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Multiple infectious diseases lead to impaired lung function. Revealing the cellular mechanisms involved in this impairment is crucial for the understanding of how the lungs shift from a physiologic to a pathologic state in each specific condition. In this context, we explored the pathogenesis of Paracoccidioidomycosis, which affects pulmonary functioning. The presence of cells expressing Nestin-GFP has been reported in different tissues, and their roles as tissue-specific progenitors have been stablished in particular organs. Here, we explored how Nestin-GFP+ cells are affected after lung infection by Paracoccidioides brasiliensis, a model of lung granulomatous inflammation with fibrotic outcome. We used Nestin-GFP transgenic mice, parabiosis surgery, confocal microscopy and flow cytometry to investigate the participation of Nestin-GFP+ cells in Paracoccidioides brasiliensis pathogenesis. We revealed that these cells increase in the lungs post-Paracoccidioides brasiliensis infection, accumulating around granulomas. This increase was due mainly to Nestin-GPF+ cells derived from the blood circulation, not associated to blood vessels, that co-express markers suggestive of hematopoietic cells (Sca-1, CD45 and CXCR4). Therefore, our findings suggest that circulating Nestin-GFP+ cells participate in the Paracoccidioides brasiliensis pathogenesis in the lungs.

Host immune responses contribute to dengue’s pathogenesis and severity, yet the possibility that failure in endogenous inflammation resolution pathways could characterise the disease has not been contemplated. The pro-resolving protein Annexin A1 (AnxA1) is known to counterbalance overexuberant inflammation and mast cell (MC) activation. We hypothesised that inadequate AnxA1 engagement underlies the cytokine storm and vascular pathologies associated with dengue disease. Levels of AnxA1 were examined in the plasma of dengue patients and infected mice. Immunocompetent, IFNα/βR-/-, AnxA1-/-and FPR2/ALX-/-mice were infected withDengue virus(DENV) and treated with the AnxA1 mimetic peptide Ac2-26for analysis. Additionally, the effect of Ac2-26on DENV-induced MC degranulation was assessedin vitroandin vivo. We observed that circulating levels of AnxA1 were reduced in dengue patients and DENV-infected mice. While the absence of AnxA1 or its receptor FPR2/ALX aggravated illness in infected mice, treatment with AnxA1 agonistic peptide attenuated disease manifestations. Both clinical outcomes were attributed to modulation of DENV-mediated viral load-independent MC degranulation. We have thereby identified that altered levels of the pro-resolving mediator AnxA1 are of pathological relevance in DENV infection, suggesting FPR2/ALX agonists as a therapeutic target for dengue disease.

Background Zika virus (ZIKV) infection during pregnancy may cause major congenital defects, including microcephaly, ocular, articular and muscle abnormalities, which are collectively defined as Congenital Zika Syndrome. Here, we performed an in-depth characterization of the effects of congenital ZIKV infection (CZI) in immunocompetent mice. Methods Pregnant dams were inoculated with ZIKV on embryonic day 5.5 in the presence or absence of a sub-neutralizing dose of a pan-flavivirus monoclonal antibody (4G2) to evaluate the potential role of antibody-dependent enhancement phenomenon (ADE) during short and long outcomes of CZI. Findings ZIKV infection induced maternal immune activation (MIA), which was associated with occurrence of foetal abnormalities and death. Therapeutic administration of AH-D antiviral peptide during the early stages of pregnancy prevented ZIKV replication and death of offspring. In the post-natal period, CZI was associated with a decrease in whole brain volume, ophthalmologic abnormalities, changes in testicular morphology, and disruption in bone microarchitecture. Some alterations were enhanced in the presence of 4G2 antibody. Interpretation Our results reveal that early maternal ZIKV infection causes several birth defects in immunocompetent mice, which can be potentiated by ADE phenomenon and are associated with MIA. Additionally, antiviral treatment with AH-D peptide may be beneficial during early maternal ZIKV infection. Fund This work was supported by the Brazilian National Science Council (CNPq, Brazil), Minas Gerais Foundation for Science (FAPEMIG), Funding Authority for Studies and Projects (FINEP), Coordination of Superior Level Staff Improvement (CAPES), National Research Foundation of Singapore and Centre for Precision Biology at Nanyang Technological University.

