14) consecutive SLE patients and 13 healthy individuals, matched by sex, age and ethnicity, were included. Demographics, laboratory and clinical data were recorded. Peripheral blood mononuclear cells (PBMCs) from patients and controls were obtained and monocytes were isolated by negative selection. Purified monocytes were stimulated with LPS in the presence or absence of Caspase-1 inhibitor. CD14 and Caspase-1 expression were analyzed by flow cytometry. Cytokine levels were determined in plasma and culture supernatants by ELISA. Student's t test and Mann-Whitney tests were used for statistical analysis. RESULTS: The percentage of CD14+/Caspase-1+ was significantly higher in monocytes from SLE patients compared to normal controls (p<0.01). These findings paralleled with higher plasma levels of IL-1ß (p<0.05) and IL-18 (p<0.01) in those patients. Purified monocytes from SLE patients displayed a robust inflammatory response after LPS stimulation where Caspase-1, IL-1ß and IL-18 were highly expressed. Plasma levels of IL-18 were also significantly higher in SLE patients with active disease (p<0.05). In addition, the production of IL-18 was reduced by 3 fold when Caspase-1 inhibitor was added to the cultures. CONCLUSIONS: Monocytes from SLE patients exhibited increased inflammasome activation, characterized by high expression of Caspase-1, IL-1ß and IL-18. Caspase-1 specific inhibitor decreased inflammasome activation (in vitro) by suppressing the production of IL-18.

Vasculitides in HIV Infection.

PURPOSE OF REVIEW: To review the spectrum of vasculitides in HIV-infected patients and to identify the clinical features that characterize vasculitis in sero-positive HIV. RECENT FINDINGS: Epidemiological studies conducted in the post-HAART era described the rarity of vasculitis in the setting of HIV-infected patients. A study identified histopathological features such as leukocytoclastic vasculitis of the vasa vasorum and adventitial inflammation in the large artery pathology of HIV-positive patients compared with HIV-negative patients with critical lower limb ischemia. A recent retrospective cohort study reported that HIV-positive patients with LVV developed more vascular complications, responded less to antiretroviral therapy, and had worse outcome than HIV-negative patients with LVV. Vasculitides continue to be a rare disease in patients with HIV. The spectrum of vasculitis ranges from life-threatening conditions to relatively mild skin conditions. Recognizing vasculitis in the setting of HIV-positive patients is important because sometimes it require immunosuppressive treatment.

Rheumatoid meningitis and infection in absence of rheumatoid arthritis history: review of 31 cases.

A 62-year-old healthy male presents with leg weakness and fever. Imaging revealed leptomeningeal enhancement (LE). After cerebrospinal fluid (CSF) cultures were negative, he was discharged with a diagnosis of aseptic meningitis, but was readmitted due to worsening symptoms. Brain biopsy suggested rheumatoid leptomeningitis associated with elevated serum rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACPA). Following discharge, the New York State Department of Health (NYSDOH) reported a polymerase chain reaction (PCR) on CSF and brain DNA consistent with Naegleria fowleri (NF). After dramatic improvement on steroids, the patient declined antimicrobial treatment. Upon prednisone taper, symptoms recurred which responded to rituximab (RTX). This case highlights a possible association between rheumatoid leptomeningitis (RM) onset and infection, in a patient without a history of rheumatoid arthritis (RA). Our goal is to assess whether this association is present in 69 RM cases reported since 2000. We also describe diagnosis and treatment of 31 new cases (January 2017 to March 2020). We did not identify evidence of active/latent infection in patients with RM and previous RA; however, patients without RA history appeared to have a significantly higher rate. This finding could demonstrate the necessity of evaluating for infection in de novo RM cases without antecedent RA history. We also describe characteristic clinical patterns for each group. More studies are needed to corroborate these results and expand into a possible distinct natural history of RM in each group, which might have an impact upon the clinical outcome.

Human immunodeficiency virus infection (HIV)-associated rheumatic manifestations in thepre- and post-HAART eras.

Rheumatic manifestations remain an important clinical manifestation associated to HIV. To date after 4 decades of the onset of the HIV/AIDS pandemic, almost 37 million individuals are living with the infection, including close to 2 million of newly infected individuals. The status, however, of a considerable proportion of HIV/AIDS patients has changed from a near fatal disorder secondary to opportunistic infections to a chronic disease in which renal cardiovascular, diabetes, malignancy, and autoimmune co-morbid disorders have become prevalent and relevant. In addition, the spectrum of rheumatic disorders also has changed since the introduction of HAART and its diagnosis and treatment represents a challenge. The purpose of this review is to define and discuss the HIV-related rheumatic manifestations in the pre- and post-HAART eras.

Catastrophic antiphospholipid syndrome: is life-long anticoagulation therapy required?

