Toxoplasma Effector MAF1 Mediates Recruitment of Host Mitochondria and Impacts the Host Response

Recent information has revealed the functional diversity and importance of mitochondria in many cellular processes including orchestrating the innate immune response. Intriguingly, several infectious agents, such as Toxoplasma, Legionella, and Chlamydia, have been reported to grow within vacuoles surrounded by host mitochondria. Although many hypotheses have been proposed for the existence of host mitochondrial association (HMA), the causes and biological consequences of HMA have remained unanswered. Here we show that HMA is present in type I and III strains of Toxoplasma but missing in type II strains, both in vitro and in vivo. Analysis of F1 progeny from a type II×III cross revealed that HMA is a Mendelian trait that we could map. We use bioinformatics to select potential candidates and experimentally identify the polymorphic parasite protein involved, mitochondrial association factor 1 (MAF1). We show that introducing the type I (HMA+) MAF1 allele into type II (HMA-) parasites results in conversion to HMA+ and deletion of MAF1 in type I parasites results in a loss of HMA. We observe that the loss and gain of HMA are associated with alterations in the transcription of host cell immune genes and the in vivo cytokine response during murine infection. Lastly, we use exogenous expression of MAF1 to show that it binds host mitochondria and thus MAF1 is the parasite protein directly responsible for HMA. Our findings suggest that association with host mitochondria may represent a novel means by which Toxoplasma tachyzoites manipulate the host. The existence of naturally occurring HMA+ and HMA- strains of Toxoplasma, Legionella, and Chlamydia indicates the existence of evolutionary niches where HMA is either advantageous or disadvantageous, likely reflecting tradeoffs in metabolism, immune regulation, and other functions of mitochondria. © 2014 Pernas et al

Effectiviteit van interventies bij kinderen met migraine

Verhagen AP, Damen L, Bruijn JKJ, Berger MY, Passchier J, Koes BW. Effectiveness of interventions in children with migraine. Huisarts Wet 2006;49(3):123-9. Objective To assess the effectiveness and tolerance of treatment methods for episodes of migraine in children. Methods We performed a systematic review. Databases were searched from inception to June 2004, and references were checked. We selected randomised and controlled trials reporting the effects of symptomatic and prophylactic treatment methods in children with migraine, using headache features as outcome measure. Two independent reviewers assessed trial quality and extracted data. Quantitative and qualitative analyses were carried out according to type of intervention. Results A total of 49 trials (total 3296 patients) were included in this review, of which 16 studies (32.7%) were considered to be of high quality. Ten studies evaluated the effectiveness of acute medication. Compared to placebo, headache improved significantly for acetaminophen, ibuprofen, and nasal sumatriptan. No significant differences were found between acetaminophen and ibuprofen or nimesulide, and between oral sumatriptan, rizatriptan and dihydroergotamine compared to placebo. All medications were well tolerated, but significantly more adverse events were reported for nasal sumatriptan. Nineteen studies evaluated the effectiveness of non-pharmacological prophylactic treatments. When compared to waiting list control, headache improved significantly for relaxation, relaxation plus biofeedback, and relaxation plus biofeedback plus cognitive behavioural treatment. There is conflicting evidence regarding the use of oligoantigenic diets. Lastly, 20 studies evaluated the effectiveness of pharmacological prophylactic treatments. Compared to placebo, headache improved significantly for flunarizine medication. There is conflicting evidence for the use of propranolol. Nimodipine, clonidine, L-5HTP, trazodone and papaverine showed no efficacy when compared to placebo. Conclusions Acetaminophen and ibuprofen are effective symptomatic pharmacological treatments of episodes of migraine in children. Nasal spray sumatriptan is also effective, but more side effects are reported. A few treatments, such as relaxation and flunarizine, may be effective as prophylactic treatment for migraine in children