Aboveground biomass is an important predictor of net primary productivity and provision of ecosystem services such as carbon storage and food supply. However, biomass can be a complex and multi-driven ecosystem feature, particularly in tropical forests experiencing human disturbances. Here we examine the potential effects of forest successional stage, species richness, plant assemblage functional composition, rainfall, grazing and soil fertility as drivers of biomass in a human-modified landscape of the Caatinga dry forest. We recorded 8911 stems (DSH ≥ 3) across 35 0.-ha plots and calculated the aboveground biomass adopting allometric model developed specifically for Caatinga dry forest. Caatinga flora was dominated by species bearing moderate to heavy wood, with aboveground biomass concentrated into a few dominating species and narrow stems. Biomass averaged 28.48 ± 23.32 Mg ha−1 with a high cross-stand variation as it resulted from a complex interaction of age of forest stand, rainfall and species richness; i.e. old-growth forest stands supported twice as much biomass (38.81 ± 25.08 Mg ha−1) than successional stands (14.68 ± 10.52 Mg ha−1). Drivers of plot-level biomass also affected biomass at species level as well as the abundance of the species which contributed most for forest biomass. Our results confirm that slash-and-burn agriculture supports the emergence of biomass mosaics associated to the presence of old-growth and successional forest stands of varying age. In this context, Caattinga supports reduced forest biomass, which responds to both natural and human–driven forces and their complex interactions. Moreover, biomass persistence in human-modified landscapes requires not only long fallow periods, but also the protection of species-rich forest assemblages.

Multiple infectious diseases lead to impaired lung function. Revealing the cellular mechanisms involved in this impairment is crucial for the understanding of how the lungs shift from a physiologic to a pathologic state in each specific condition. In this context, we explored the pathogenesis of Paracoccidioidomycosis, which affects pulmonary functioning. The presence of cells expressing Nestin-GFP has been reported in different tissues, and their roles as tissue-specific progenitors have been stablished in particular organs. Here, we explored how Nestin-GFP

ObjectiveDengue fever is one of the most important arboviral diseases in the world, and its severe forms are characterised by a broad spectrum of systemic and cardiovascular hallmarks. However, much remains to be elucidated regarding the pathogenesis triggered by Dengue virus (DENV) in the heart. Herein, we evaluated the cardiac outcomes unleashed by DENV infection and the possible mechanisms associated with these effects.MethodsA model of an adapted DENV-3 strain was used to infect male BALB/c mice to assess haemodynamic measurements and the functional, electrophysiological, inflammatory and oxidative parameters in the heart.ResultsDENV-3 infection resulted in increased systemic inflammation and vascular permeability with consequent reduction of systolic blood pressure and increase in heart rate. These changes were accompanied by a decrease in the cardiac output and stroke volume, with a reduction trend in the left ventricular end-systolic and end-diastolic diameters and volumes. Also, there was a reduction trend in the calcium current density in the ventricular cardiomyocytes of DENV-3 infected mice. Indeed, DENV-3 infection led to leucocyte infiltration and production of inflammatory mediators in the heart, causing pericarditis and myocarditis. Moreover, increased reactive oxygen species generation and lipoperoxidation were also verified in the cardiac tissue of DENV-3 infected mice.ConclusionsDENV-3 infection induced a marked cardiac dysfunction, which may be associated with inflammation, oxidative stress and electrophysiological changes in the heart. These findings provide new cardiac insights into the mechanisms involved in the pathogenesis triggered by DENV, contributing to the research of new therapeutic targets for clinical practice.

Mayaro virus (MAYV) is endemic in South American countries where it is responsible for sporadic outbreaks of acute febrile illness. The hallmark of MAYV infection is a highly debilitating and chronic arthralgia. Although MAYV emergence is a potential threat, there are no specific therapies or licensed vaccine. In this study, we developed a murine model of MAYV infection that emulates many of the most relevant clinical features of the infection in humans and tested a live-attenuated MAYV vaccine candidate (MAYV/IRES). Intraplantar inoculation of a WT strain of MAYV into immunocompetent mice induced persistent hypernociception, transient viral replication in target organs, systemic production of inflammatory cytokines, chemokines and specific humoral IgM and IgG responses. Inoculation of MAYV/IRES in BALB/c mice induced strong specific cellular and humoral responses. Moreover, MAYV/IRES vaccination of immunocompetent and interferon receptor-defective mice resulted in protection from disease induced by the virulent wt MAYV strain. Thus, this study describes a novel model of MAYV infection in immunocompetent mice and highlights the potential role of a live-attenuated MAYV vaccine candidate in host’s protection from disease induced by a virulent MAYV strain.

