Human galectin-1 and galectin-3 promote Tropheryma whipplei infection.

Tropheryma whipplei, is an actinobacterium that causes different infections in humans, including Whipple's disease. The bacterium infects and replicates in macrophages, leading to a Th2-biased immune response. Previous studies have shown that T. whipplei harbors complex surface glycoproteins with evidence of sialylation. However, the exact contribution of these glycoproteins for infection and survival remains obscure. To address this, we characterized the bacterial glycoprofile and evaluated the involvement of human ß-galactoside-binding lectins, Galectin-1 (Gal-1) and Galectin-3 (Gal-3) which are highly expressed by macrophages as receptors for bacterial glycans. Tropheryma whipplei glycoproteins harbor different sugars including glucose, mannose, fucose, ß-galactose and sialic acid. Mass spectrometry identification revealed that these glycoproteins were membrane- and virulence-associated glycoproteins. Most of these glycoproteins are highly sialylated and N-glycosylated while some of them are rich in poly-N-acetyllactosamine (Poly-LAcNAc) and bind Gal-1 and Gal-3. In vitro, T. whipplei modulates the expression and cellular distribution of Gal-1 and Gal-3. Although both galectins promote T. whipplei infection by enhancing bacterial cell entry, only Gal-3 is required for optimal bacterial uptake. Finally, we found that serum levels of Gal-1 and Gal-3 were altered in patients with T. whipplei infections as compared to healthy individuals, suggesting that galectins are also involved in vivo. Among T. whipplei membrane-associated proteins, poly-LacNAc rich-glycoproteins promote infection through interaction with galectins. T. whipplei modulates the expression of Gal-1 and Gal-3 both in vitro and in vivo. Drugs interfering with galectin-glycan interactions may provide new avenues for the treatment and diagnosis of T. whipplei infections.

Unintentional weight loss as presenting form of Whipple's disease. Role of PET-CT scanning and review of the literature

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Thrombocytopenia and endocarditis in a patient with Whipple's disease: case report.

BACKGROUND: Whipple's disease (WD) is a rare multisystem infectious disorder that is caused by the actinomycete Tropheryma whipplei. It presents with joint pain followed by abdominal pain, diarrhea, malabsorption and finally failure to thrive. Diagnosis requires tissue sampling and histology with periodic acid-Schiff [PAS] staining. Thrombocytopenia associated with endocarditis associated with WD has been reported twice. CASE PRESENTATION: A 56 year old Caucasian male presented with years of steroid treated joint pain and recent onset diarrhea, weight loss and abdominal pain. Ultimately he was found to have a platelet count of 4000 with concomitant endocarditis and embolic stroke. Small bowel biopsy confirmed the diagnosis of WD approximately 1 year after his first visit. His platelets improved with antibiotic treatment but he eventually expired 16 months after his initial consult and 5 months after his definitive diagnosis. CONCLUSION: WD can remain undiagnosed and untreated until late in the course of the illness. A high index of suspicion is recognized as necessary for early diagnosis to begin treatment. Critical thrombocytopenia associated with endocarditis is a rare and potentially poor prognostic sign in late stage Whipple's disease.

Fatal Whipple's disease with severe mental manifestations on relapse - case report and brief advances update.

We present the case of a 51-year-old male admitted for asthenia, fatigability, nausea, inappetence, weight loss, watery diarrhea, lower limb paresthesia and diagnosed after further investigations with Whipple's disease (WD). The evolution was favorable under antibiotic therapy but after a period of time the patient was no longer compliant to the treatment and psychotic manifestations, general status alteration and finally the decease occurred. WD is a condition caused by Tropheryma whipplei (TW) bacterium in people with altered macrophage degrading capacity and it is lethal without early treatment.

A rare presentation of hypovolemic shock secondary to Whipple's disease.

Whipple's disease is a rare, multisystem infection caused by the Gram-positive Tropheryma whippelii organism. In addition to neurological and rheumatological manifestations, this disease can result in significant gastrointestinal symptoms such as malabsorption, diarrhea, and weight loss. Given the diagnostic challenge and rare occurrence, a high index of suspicion is critical to prevent morbidity and mortality from this otherwise highly infectious disease transmitted via the fecal-oral route. We present a very rare but near-fatal case of hypovolemic shock secondary to protein-losing enteropathy and gastrointestinal bleeding from small bowel T. whippelii infection. Furthermore, the epidemiology, clinical presentation, diagnosis, and management of Whipple's disease is reviewed.

IRF4 haploinsufficiency in a family with Whipple's disease.

Most humans are exposed to Tropheryma whipplei (Tw). Whipple's disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance.

Impaired intracellular pathogen clearance and inflammatory joint disease: Is Whipple's disease a guiding light?

