Visualizing thymocyte motility using 2-photon microscopy

Summary: Our view of a thymocyte based on its behavior in tissue culture and appearance in fixed tissue sections was of a round sessile cell. Its travel through the thymus might occur slowly, perhaps even passively, leaving it in contact with the support cells that happened to be in its immediate environment. However, when we got our first look at the behavior of thymocytes in a 3D cellular stromal cell environment, that picture changed dramatically. Instead we found that thymocytes are actively crawling, allowing them to explore their environment over relatively long distances and interact with peptide‐major histocompatibility complex (pMHC)‐bearing thymic stromal cells in both dynamic and stable modes. In this review, we discuss the implications of thymocyte motility for T‐cell repertoire selection and for the mechanisms that determine the spatial organization of thymocyte subsets within the thymus.     

Tropheryma whipplei as a Cause of Epidemic Fever,Senegal, 2010–2012

The bacterium Tropheryma whipplei, which causes Whipple disease in humans, is commonly detected in the feces of persons in Africa. It is also associated with acute infections. We investigated the role of T. whipplei in febrile patients from 2 rural villages in Senegal. During June 2010–March 2012, we collected whole-blood finger-prick samples from 786 febrile and 385 healthy villagers. T. whipplei was detected in blood specimens from 36 (4.6%) of the 786 febrile patients and in 1 (0.25%) of the 385 apparently healthy persons. Of the 37 T. whipplei cases, 26 (70.2%) were detected in August 2010. Familial cases and a potential new genotype were observed. The patients’ symptoms were mainly headache (68.9%) and cough (36.1%). Our findings suggest that T. whipplei is a cause of epidemic fever in Senegal.Key words: Tropheryma whipplei, fever, epidemic fever, bacteremia, Whipple disease, bacteria, SenegalDetermining the etiologic causes of febrile illness in tropical settings provides public health and local community benefits. In the context of a decline in malaria cases in many parts of sub-Saharan Africa, the few studies that have been conducted in recent years to analyze the burden of bacterial infections used traditional blood cultures and identified typhoid fever and Streptococcus pneumoniae as the leading documented causes of nonmalarial bloodstream infections (1–3). However, this method does not enable the identification of intracellular organisms, and most causes of fever remain unknown. In 2008, we initiated a study of the etiologies of fevers of unknown origin in Africa, particularly in Senegal. Our preliminary studies showed the presence of previously known pathogenic microorganisms, such as Borrelia crocidurae, Rickettsia felis, R. conorii, and Coxiella burnetii, and the unexpected presence of Tropheryma whipplei (4–9).T. whipplei was first considered to be an uncommon bacterium that causes Whipple disease, a rare chronic disease (10). However, T. whipplei is in fact a common bacterium associated with various conditions, such as acute infections (pneumonia and gastroenteritis) and chronic infections (classic Whipple disease and other infections without digestive involvement, including endocarditis and encephalitis) (10–19). T. whipplei can also be carried in human feces and, less commonly, in the saliva (20–23); carriage prevalence varies by the age and exposure of the population and by geographic area (21–30).T. whipplei is highly prevalent in rural Senegal, where carriage rates reach 75% among children <2 years of age, and overall seroprevalence is 72% (21–26). In our preliminary study in Senegal, which was conducted in 2 villages (Dielmo and Ndiop) during December 2008–July 2009, we detected T. whipplei bacteremia in 6.4% of the analyzed specimens (8). Bacteremia was significantly associated with cough, but no link to feces carriage was observed (8). However, our study had several limitations, such as a small number of febrile patients, no local control group of afebrile persons, and a short study period. In this same area, we recently showed that humans comprise the only source of T. whipplei among the populations in whom the bacterium is highly prevalent. Moreover, our findings showed that limited access to toilets and exposure to human feces was associated with the high prevalence of T. whipplei, suggesting that these conditions may facilitate fecal–oral transmission of the bacterium (31). To better characterize T. whipplei bacteremia, we extended our analysis, beginning in 2010, in this same area of rural Senegal to include the collection of >1,000 blood samples from healthy persons and ambulatory patients with acute fever.     

Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency

Energy production via the mitochondrial electron transport chain (ETC) and mitophagy are two important processes affected in Parkinson’s disease (PD). Interestingly, PINK1, mutations of which cause early-onset PD, plays a key role in both processes, suggesting that these two mechanisms are connected. However, the converging link of both pathways currently remains enigmatic. Recent findings demonstrated that lipid aggregation, along with defective mitochondria, is present in postmortem brains of PD patients. In addition, an increasing body of evidence shows that sphingolipids, including ceramide, are altered in PD, supporting the importance of lipids in the pathophysiology of PD. Here, we identified ceramide to play a crucial role in PINK1-related PD that was previously linked almost exclusively to mitochondrial dysfunction. We found ceramide to accumulate in mitochondria and to negatively affect mitochondrial function, most notably the ETC. Lowering ceramide levels improved mitochondrial phenotypes in pink1-mutant flies and PINK1-deficient patient-derived fibroblasts, showing that the effects of ceramide are evolutionarily conserved. In addition, ceramide accumulation provoked ceramide-induced mitophagy upon PINK1 deficiency. As a result of the ceramide accumulation, β-oxidation in PINK1 mutants was decreased, which was rescued by lowering ceramide levels. Furthermore, stimulation of β-oxidation was sufficient to rescue PINK1-deficient phenotypes. In conclusion, we discovered a cellular mechanism resulting from PD-causing loss of PINK1 and found a protective role of β-oxidation in ETC dysfunction, thus linking lipids and mitochondria in the pathophysiology of PINK1-related PD. Furthermore, our data nominate β-oxidation and ceramide as therapeutic targets for PD.

Loss of PINK1 function causes autosomal recessive early-onset Parkinson’s disease (PD). Most patients present with bradykinesia, rigidity, resting tremor, and dyskinesia and are responsive to dopamine replacement therapy (1). On the cellular level, PINK1 disease mutations result in impaired energy metabolism and a variety of mitochondrial defects that can partially be alleviated by stimulation of energy metabolism (2–4). Intriguingly, abnormal mitochondrial morphology, along with lipid aggregates, was recently discovered to be present in Lewy bodies of postmortem PD patients’ brains (5), challenging the previously held notion of alpha-synuclein being the almost exclusive neuropathological correlate. This finding confirms the involvement of mitochondrial dysfunction in PD and additionally suggests a critical role of lipids in the pathogenesis of PD.PINK1 is important for the phosphorylation of the Complex I subunit NdufA10 resulting in efficient Complex I and electron transport chain (ETC) activity (6, 7). This function is evolutionarily conserved between Drosophila and humans. Hence, in both flies and humans, loss of PINK1 results in an impaired ETC, reduced ATP levels, and defective mitochondrial morphology (6, 8, 9), all of which are ubiquitously observed in the fly already at the early larval stage. Furthermore, alongside Parkin, PINK1 plays a crucial role in mitophagy to remove defective mitochondria that appears to be defective in an age-dependent fashion (10–13). Pink1-mutant Drosophila melanogaster additionally show thorax muscle degeneration and defective flying ability (8, 9). These latter defects, together with impaired mitochondrial morphology, can be rescued by expressing the fission-promoting protein Drp1 (14). However, increased fission does not improve ETC-related defects (15). Furthermore, stimulation or facilitation of the ETC rescues ETC-related phenotypes in pink1-mutant Drosophila, including ATP levels and mitochondrial morphology (3, 4, 7, 15, 16). These data collectively suggest two parallel mechanisms that converge on a shared common pathway leading to the development of PD. However, the link between these two pathways has yet to be resolved.Recently, disrupted lipid homeostasis has garnered increasing attention in PD (16–18). Furthermore, ceramide, the basic sphingolipid, is altered in several PD models and has been implicated in PD-related alpha-synuclein toxicity (17–20). Interestingly, ceramide induces mitophagy that is facilitated by Drp1 (21). Furthermore, pathogenic variants in Glucocerebrosidase (GCase), an enzyme involved in ceramide synthesis, are known to be the most common risk factor for PD (22, 23). However, the exact mechanism remains enigmatic. We found increased ceramide levels in isolated mitochondria of Pink1^−/− knockout (KO) mouse embryonic fibroblasts (MEFs) (16) and Pink1-deficient flies. Increased ceramide levels are detrimental for proper ETC function (24). Hence, we hypothesize that ceramide accumulation in PINK1 deficiency affects ETC function and mitophagy and constitutes the missing link between these two important processes affected in PD.     

Chronic infections capture little attention of the masses

In this issue of Immunity, Egen et?al. (2011) provide compelling evidence that only a minute fraction of mycobacteria-specific T?cells present in a granuloma are actively fulfilling effector functions, an observation that may in fact be a general feature of chronic infections.     

Mamadou or anxiety resulting from a departure for the European Eldorado

Candidates for emigration are susceptible to a psychotic breakdown accompanied by feelings of guilt arising from abandoning their community of origin. The elimination of this guilt involves, essentially, a denial of identity with a touch of megalomania which makes treatment difficult.     

Congenital serous cyst of the orbit with anophthalmos

The authors reported a case of orbital congenital serous cyst with anophtalmos. It was a third type of Duke Elder classification. Although it looked sporadic, this malformation is hereditary and due to a disharmony between optic cup growth and differenciation. Ultrasonography and scanner could confirm the diagnosis and helped to discard orbital and eyelid angioma and meningocele. After excision, a prosthesis must be adapted in the orbit.