Chronic ethanol consumption is a leading cause of mortality worldwide, with higher risks to develop pulmonary infections, including Aspergillus infections. Mechanisms underlying increased susceptibility to infections are poorly understood. Chronic ethanol consumption induced increased mortality rates, higher Aspergillus fumigatus burden and reduced neutrophil recruitment into the airways. Intravital microscopy showed decrease in leukocyte adhesion and rolling after ethanol consumption. Moreover, downregulated neutrophil activation and increased levels of serum CXCL1 in ethanol-fed mice induced internalization of CXCR2 receptor in circulating neutrophils. Bone marrow-derived neutrophils from ethanol-fed mice showed lower fungal clearance and defective reactive oxygen species production. Taken together, results showed that ethanol affects activation, recruitment, phagocytosis and killing functions of neutrophils, causing susceptibility to pulmonary A. fumigatus infection. This study establishes a new paradigm in innate immune response in chronic ethanol consumers., eLife digest Alcoholism is a chronic disease that has many damaging effects on the body. Over long periods, excessive alcohol intake weakens the immune system, putting consumers at increased risk of getting lung infections such as pneumonia. Some forms of pneumonia can be caused by the fungus Aspergillus fumigatus. This microbe does not tend to be a problem for healthy individuals, but it can be fatal for those with impaired immune systems. Here, Malacco et al. wanted to find out why excessive alcohol consumers are more prone to pneumonia. To test this, the researchers used two groups of mice that were either fed plain water or water containing ethanol. After 12 weeks, both groups were infected with Aspergillus fumigatus. The results showed that alcohol-fed mice were more susceptible to the infection caused by strong inflammation of the lungs. Normally, the immune system confronts a lung infection by activating a group of defense cells called neutrophils, which travel through the blood system to the infection site. Once in the right spot, neutrophils get to work by releasing toxins that kill the fungus. Malacco et al. discovered that after chronic alcohol consumption, neutrophils were less reactive to inflammatory signals and less likely to reach the lungs. They were also less effective in dealing with the infection. Neutrophil released fewer toxins and were thus less able to kill the microbial cells. These findings demonstrate for the first time how alcohol can affect immune cells during infection and pave the way for new possibilities to prevent fatal lung infections in excessive alcohol consumers. A next step would be to identify how alcohol acts on other processes in the body and to find a way to modulate or even revert the changes it causes.

Transplacental transmission of Zika virus (ZIKV) during early pregnancy may lead to several neurological alterations, known as congenital Zika syndrome. We have previously shown that intravaginal infection of immunocompetent dams with ZIKV during the early stage of pregnancy triggers neuroinflammation in fetuses, characterized by increased brain expression of inflammatory factors, including IL-6, IL-18, CCL2, CXCL1, and CXCL10. The present study sought to understand the long-term consequences of these early cerebral alterations. For that, pregnant FVB/NJ immunocompetent females were infected intravaginally on the gestational day (GD) 4.5 and experiments were performed when offspring reached between 4 to 5 months of age. The exposure to ZIKV promoted significant neuronal cell loss detected in the CA1 region of the hippocampus of adult mice. However, only females showed reduced expression levels of brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD95), and syntaxin-1A, which are important genes related to neuronal function and synaptic plasticity. Moreover, the protein levels of the pre- and postsynaptic markers, SNAP25 and PSD95, respectively, were decreased exclusively in ZIKV-exposed female mice, indicating that ZIKV exposure in utero induces synaptic loss. Additionally, only females exposed to ZIKV showed risk-taking behavior and hippocampal-dependent spatial memory deficit. Together, these results demonstrate that intravaginal infection of mice on GD4.5 induces neurological alterations in the offspring detectable in their adulthood and that female mice, rather than male mice, are more susceptible to ZIKV-induced neurobehavioral alterations. Summary Statement In utero exposure to ZIKV leads to decreased number of neurons in adult mice. Female mice exposed to ZIKV in utero exhibit lower levels of BDNF, a decrease in synaptic markers, memory deficits, and risk-taking behavior during adulthood.

