We identified seasonal human coronaviruses, influenza viruses and rhinoviruses in exhaled breath and coughs of children and adults with acute respiratory illness. Surgical face masks significantly ...reduced detection of influenza virus RNA in respiratory droplets and coronavirus RNA in aerosols, with a trend toward reduced detection of coronavirus RNA in respiratory droplets. Our results indicate that surgical face masks could prevent transmission of human coronaviruses and influenza viruses from symptomatic individuals.
Interleukin 10 (IL-10) is an anti-inflammatory cytokine that plays a critical role in the control of immune responses. However, its mechanisms of action remain poorly understood. Here, we show that ...IL-10 opposes the switch to the metabolic program induced by inflammatory stimuli in macrophages. Specifically, we show that IL-10 inhibits lipopolysaccharide-induced glucose uptake and glycolysis and promotes oxidative phosphorylation. Furthermore, IL-10 suppresses mammalian target of rapamycin (mTOR) activity through the induction of an mTOR inhibitor, DDIT4. Consequently, IL-10 promotes mitophagy that eliminates dysfunctional mitochondria characterized by low membrane potential and a high level of reactive oxygen species. In the absence of IL-10 signaling, macrophages accumulate damaged mitochondria in a mouse model of colitis and inflammatory bowel disease patients, and this results in dysregulated activation of the NLRP3 inflammasome and production of IL-1β.
Interstitial osmolality is a key homeostatic variable that varies depending on the tissue microenvironment. Mammalian cells have effective mechanisms to cope with osmotic stress by engaging various ...adaptation responses. Hyperosmolality due to high dietary salt intake has been linked to pathological inflammatory conditions. Little is known about the mechanisms of sensing the hyperosmotic stress by the innate immune system. Here we report that caspase-1 is activated in macrophages under hypertonic conditions. Mice with high dietary salt intake display enhanced induction of Th17 response upon immunization, and this effect is abolished in caspase-1-deficient mice. Our findings identify an unknown function of the inflammasome as a sensor of hyperosmotic stress, which is crucial for the induction of inflammatory Th17 response.
Plasticity of cortical responses in vivo involves activity-dependent changes at synapses, but the manner in which different forms of synaptic plasticity act together to create functional changes in ...neurons remains unknown. We found that spike timing-induced receptive field plasticity of visual cortex neurons in mice is anchored by increases in the synaptic strength of identified spines. This is accompanied by a decrease in the strength of adjacent spines on a slower time scale. The locally coordinated potentiation and depression of spines involves prominent AMPA receptor redistribution via targeted expression of the immediate early gene product Arc. Hebbian strengthening of activated synapses and heterosynaptic weakening of adjacent synapses thus cooperatively orchestrate cell-wide plasticity of functional neuronal responses.
Mannose-binding lectin and innate immunity Eddie Ip, W.K; Takahashi, Kazue; Alan Ezekowitz, R ...
Immunological reviews,
July 2009, Letnik:
230, Številka:
1
Journal Article
Recenzirano
Innate immunity is the earliest response to invading microbes and acts to contain infection in the first minutes to hours of challenge. Unlike adaptive immunity that relies upon clonal expansion of ...cells that emerge days after antigenic challenge, the innate immune response is immediate. Soluble mediators, including complement components and the mannose binding lectin (MBL) make an important contribution to innate immune protection and work along with epithelial barriers, cellular defenses such as phagocytosis, and pattern-recognition receptors that trigger pro-inflammatory signaling cascades. These four aspects of the innate immune system act in concert to protect from pathogen invasion. Our work has focused on understanding the protection provided by this complex defense system and, as discussed in this review, the particular contribution of soluble mediators such as MBL and phagocytic cells. Over the past two decades both human epidemiological data and mouse models have indicated that MBL plays a critical role in innate immune protection against a number of pathogens. As demonstrated by our recent in vitro work, we show that MBL and the innate immune signaling triggered by the canonical pattern-recognition receptors (PRRs), the Toll-like receptors (TLRs), are linked by their spatial localization to the phagosome. These observations demonstrated a novel role for MBL as a TLR co-receptor and establishes a new paradigm for the role of opsonins, which we propose to function not only to increase microbial uptake but also to spatially coordinate, amplify, and synchronize innate immune defenses mechanism. In this review we discuss both the attributes of MBL that make it a unique soluble pattern recognition molecule and also highlight its broader role in coordinating innate immune activation.
