Interferon Regulatory Factor-1 schützt vor tödlicher neurotropischer Infektion mit Vesicular Stomatitis Virus

Interferon regulatory factors (IRFs) are a family of transcription factors that play a key role in viral defense. Apart from their function in the adaptive immune system recent work revealed that several IRFs contribute to antiviral response independent of secreted IFN. IRFs have been developed earlier in evolution than IFN and are regarded as precursor of today’s IFN system, acting only on an intrinsic level. IRF-1 by itself exhibits antiviral effects that are exerted by the induction of a set of genes that overlaps the set of IFN-induced genes (ISGs). This work shows that IRF-1 contributes decisively for the protection of mice from neurotropic vesicular stomatitis virus (VSV), a virus similar to rabies virus. Mice, deficient in IRF-1, are highly vulnerable to VSV infection and succumb with signs of encephalitis. Unlike the effects of the type I IFN which is essential in restricting VSV both in the periphery and the CNS, IRF-1 mediated antiviral effects are redundant in the periphery but highly crucial for restricting viral replication and spread in the neuronal tissues. Although type I IFN action is a prerequisite for survival from the infection, IRF-1 becomes increasingly crucial in neuronal tissue at a time point where clearance of the virus has not been achieved. The data highlight the importance of IRF-1 as an innate immune mediated antiviral agent that acts in combination with the IFN system. Moreover, our data suggests that IRF-1 responses protect against VSV infection through an IFN-independent program in the brain which could be crucial, in situations where viruses evade immunity by the inhibition of the IFN system.Die Interferon regulierenden Faktoren (IRFs) sind eine Familie von Transkriptionsfaktoren, die eine wichtige Rolle bei der antiviralen Abwehr spielen. Abgesehen von ihrer Funktion innerhalb des adaptiven Immunsystems zeigen neuere Arbeiten einen Beitrag der IRFs zur antiviralen Antwort, die unabhängig von sekretiertem Interferon (IFN) ist. IRFs haben sich in der Evolution früher als IFNs entwickelt und werden als Vorläufer des heutigen Typ-I-IFN–System angesehen, die nur auf intrinsischem Niveau agieren. IRF-1 selbst besitzt eine antivirale Wirkung, die durch die Induktion einer Reihe von Genen ausgeübt wird, darunter auch die Gruppe der IFN-induzierten Gene (ISG). Diese Arbeit zeigt, dass IRF -1 entscheidend zum Schutz von Mäusen vor dem neurotropen vesikulären Stomatitis-Virus (VSV), einem Verwandten desRabiesvirus (Erreger der Tollwut), beiträgt. IRF-1 defiziente Mäuse sind hoch anfällig für eine VSV-Infektion und sterben nach dem sie Symptomen einer Enzephalitis zeigen. Im Gegensatz zum Typ-I-IFN, das essentiell für die Kontrolle von VSV in der Peripherie und im ZNS ist, bleiben IRF- 1-vermittelte antiviralen Effekte in der Peripherie redundant. IRF-1 ist allerdings sehr entscheidend bei der Kontrolle der viraler Replikation und Ausbreitung im zentralen Nervensystem (ZNS). Obwohl die Aktivierung von Typ–I-IFN für das Überleben der Infektion unerlässlich ist, übernimmt IRF-1 im späteren Verlauf der Infektion eine wichtige Rolle und ist für die Eliminierung der Virusinfektion im ZNS verantwortlich.Die Daten unterstreichen die Bedeutung von IRF-1 als einen antiviral agierenden Vertreter des angeborenen Immunsystems, der in Kombination mit dem IFN -System wirkt. Darüber hinaus zeigen unsere Daten, dass die IRF-1-Antwort durch einen IFN-unabhängigen Mechanismus gegen VSV-Infektion im Gehirn schützt, was immer dann entscheidend ist, wenn sich das Virus der Kontrolle des IFN-Systems der Immunantwort entzieht

Young Abusers

Mass Communication student Katherine does not think that she is a drug addict. Even though she has smoked marijuana for eight years, the bubbly college student believes she is not dependent on drugs. It has been two months since Katherine last smoked a joint, and she is confident she can hold off till the next semester break in July