The development of multi-metric indices of chronic anthropogenic disturbance (CAD) from disparate disturbance indicators represents a major challenge for understanding the impacts of CAD on biodiversity, especially in tropical dry areas where livelihoods of local populations are highly dependent on natural resources. We present a conceptual framework for deriving variably integrated, multi-metric measures of CAD from disparate disturbance indicators. Our framework has three steps: (1) identifying the main sources of CAD in the target region, and quantifying them using data of varying levels of spatial and intensity precision; (2) classifying the sources of disturbance into general disturbance pressures, and deriving an index for each; and (3) combining the individual disturbance pressure indices into a fully integrated index that characterizes the overall level of CAD. We apply this framework to Catimbau National Park in the Brazilian Caatinga, using 12 primary data sources to derive disturbance pressure indices relating to livestock, wood extraction and people pressure. The meaningfulness of pressure and overall CAD indices were validated by reference to variation in ant communities. Our analysis revealed notable findings. First, indirect measures from the geographic and socio-ecological context were poorly correlated with direct, field-based measurements, and were therefore of questionable reliability. Second, the three main disturbance pressures were largely independent of each other, which points to complex patterns of resource use by local communities. Third, different weightings of component disturbance pressure indices had little influence on the Global index, making our Global CAD index somewhat insensitive to assessments of the relative importance of different disturbance pressures. Finally, our results caution against a reliance on multivariate ordination to derive integrated indices of disturbance from disparate data sources. Our multi-scale integration of disturbance data can facilitate the analysis of the resource use effects on biodiversity, contributing to effective conservation management and sustainable livelihood development.

Urbanization causes species loss around the world, but its effects on phylogenetic diversity are poorly known in tropical forests. Using a patch-landscape approach in an urbanizing region of the Brazilian Atlantic Forest, we tested whether the increase in landscape urbanization reduces plant species density, phylogenetic richness and divergence, and increases the relatedness among co-occurring individuals and species. We assessed plant responses to urbanization in adult (diameter at breast height > 10 cm) and sapling communities (2.5–10 cm diameter) separately, as saplings are proxies of the future flora. We sampled 2860 woody plants belonging to 155 species in nine circular landscapes with urbanization level varying from 0% to 45%, and estimated the relatedness among the species that have increased and decreased in relative abundance in more urbanized landscapes (winner and losers, respectively). As expected, species density and phylogenetic richness decreased with the increase in urbanization. These responses were consistent for adult and sapling communities, suggesting a persistent loss of species and lineages in more urbanized landscapes. Contrary to our expectations, phylogenetic divergence and structure did not respond to urbanization, indicating that the more urbanized landscapes still retain much evolutionary history. However, because the relatedness among winners was greater than among losers, it is likely that the phylogenetic divergence gradually reduces and the relatedness increases, resulting in impoverished forests with uncertain ability to provide ecosystem services such as carbon storage and pest control. This environmental cost should be taken into account to align urban sprawl with biodiversity conservation.

Zika virus (ZIKV) only induces mild symptoms in adults, however, it can cause congenital Zika syndrome (CZS), including microcephaly. Most of the knowledge on ZIKV pathogenesis was gained using immunocompromised mouse models, which do not fully recapitulate human pathology. Moreover, the study of the host immune response to ZIKV becomes challenging in these animals. Thus, the main goal of this study was to develop an immunocompetent mouse model to study the ZIKV spread and teratogeny. FVB/NJ immune competent dams were infected intravaginally with ZIKV during the early stage of pregnancy. We found that the placentae of most fetuses were positive for ZIKV, while the virus was detected in the brain of only about 42% of the embryos. To investigate the host immune response, we measured the expression of several inflammatory factors. Embryos from ZIKV-infected dams had an increased level of inflammatory factors, as compared to Mock. Next, we compared the gene expression levels in embryos from ZIKV-infected dams that were either negative or positive for ZIKV in the brain. The mRNA levels of viral response genes and cytokines were increased in both ZIKV-positive and negative brains. Interestingly, the levels of chemokines associated with microcephaly in humans, including CCL2 and CXCL10, specifically increased in embryos harboring ZIKV in the embryo brains.