Catastrophic antiphospholipid syndrome (CAPS) is an unusual complication of antiphospholipid syndrome (APS) occurring in about 1% of patients. If left untreated, mortality can be as high as 50%. Therapy of APS and its complication CAPS is hampered by the lack of validated prospective, controlled, intervention clinical trials, although there is consensus that treatment should include anticoagulation therapy. But there are issues that need to be addressed such as duration and intensity of therapy. The present report describes our experience in 7 patients with CAPS in whom anticoagulation was discontinued after 6 months of therapy. During an average follow-up of 5.5 years, only 2 patients exhibited one episode each of recurrent venous thrombosis, but none of the patients in whom anticoagulation was discontinued experienced recurrent CAPS.Key Points• Discontinuation of long-term anticoagulation therapy in CAPS patients was not followed by recurrence of CAPS.

Eosinophilic Vasculitis.

PURPOSE OF REVIEW: Eosinophilic granulomatosis with polyangiitis (EGPA) represents a rare clinical entity, which is getting increasing attention and relevance in view of our better understanding and newer insights into its pathogenesis. Concomitantly better recognition and understanding of the immune pathophysiologic role of eosinophils provide a solid ground of their role on systemic inflammatory disorders and defense against infectious triggers, especially parasites. This review will focus on describing the physiopathology of eosinophils, as well as providing an in depth description of the natural history, clinical spectrum, and therapy of EGPA. RECENT FINDINGS: Several studies have aimed at finding useful biomarkers to monitor disease activity, and reported data have shown that eotaxin 3, IL25, IL33, and some eicosanoids to be promising options. Regarding therapeutic advances, recently published studies have revealed the efficacy of mepolizumab during induction and maintenance of EGPA. Recently published data confirmed earlier studies that the use of azathioprine during the induction phase is of no benefit during long-term follow-up. In addition, data from the REOVAS study, which uses rituximab, is still ongoing and apparently with promising results. Eosinophils are involved in several systemic inflammatory disorders, and recent gathered data provide support for their role in triggering EGPA. Better understanding of its pathophysiology should generate newer insights into the pathogenesis, biomarkers of disease activity, and therapeutic targets.

Takayasu Arteritis: Recent Developments.

PURPOSE OF REVIEW: Takayasu arteritis (TA) is a granulomatous inflammatory disorder that affects large vessels, especially aorta and its proximal branches. Its diagnosis can be extremely challenging due to the non-specificity of the systemic inflammatory manifestations during the early phase of the disease and usually follows an insidious clinical course until the emergence of vascular ischemic complications. RECENT FINDINGS: Its pathogenesis has been better delineated in recent years, especially the role of HLA-B*52 allele in certain ethnic groups, as well as the use of biological therapy, and surgical revascularization. Recent findings are discussed in depth. Clinical and epidemiological aspects of TA, recent developments in pathogenesis, and therapy are presented.

Trauma-induced concomitant psoriatic arthritis and complex regional pain syndrome.

To report the simultaneous occurrence of psoriatic arthritis (PsA) and chronic regional pain syndrome type I (CRPS I) both triggered by intense walking in a male golfer with a history of scalp psoriasis. Sequential existence of these two conditions have been reported in the literature; however, to our knowledge, this is the first report of a simultaneous occurrence of PsA and CRPS I. This case illustrates the complex interplay between genetic predisposition and environmental risk factors with the central nervous and immune systems. As the pathogenesis of PsA has been better understood in recent years, we propose a mechanism that explains how the release of pro-inflammatory cytokines and neuropeptides following a traumatic event elicits a vicious cycle that is a common ground for the development of both PsA and CRPS I. Even unperceived trauma, such as intense walking, when directed to the synovio-entheseal complex, can precipitate the development of PsA and CRPS I in predisposed individuals.

Distinguishing rheumatoid arthritis from psoriatic arthritis.

Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) have key differences in clinical presentation, radiographic findings, comorbidities and pathogenesis to distinguish between these common forms of chronic inflammatory arthritis. Joint involvement is typically, but not always, asymmetric in PsA, while it is predominantly symmetric in RA. Bone erosions, without new bone growth, and cervical spine involvement are distinctive of RA, while axial spine involvement, psoriasis and nail dystrophy are distinctive of PsA. Patients with PsA typically have seronegative test findings for rheumatoid factor (RF) and cyclic citrullinated peptide (CCP) antibodies, while approximately 80% of patients with RA have positive findings for RF and CCP antibodies. Although there is overlap in the pathogenesis of PsA and RA, differences are also present that affect the efficacy of treatment. In PsA, levels of interleukin (IL)-1ß, IL-6, IL-17, IL-22, IL-23, interferon-γ and tumour necrosis factor-α (TNF-α) are elevated, and in RA, levels of IL-1, IL-6, IL-22, IL-33, TNF-α, chemokine ligand 11 and chemokine C-X-C motif ligand 13 are elevated. Differences in the pathogenesis of RA and PsA translate into some variances in the specificity and efficacy of therapies.

The History of Psoriatic Arthritis (PsA): From Moll and Wright to Pathway-Specific Therapy.