Whipple's disease can mimic spondyloarthritis (SpA) or rheumatoid arthritis (RA) for many years and, in a few cases, induces the development of antibodies to cyclic citrullinated peptides. The causative agent Tropheryma whipplei can smolder within cells, including macrophages, by suppressing the xenophagic process, a type of selective autophagy that targets pathogens. Other inflammatory joint diseases may also stem from impaired xenophagy with persistence of bacteria or viruses that can eventually migrate from the mucous membranes to the joints and entheses, where they may exert adverse effects on immune responses, even if they fail to replicate. Xenophagy interferes with the loading of peptides (including self-peptides) onto major histocompatibility complex proteins. Another effect of xenophagy is the induction of citrullination, which accelerates pathogen clearance but can also contribute to loss of self-tolerance. Pathogens react to citrullination by becoming dormant. These facts suggest a role in SpA and RA for impaired xenophagy with migration of pathogens to joints and entheses, where they may remain dormant. Studies of fibroblast-like synoviocytes showed alterations in autophagy that correlated with citrullination of vimentin, alpha-enolase, and filaggrin, which are targets of RA-specific autoantibodies. Compared to autoimmune responses (T-cell or B-cell clones, autoantibodies) alone, metastatic spread of pathogens initially located in the mucous membranes as the event inducing inflammatory joint disease would constitute a better explanation to the heterogeneous distribution of the joint involvement, palindromic onset in some cases (as seen in Whipple's disease), occurrence of flares, and possible development of escape phenomenon to immunomodulating drugs in a manner reminiscent of delayed antibiotic resistance.

Role of dendritic cells in the pathogenesis of Whipple's disease.

Accumulation of Tropheryma whipplei-stuffed macrophages in the duodenum, impaired T. whipplei-specific Th1 responses, and weak secretion of interleukin-12 (IL-12) are hallmarks of classical Whipple's disease (CWD). This study addresses dendritic cell (DC) functionality during CWD. We documented composition, distribution, and functionality of DC ex vivo or after in vitro maturation by fluorescence-activated cell sorting (FACS) and by immunohistochemistry in situ. A decrease in peripheral DC of untreated CWD patients compared to healthy donors was due to reduced CD11c(high) myeloid DC (M-DC). Decreased maturation markers CD83, CD86, and CCR7, as well as low IL-12 production in response to stimulation, disclosed an immature M-DC phenotype. In vitro-generated monocyte-derived DC from CWD patients showed normal maturation and T cell-stimulatory capacity under proinflammatory conditions but produced less IL-12 and failed to activate T. whipplei-specific Th1 cells. In duodenal and lymphoid tissues, T. whipplei was found within immature DC-SIGN(+) DC. DC and proliferating lymphocytes were reduced in lymph nodes of CWD patients compared to levels in controls. Our results indicate that dysfunctional IL-12 production by DC provides suboptimal conditions for priming of T. whipplei-specific T cells during CWD and that immature DC carrying T. whipplei contribute to the dissemination of the bacterium.

Varón de 33 años con poliartritis recurrente / A 33-year-old man with recurrent polyarthritis

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Update in sepsis and pulmonary infections 2013.

The Journal has been in the vanguard of publications of the respiratory microbiome, including a National Institutes of Health Workshop report, establishing the normal microbiome in patients with various risks, and in the correlation of microbiome changes with disease exacerbations and lung transplant. A new classification scheme for healthcare-associated pneumonia, risks for nosocomial Pseudomonas pneumonia, and associations between community-acquired pneumonia and risks or outcomes have been reported. The increasingly recognized role of viral respiratory tract infections was reflected in publications regarding incidence rates, risk factors, and associations with other respiratory diseases. Significant contributions to understanding and treating sepsis emerged in 2013. The role of tissue damage was highlighted in a series of publications. A much greater understanding of the importance of pathways that directly impact the pathogen at the site of infection and subsequent pathogen clearance has emerged. The Journal published important contributions across the spectrum of ineffective therapy (activated protein C), novel therapeutic ideas (statins and extracorporeal membrane oxygenation), and solidly beneficial approaches (early protocolized care). Biomarker development is maturing to include a wide array of molecular measurements increasingly aimed at aiding improved therapy.

Central nervous system involvement in Whipple disease: clinical study of 18 patients and long-term follow-up.