Background The Mayaro virus (MAYV) is an endemic arbovirus in South American countries, where it is responsible for sporadic outbreaks of Mayaro fever. Clinical manifestations include fever, headache, ocular pain, rash, myalgia, and debilitating and persistent polyarthralgia. Understanding the mechanisms associated with MAYV-induced arthritis is of great importance due to the potential for its emergence, urbanization and dispersion to other regions. Methods 15-day old Balb/c mice were infected by two distinct pathways, below the forelimb and in the rear footpad. Animals were observed for a period of 21 days. During this time, they were monitored every 24 hours for disease signs, such as weight loss and muscle weakness. Histological damage in the muscles and joints was evaluated 3, 7, 10, 15 and 20 days post-infection. The cytokine profile in serum and muscles during MAYV infection was evaluated by flow cytometry at different post-infection times. For pain analysis, the animals were submitted to the von Frey test and titre in different organs was evaluated throughout the study to obtain viral kinetics. Findings Infection by two distinct pathways, below the forelimb and in the rear footpad, resulted in a homogeneous viral spread and the development of acute disease in animals. Clinical signs were observed such as ruffled fur, hunched posture, eye irritation and slight gait alteration. In the physical test, both groups presented loss of resistance, which was associated with histopathological damage, including myositis, arthritis, tenosynovitis and periostitis. The immune response was characterized by a strong inflammatory response mediated by the cytokines TNF-α, IL-6 and INF-γ and chemokine MCP-1, followed by the action of IL-10 and IL-4 cytokines. Interpretation The results showed that Balb/c mice represent a promising model to study mechanisms involved in MAYV pathogenesis and for future antiviral testing., Author summary The Mayaro virus, although restricted to some regions of Latin America, has great potential for emergence, which makes it of great medical-scientific interest. Therefore, pathogenesis study of the MAYV in an animal model has fundamental importance for the determination of viral and host factors that contribute to disease development. In addition, it will allow develop and evaluate the effectiveness of possible antiviral agents. In this study, the authors were able to standardize a disease model for the MAYV in BALB / c mice. From the obtained data it is possible to observe the induction of acute arthritis and myositis, accompanied by the reduction of physical strength of the animals. As described for other alphaviruses in both animal models and patient, the proinflammatory mediators TNF-α, IL-6, INF-γ and MCP-1 were elevated in the serum of MAYV-infected animals and therefore appeared to be mediators which also play an important role in the pathogenesis of MAYV.

Irinotecan is a useful chemotherapeutic agent for the treatment of several solid tumors. However, this therapy is associated with side effects, including leukopenia and mucositis. Reactive oxygen species (ROS) activate inflammatory pathways and contribute to Irinotecan-induced mucositis. Fullerol is a nanocomposite with anti-oxidant properties that may reduce tissue damage after inflammatory stimuli. In this paper, the effects of Fullerol and mechanisms of protection were investigated in a model of Irinotecan-induced mucositis. Mucositis was induced by an injection of Irinotecan per 4 days in C57BL/6. Fullerol or a vehicle was injected every 12h. On day 7, the intestines were removed to evaluate histological changes, leukocyte influx, and the production of cytokines and ROS. Irinotecan therapy resulted in weight loss, an increased clinical score and intestinal injury. Treatment with Fullerol attenuated weight loss, decreased clinical score and intestinal damage. Irinotecan also induced increased ROS production in enterocytes, oxidative stress, IL-1β production, neutrophil and eosinophil influx in the ileum. Fullerol treatment decreased production of ROS in the enterocytes, oxidative stress, IL-1β production, neutrophil and eosinophil influx in the ileum. Irinotecan therapy also induced leukopenia in an ROS-dependent manner because leukopenia reverted in WT mice treated with Fullerol or Apocynin or in Gp91phox(-/-) mice. Mice treated with Irinotecan presented less melanoma tumor growth compared to the control group. Fullerol does not interfere in the anti-tumor action of Irinotecan. Fullerol has a great pharmacology potential to decreases the severity of mucositis and of leukopenia during chemotherapy treatment.