PURPOSE OF REVIEW: Psoriatic arthritis is a distinct disorder, separate from rheumatoid arthritis, and first recognized in a thirteenth century Saxon skeleton. It was, however, the monumental work of Verna Wright in the 1950s that led to the acceptance by the American Rheumatism Association (now American College of Rheumatology) in 1964 as a distinct entity. Wright's work provided the framework for a better understanding of the pathogenic mechanisms operating on this condition, and eventually led to the development of targeted therapy that has proven to be more effective and safe than conventional therapy. RECENT FINDINGS: Pathogenesis of psoriatic arthritis has been better delineated in recent years, as well as the use of biological therapy. Recent findings are discussed in detail. Historical aspects of psoriatic arthritis, recent developments in pathogenesis, and therapy are discussed, and the contributions of Verna Wright to our understanding of the disorder are presented.

Ustekinumab for the treatment of psoriasis and psoriatic arthritis: a drug evaluation and literature review.

INTRODUCTION: Psoriasis (PsO) is an inflammatory disorder characterized by proliferation of keratinocytes, and it may be associated with a systemic inflammatory articular disorder, psoriatic arthritis (PsA). The presentations of PsO and PsA are heterogeneous, and our understanding of pathogenesis has led to a better understanding of the role of the interleukin (IL)-23/T-helper 17 (Th17) axis. Areas covered: Ustekinumab is a monoclonal antibody against IL-12 and IL-23. The pathogenesis of PsO and PsA is a multifactorial process involving genetic, environmental, and lifestyle factors. IL-23 signaling and activation of Th17 cells leads to a self-perpetuating inflammatory loop resulting in continuous keratinocyte proliferation and synovitis. Treatment options are varied, ranging from topical therapy to injection of targeted biologic disease-modifying antirheumatic drugs (bDMARDs). Evidence on the use of ustekinumab in the management of PsO is strong, but it is not as impressive in management of PsA. Expert opinion: IL-12/23 inhibition appears to be a good first-line option for plaque PsO, but efficacy in PsA does not compare favorably to IL-17 inhibition. In general, poorer responses to therapy with any bDMARD in PsA cohorts highlight psoriatic disease heterogeneity. Until new knowledge can remedy the failure of monotherapy, synergistic methods may have to be explored, including combination biologic therapy.

HIV infection and its effects on the development of autoimmune disorders.

More than 35 years have elapsed since the initial outbreak of the HIV/AIDS epidemic and the status of a considerable number of patients has changed from a fatal disorder to a chronic one where comorbidities including sarcoidosis and autoimmune diseases have become relevant and dominant. HIV targets the immune system leading to a state of immunodeficiency in a setting of immune activation in which CD4+ T cell depletion plays a critical role. The onset, natural history and course of HIV-associated autoimmune disease has dramatically changed according to the stage of HIV infection and since the introduction of combined anti-retroviral therapy. There are some issues that need further study regarding therapy, especially when immunosuppressive drugs and biologic agents are under consideration. Currently, biologic agents and others immunosuppressive agents are recommended when patients have CD4+ T cell counts above 200 cells/mm3 and the HIV viral activity is completely suppressed.

Gut Microbiota Perturbations in Reactive Arthritis and Postinfectious Spondyloarthritis.

OBJECTIVE: Reactive arthritis (ReA) is an inflammatory disorder occurring several weeks after gastrointestinal or genitourinary tract infections. HLA-B27 positivity is considered a risk factor, although it is not necessarily predictive of disease incidence. Among nongenetic factors, the intestinal microbiome may play a role in disease susceptibility. The objective of this study was to characterize the gut microbiota and host gene interactions in ReA and postinfectious spondyloarthritis. METHODS: Adult subjects with peripheral spondyloarthritis and control subjects with preceding infections who did not develop arthritis were prospectively recruited from a geographic region with a high prevalence of ReA. Clinical variables, HLA status, and 16S ribosomal RNA gene sequencing of intestinal microbiota were analyzed. RESULTS: Subjects with ReA showed no significant differences from controls in gut bacterial richness or diversity. However, there was a significantly higher abundance of Erwinia and Pseudomonas and an increased prevalence of typical enteropathogens associated with ReA. Subjects with ultrasound evidence of enthesitis were enriched in Campylobacter, while subjects with uveitis and radiographic sacroiliitis were enriched in Erwinia and unclassified Ruminococcaceae, respectively; both were enriched in Dialister. Host genetics, particularly HLA-A24, were associated with differences in gut microbiota diversity irrespective of disease status. We identified several co-occurring taxa that were also predictive of HLA-A24 status. CONCLUSION: This is the first culture-independent study characterizing the gut microbial community in postinfectious arthritis. Although bacterial factors correlated with disease presence and clinical features of ReA, host genetics also appeared to be a major independent driver of intestinal community composition. Understanding of these gut microbiota-host genetic relationships may further clarify the pathogenesis of postinfectious spondyloarthritides.