Whipple disease (WD) is a rare multisystemic infection with a protean clinical presentation. The central nervous system (CNS) is involved in 3 situations: CNS involvement in classic WD, CNS relapse in previously treated WD, and isolated CNS infection. We retrospectively analyzed clinical features, diagnostic workup, brain imaging, cerebrospinal fluid (CSF) study, treatment, and follow-up data in 18 patients with WD and CNS infection. Ten men and 8 women were included with a median age at diagnosis of 47 years (range, 30-56 yr). The median follow-up duration was 6 years (range, 1-19 yr). As categorized in the 3 subgroups, 11 patients had classic WD with CNS involvement, 4 had an isolated CNS infection, and 3 had a neurologic relapse of previously treated WD. CNS involvement occurred during prolonged trimethoprim-sulfamethoxazole (TMP-SMX) treatment in 1 patient with classic WD. The neurologic symptoms were various and always intermingled, as follows: confusion or coma (17%) related to meningo-encephalitis or status epilepticus; delirium (17%); cognitive impairment (61%) including memory loss and attention defects or typical frontal lobe syndrome; hypersomnia (17%); abnormal movements (myoclonus, choreiform movements, oculomasticatory myorhythmia) (39%); cerebellar ataxia (11%); upper motor neuron (44%) or extrapyramidal symptoms (33%); and ophthalmoplegia (17%) in conjunction or not with progressive supranuclear palsy. No specific pattern was correlated with any subgroup. Brain magnetic resonance imaging (MRI) revealed a unique focal lesion (35%), mostly as a tumorlike brain lesion, or multifocal lesions (23%) involving the medial temporal lobe, midbrain, hypothalamus, and thalamus. Periventricular diffuse leukopathy (6%), diffuse cortical atrophy (18%), and pachymeningitis (12%) were observed. The spinal cord was involved in 2 cases. MRI showed ischemic sequelae at diagnosis or during follow-up in 4 patients. Brain MRI was normal despite neurologic symptoms in 3 cases. CSF cytology was normal in 62% of patients, whereas Tropheryma whipplei polymerase chain reaction (PCR) analysis was positive in 92% of cases with tested CSF. Periodic acid-Schiff (PAS)-positive cells were identified in cerebral biopsies of 4 patients. All patients were treated with antimicrobial therapy for a mean duration of 2 years (range, 1-7 yr) with either oral monotherapy (TMP-SMX, doxycycline, third-generation cephalosporins) or a combination of antibiotics that sometimes followed parenteral treatment with beta-lactams and aminoglycosides. Eight patients also received hydroxychloroquine. At the end of follow-up, the clinical outcome was favorable in 14 patients (78%), with mild to moderate sequelae in 9. Thirteen patients (72%) had stopped treatment for an average time of 4 years (range, 0.7-14 yr). Four patients had clinical worsening despite antimicrobial therapy; 2 of those died following diffuse encephalitis (n = 1) and lung infection (n = 1). In conclusion, the neurologic manifestations of WD are diverse and may mimic almost any neurologic condition. Brain involvement may occur during or after TMP-SMX treatment. CSF T. whipplei PCR analysis is a major tool for diagnosis and may be positive in the absence of meningitis. Immune reconstitution syndrome may occur in the early months of treatment. Late prognosis may be better than previously reported, as a consequence of earlier diagnosis and a better use of antimicrobial therapy, including hydroxychloroquine and doxycycline combination.

Enfermedad de Whipple: presentación de un caso infrecuente de afectación cerebral aislada / Whipple's disease: presentation of an unusual case with isolated cerebral involvement

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Enfermedad de Whipple: Múltiples recaídas sistémicas y neurológicas / Whipple’s disease: multiple systemic and neurological relapses

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Looking for Tropheryma whipplei source and reservoir in rural Senegal.

Tropheryma whipplei, the bacterium linked to Whipple's disease, is involved in acute infections and asymptomatic carriage. In rural Senegal, the prevalence of T. whipplei is generally high but is not homogeneous throughout households in the same village. We studied environmental samples collected in two Senegalese villages and conducted the survey to investigate the difference between households. Overall, the comparison between five households with very high T. whipplei prevalence and three households without any registered cases showed that the only difference was the presence of toilets in the latter (1/5 versus 3/3; P = 0.01423). Among the 1,002 environmental specimens (including domestic and synanthropic animals and dust sampled in households) tested for T. whipplei DNA, only four specimens were slightly positive. Humans are currently the predominant identified reservoir and source of T. whipplei in these populations. Limited access to toilets and exposure to human feces facilitate the fecal-oral transmission of T. whipplei.

Tratamiento de la endocarditis por Tropheryma whipplei en paciente con grave intolerancia al cotrimoxazol / Treatment of Tropherima whipplei endocarditis in cases of intolerance to cothrimoxazole

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A case of Tropheryma whipplei infective endocarditis of the aortic and mitral valves in association with psoriatic arthritis and lumbar discitis.

Whipple's disease is a chronic condition that is characterized by diarrhea, weight loss and arthropathy, and caused by infection with the fastidious bacterium Tropheryma whipplei. Although once rare, Whipple's disease is being increasingly described owing mainly to advances in molecular genetics and an improved isolation of the organism. Whilst cardiac Whipple's disease occurs less commonly, especially in the absence of gastrointestinal symptoms, it has become apparent that some cases of culture-negative endocarditis may well be attributable to T. whipplei. The case is reported of a patient with Whipple's disease endocarditis in association with psoriatic arthritis and lumbar discitis.