The leaves of Echinodorus grandiflorus are traditionally used in Brazil to treat several inflammatory conditions, including arthritis. This study aimed to investigate the antiarthritis activity of the 70 % ethanol extract of E. grandiflorus leaves and a standardized flavonoid-rich fraction in an antigen-induced arthritis model in mice. Previously immunized mice were treated per os with saline (control group), 70 % ethanol extract (100–1000 mg/kg), or a flavonoid-rich fraction (0.7–7.2 mg/kg) 40 minutes before and 3 and 6 hours after the challenge with antigen into the knee joint. The administration of the 70 % ethanol extract and flavonoid-rich fraction to mice significantly reduced neutrophil recruitment to the joint cavity and in periarticular tissue. The levels of chemokine (C–X-C motif) ligand 1, tumor necrosis factor-α, and interleukin-1β quantified by the enzyme-linked immunosorbent assay (ELISA) in the periarticular tissue were also diminished in mice treated with the 70 % ethanol extract and flavonoid-rich fraction, as well as mechanical hypernociception. Histological analysis confirmed that both the 70 % ethanol extract and flavonoid-rich fraction suppressed joint inflammation and inhibited cartilage and bone destruction when compared to the control group. Our results demonstrate, for the first time, that E. grandiflorus has anti-inflammatory activity in an experimental arthritis model and highlights the role of flavonoids in the observed response.

Stryphnodendronspecies, popularly named “barbatimão,” are traditionally used in Brazil as anti-inflammatory agents. This study aimed to investigate the effect of barbatimão and 11 other species on the production of tumor necrosis factor-alpha (TNF-α) in lipopolysaccharide- (LPS-) stimulated THP-1 cells, as well as their anti-arthritis activity. The extracts ofStryphnodendron adstringens,Stryphnodendron obovatum,Campomanesia lineatifolia, andTerminalia glabrescenspromoted a concentration-dependent inhibition of TNF-α. Mice injected with LPS in the knee joint were treatedper oswith fractions from the selected extracts. Both the organic (SAO) and the aqueous (SAA) fractions ofS. adstringenspromoted a dose-dependent reduction of leukocyte migration and neutrophil accumulation into the joint, but none of them reduced CXCL1 concentration in the periarticular tissue. In contrast, treatment withC. lineatifoliaandT. glabrescensfractions did not ameliorate the inflammatory parameters. Analyses of SAO by Ultra Performance Liquid Chromatography (UPLC) coupled to electrospray ionization mass spectrometry (ESI-MS) led to the identification of gallic acid along with 11 prodelphinidins, characterized as monomers and dimers of the B-type. Our findings contribute to some extent to corroborating the traditional use ofS. adstringensas an anti-inflammatory agent. This activity is probably related to a decrease of leukocyte migration into the inflammatory site. Polyphenols like gallic acid and prodelphinidins, identified in the active fraction, may contribute to the observed activity.

International audience; The excessive inflammation often present in patients with severe dengue infection is considered both a hallmark of disease and a target for potential treatments. IL-33 is a pleiotropic cytokine with pro-inflammatory effects whose role in dengue has not been fully elucidated. Here we demonstrate that IL-33 plays a disease-exacerbating role during experimental dengue infection in immunocompetent mice. Mice infected with Dengue virus serotype 2 (DENV2) produced high levels of IL-33. DENV2-infected mice treated with recombinant IL-33 developed markedly more severe disease compared to untreated mice as assessed by mortality, granulocytosis, liver damage and pro-inflammatory cytokine production. Conversely, ST2-/- mice (deficient in IL-33 receptor) infected with DENV2 developed significantly less severe disease compared to wild-type (WT) mice. Furthermore, the increased disease severity and the accompanying pathology induced by IL-33 during dengue infection were reversed by the simultaneous treatment with a CXCR2 receptor antagonist (DF2156A). Together, these results indicate that IL-33 plays a disease-exacerbating role in experimental dengue infection, likely driven by CXCR2-expressing cells, leading to elevated pro-inflammatory response-mediated pathology. Our results also indicate that IL-33 is a potential therapeutic target for dengue infection.

The clinical pathogen Klebsiella pneumoniae is a relevant cause of nosocomial infections, and resistance to current treatment with carbapenem antibiotics is becoming a significant problem. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) used for controlling plasma cholesterol levels. There is clinical evidence showing other effects of statins, including decrease of lung inflammation. In the current study, we show that pretreatment with atorvastatin markedly attenuated lung injury, which was correlated with a reduction in the cellular influx into the alveolar space and lungs and downmodulation of the production of proinflammatory mediators in the initial phase of infection in C57BL/6 mice with K. pneumoniae . However, atorvastatin did not alter the number of bacteria in the lungs and blood of infected mice, despite decreasing local inflammatory response. Interestingly, mice that received combined treatment with atorvastatin and imipenem displayed better survival than mice treated with vehicle, atorvastatin, or imipenem alone. These findings suggest that atorvastatin could be an adjuvant in host-directed therapies for multidrug-resistant K. pneumoniae , based on its powerful pleiotropic immunomodulatory effects. Together with antimicrobial approaches, combination therapy with anti-inflammatory compounds could improve the efficiency of therapy during acute lung infections.