Phagocytosis is a fundamental cellular process that is pivotal for immunity as it coordinates microbial killing, innate immune activation and antigen presentation. An essential step in this process ...is phagosome acidification, which regulates many functions of these organelles that allow phagosomes to participate in processes that are essential to both innate and adaptive immunity. Here we report that acidification of phagosomes containing Gram-positive bacteria is regulated by the NLRP3 inflammasome and caspase-1. Active caspase-1 accumulates on phagosomes and acts locally to control the pH by modulating buffering by the NADPH oxidase NOX2. These data provide insight into a mechanism by which innate immune signals can modify cellular defenses and establish a new function for the NLRP3 inflammasome and caspase-1 in host defense.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Rett syndrome (RTT) is an X-linked, neurodevelopmental disorder caused primarily by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, which encodes a multifunctional epigenetic regulator ...with known links to a wide spectrum of neuropsychiatric disorders. Although postnatal functions of MeCP2 have been thoroughly investigated, its role in prenatal brain development remains poorly understood. Given the well-established importance of microRNAs (miRNAs) in neurogenesis, we employed isogenic human RTT patient-derived induced pluripotent stem cell (iPSC) and MeCP2 short hairpin RNA knockdown approaches to identify novel MeCP2-regulated miRNAs enriched during early human neuronal development. Focusing on the most dysregulated miRNAs, we found miR-199 and miR-214 to be increased during early brain development and to differentially regulate extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase and protein kinase B (PKB/AKT) signaling. In parallel, we characterized the effects on human neurogenesis and neuronal differentiation brought about by MeCP2 deficiency using both monolayer and three-dimensional (cerebral organoid) patient-derived and MeCP2-deficient neuronal culture models. Inhibiting miR-199 or miR-214 expression in iPSC-derived neural progenitors deficient in MeCP2 restored AKT and ERK activation, respectively, and ameliorated the observed alterations in neuronal differentiation. Moreover, overexpression of miR-199 or miR-214 in the wild-type mouse embryonic brains was sufficient to disturb neurogenesis and neuronal migration in a similar manner to Mecp2 knockdown. Taken together, our data support a novel miRNA-mediated pathway downstream of MeCP2 that influences neurogenesis via interactions with central molecular hubs linked to autism spectrum disorders.
Influenza A viruses evolve rapidly to escape host immunity, causing reinfection. The form and duration of protection after each influenza virus infection are poorly understood. We quantify the ...dynamics of protective immunity by fitting individual-level mechanistic models to longitudinal serology from children and adults. We find that most protection in children but not adults correlates with antibody titers to the hemagglutinin surface protein. Protection against circulating strains wanes to half of peak levels 3.5-7 years after infection in both age groups, and wanes faster against influenza A(H3N2) than A(H1N1)pdm09. Protection against H3N2 lasts longer in adults than in children. Our results suggest that influenza antibody responses shift focus with age from the mutable hemagglutinin head to other epitopes, consistent with the theory of original antigenic sin, and might affect protection. Imprinting, or primary infection with a subtype, has modest to no effect on the risk of non-medically attended infections in adults.
Background. The relationship between seasonal influenza vaccine and susceptibility to 2009 pandemic A/H1N1 virus infection is not fully understood. Methods. One child 6–15 years of age from each of ...119 households was randomized to receive 1 dose of inactivated trivalent seasonal influenza vaccine (TIV) or saline placebo in November 2008. Serum samples were collected from study subjects and their household contacts before and 1 month after vaccination (December 2008), after winter (April 2009) and summer influenza (September–October 2009) seasons. Seasonal and pandemic influenza were confirmed by serum hemagglutinination inhibition, viral neutralization titers, and reverse-transcription polymerase chain reaction performed on nasal and throat swab samples collected during illness episodes. Results. TIV recipients had lower rates of serologically confirmed seasonal A/H1N1 infection (TIV group, 8%; placebo group, 21%; P = .10) and A/H3N2 infection (7% vs 12%; P = .49), but higher rates of pandemic A/H1N1 infection (32% vs 17%; P = .09). In multivariable analysis, those infected with seasonal influenza A during the study had a lower risk of laboratory-confirmed pandemic A/H1N1 infection (adjusted odds ratio OR, 0.35; 95% confidence interval CI, 0.14–0.87), and receipt of seasonal TIV was unassociated with risk of pandemic A/H1N1 infection (adjusted OR, 1.11; 95% CI, 0.54–2.26). Conclusions. TIV protected against strain-matched infection in children. Seasonal influenza infection appeared to confer cross-protection against pandemic influenza. Whether prior seasonal influenza vaccination affects the risk of infection with the pandemic strain requires additional study. Clinical trials registration. ClinicalTrials.gov number NCT00792051.
Influenza A viruses are believed to spread between humans through contact, large respiratory droplets and small particle droplet nuclei (aerosols), but the relative importance of each of these modes ...of transmission is unclear. Volunteer studies suggest that infections via aerosol transmission may have a higher risk of febrile illness. Here we apply a mathematical model to data from randomized controlled trials of hand hygiene and surgical face masks in Hong Kong and Bangkok households. In these particular environments, inferences on the relative importance of modes of transmission are facilitated by information on the timing of secondary infections and apparent differences in clinical presentation of secondary infections resulting from aerosol transmission. We find that aerosol transmission accounts for approximately half of all transmission events. This implies that measures to reduce transmission by contact or large droplets may not be sufficient to control influenza A virus transmission in households.
PDF