Metagenome of the gut of a malnourished child

<p>Abstract</p> <p>Background</p> <p>Malnutrition, a major health problem, affects a significant proportion of preschool children in developing countries. The devastating consequences of malnutrition include diarrhoea, malabsorption, increased intestinal permeability, suboptimal immune response, etc. Nutritional interventions and dietary solutions have not been effective for treatment of malnutrition till date. Metagenomic procedures allow one to access the complex cross-talk between the gut and its microbial flora and understand how a different community composition affects various states of human health. In this study, a metagenomic approach was employed for analysing the differences between gut microbial communities obtained from a malnourished and an apparently healthy child.</p> <p>Results</p> <p>Our results indicate that the malnourished child gut has an abundance of enteric pathogens which are known to cause intestinal inflammation resulting in malabsorption of nutrients. We also identified a few functional sub-systems from these pathogens, which probably impact the overall metabolic capabilities of the malnourished child gut.</p> <p>Conclusion</p> <p>The present study comprehensively characterizes the microbial community resident in the gut of a malnourished child. This study has attempted to extend the understanding of the basis of malnutrition beyond nutrition deprivation.</p

GpnmbR150X allele must be present in bone marrow derived cells to mediate DBA/2J glaucoma

<p>Abstract</p> <p>Background</p> <p>The <it>Gpnmb </it>gene encodes a transmembrane protein whose function(s) remain largely unknown. Here, we assess if a mutant allele of <it>Gpnmb </it>confers susceptibility to glaucoma by altering immune functions. DBA/2J mice have a mutant <it>Gpnmb </it>gene and they develop a form of glaucoma preceded by a pigment dispersing iris disease and abnormalities of the immunosuppressive ocular microenvironment.</p> <p>Results</p> <p>We find that the <it>Gpnmb </it>genotype of bone-marrow derived cell lineages significantly influences the iris disease and the elevation of intraocular pressure. GPNMB localizes to multiple cell types, including pigment producing cells, bone marrow derived F4/80 positive antigen-presenting cells (APCs) of the iris and dendritic cells. We show that APCs of DBA/2J mice fail to induce antigen induced immune deviation (a form of tolerance) when treated with TGFβ2. This demonstrates that some of the immune abnormalities previously identified in DBA/2J mice result from intrinsic defects in APCs. However, the tested APC defects are not dependent on a mutant <it>Gpnmb </it>gene. Finally, we show that the <it>Gpnmb </it>mediated iris disease does not require elevated IL18 or mature B or T lymphocytes.</p> <p>Conclusion</p> <p>These results establish a role for <it>Gpnmb </it>in bone marrow derived lineages. They suggest that affects of <it>Gpnmb </it>on innate immunity influence susceptibility to glaucoma in DBA/2J mice.</p

Profiling leucocyte subsets in tuberculosis-diabetes co-morbidity

The immune system plays an important role in the pathogenesis of pulmonary tuberculosis–type 2 diabetes mellitus (PTB-DM) co-morbidity. However, the phenotypic profile of leucocyte subsets at homeostasis in individuals with active or latent tuberculosis (LTB) with coincident diabetes is not known. To characterize the influence of diabetes on leucocyte phenotypes in PTB or LTB, we examined the frequency (F(o)) of leucocyte subsets in individuals with TB with (PTB-DM) or without (PTB) diabetes; individuals with latent TB with (LTB-DM) or without (LTB) diabetes and non-TB-infected individuals with (NTB-DM) or without (NTB) diabetes. Coincident DM is characterized by significantly lower F(o) of effector memory CD4(+) T cells in LTB individuals. In contrast, DM is characterized by significantly lower F(o) of effector memory CD8(+) T cells and significantly higher F(o) of central memory CD8(+) T cells in PTB individuals. Coincident DM resulted in significantly higher F(o) of classical memory B cells in PTB and significantly higher F(o) of activated memory and atypical B cells in LTB individuals. Coincident DM resulted in significantly lower F(o) of classical and intermediate monocytes in PTB, LTB and NTB individuals. Finally, DM resulted in significantly lower F(o) of myeloid and plasmacytoid dendritic cells in PTB, LTB and NTB individuals. Our data reveal that coincident diabetes alters the cellular subset distribution of T cells, B cells, dendritic cells and monocytes in both individuals with active TB and those with latent TB, thus potentially impacting the pathogenesis of this co-morbid condition

Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation

Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the pro-inflammatory IL-1β-HIF-1α axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions by inhibiting succinate dehydrogenase-mediated oxidation of succinate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1(−/−) mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages

Neurodevelopmental disorders in children aged 2-9 years: Population-based burden estimates across five regions in India.

BACKGROUND: Neurodevelopmental disorders (NDDs) compromise the development and attainment of full social and economic potential at individual, family, community, and country levels. Paucity of data on NDDs slows down policy and programmatic action in most developing countries despite perceived high burden. METHODS AND FINDINGS: We assessed 3,964 children (with almost equal number of boys and girls distributed in 2-<6 and 6-9 year age categories) identified from five geographically diverse populations in India using cluster sampling technique (probability proportionate to population size). These were from the North-Central, i.e., Palwal (N = 998; all rural, 16.4% non-Hindu, 25.3% from scheduled caste/tribe [SC-ST] [these are considered underserved communities who are eligible for affirmative action]); North, i.e., Kangra (N = 997; 91.6% rural, 3.7% non-Hindu, 25.3% SC-ST); East, i.e., Dhenkanal (N = 981; 89.8% rural, 1.2% non-Hindu, 38.0% SC-ST); South, i.e., Hyderabad (N = 495; all urban, 25.7% non-Hindu, 27.3% SC-ST) and West, i.e., North Goa (N = 493; 68.0% rural, 11.4% non-Hindu, 18.5% SC-ST). All children were assessed for vision impairment (VI), epilepsy (Epi), neuromotor impairments including cerebral palsy (NMI-CP), hearing impairment (HI), speech and language disorders, autism spectrum disorders (ASDs), and intellectual disability (ID). Furthermore, 6-9-year-old children were also assessed for attention deficit hyperactivity disorder (ADHD) and learning disorders (LDs). We standardized sample characteristics as per Census of India 2011 to arrive at district level and all-sites-pooled estimates. Site-specific prevalence of any of seven NDDs in 2-<6 year olds ranged from 2.9% (95% CI 1.6-5.5) to 18.7% (95% CI 14.7-23.6), and for any of nine NDDs in the 6-9-year-old children, from 6.5% (95% CI 4.6-9.1) to 18.5% (95% CI 15.3-22.3). Two or more NDDs were present in 0.4% (95% CI 0.1-1.7) to 4.3% (95% CI 2.2-8.2) in the younger age category and 0.7% (95% CI 0.2-2.0) to 5.3% (95% CI 3.3-8.2) in the older age category. All-site-pooled estimates for NDDs were 9.2% (95% CI 7.5-11.2) and 13.6% (95% CI 11.3-16.2) in children of 2-<6 and 6-9 year age categories, respectively, without significant difference according to gender, rural/urban residence, or religion; almost one-fifth of these children had more than one NDD. The pooled estimates for prevalence increased by up to three percentage points when these were adjusted for national rates of stunting or low birth weight (LBW). HI, ID, speech and language disorders, Epi, and LDs were the common NDDs across sites. Upon risk modelling, noninstitutional delivery, history of perinatal asphyxia, neonatal illness, postnatal neurological/brain infections, stunting, LBW/prematurity, and older age category (6-9 year) were significantly associated with NDDs. The study sample was underrepresentative of stunting and LBW and had a 15.6% refusal. These factors could be contributing to underestimation of the true NDD burden in our population. CONCLUSIONS: The study identifies NDDs in children aged 2-9 years as a significant public health burden for India. HI was higher than and ASD prevalence comparable to the published global literature. Most risk factors of NDDs were modifiable and amenable to public health interventions

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570