Aims To determine the effects of cytochalasin E, isolated from the extremophile fungus Aspergillus felis, on the cells of Paracoccidioides brasiliensis Pb18. Methods and results Cytochalasin E showed a minimal inhibitory concentration of 3·6 μmol l-1 and minimum fungicidal concentration of 7·2 μmol l-1 on P. brasiliensis by in vitro microdilution and IC50 >964·0 μmol l-1 on murine macrophages. Its selectivity index (>263) indicated that this compound has selectivity for fungal cells. Morphological alterations were determined by optical and fluorescence microscopy, as well as scanning and transmission electron microscopy. Cytochalasin E affected P. brasiliensis bud-forming pseudohyphae, cell morphology, cell walls and cell membranes; caused the release of cellular material; and resulted in the production of reactive oxygen species. In murine macrophages, it affected cytoskeletal actin and inhibited phagocytosis. Conclusion Cytochalasin E may be useful as an antifungal prototype against P. brasiliensis and in studies on phagocytosis. Significance and impact of the study Paracoccidioides spp. are the etiological agents of paracoccidioidomycosis (PCM). Treatment is prolonged to control the clinical manifestations and prevent relapse. The study on the effects of cytochalasin E in P. brasiliensis is important because it can be used as a prototype for new antifungal drugs and consequently, broadens the treatment options for PCM.

Zika virus is a mosquito-borne virus that is associated with neurodegenerative diseases, including Guillain–Barre syndrome1 and congenital Zika syndrome2. As Zika virus targets the nervous system, there is an urgent need to develop therapeutic strategies that inhibit Zika virus infection in the brain. Here, we have engineered a brain-penetrating peptide that works against Zika virus and other mosquito-borne viruses. We evaluated the therapeutic efficacy of the peptide in a lethal Zika virus mouse model exhibiting systemic and brain infection. Therapeutic treatment protected against mortality and markedly reduced clinical symptoms, viral loads and neuroinflammation, as well as mitigated microgliosis, neurodegeneration and brain damage. In addition to controlling systemic infection, the peptide crossed the blood–brain barrier to reduce viral loads in the brain and protected against Zika-virus-induced blood–brain barrier injury. Our findings demonstrate how engineering strategies can be applied to develop peptide therapeutics and support the potential of a brain-penetrating peptide to treat neurotropic viral infections. The Zika virus infects the central nervous system and results in severe brain malformation. An amphiphatic peptide is now shown to penetrate the blood–brain barrier, reducing viral loads due to its activity against Zika and other mosquito-borne viruses.

Animal experimentation is still an important part in research and experimentation, since it is still not possible to completely eliminate animal testing. Therefore, it is necessary to find efficient ways to manage the processes that take place in animal facilities, thus aiding in the achievement of the use of fewer animals and in more humane research methods. Animals for research purposes are usually kept at vivariums. One approach to help in the management of data in these facilities is the use of Laboratory Information Management Systems (LIMS), specific software for the management of laboratory information with emphasis on quality. The present work describes ViMT, a LIMS designed to manage the animal facility of the Federal University of Minas Gerais (UFMG), Brazil. ViMT has been designed as a specialized LIMS having as major objectives a flexible structure that makes it simple to model day by day operations at a vivarium, trackability of operations and an easy to use interface accessible from any computer or smartphone. ViMT has been developed jointly with the UFMG Rodents Vivarium, and is currently being deployed at this facility. It is a fully web-based, platform independent system and can be accessed using browsers.

This study aimed to evaluate the effect of various extracts and fractions obtained from Echinodorus grandiflorus leaves on tumor necrosis factor-α release by lipopolysaccharide-stimulated THP-1 cells, as well as to look at the association between bioactivity and phytochemical composition. To this end, a high-performance liquid chromatography with diode-array detection method was developed and validated, enabling the quantification of seven compounds in E. grandiflorus extracts and fractions. All of these samples showed antitumor necrosis factor-α activity, however, extracts prepared from 50 % EtOH, water and dichloromethane, and a flavonoid-rich fraction elicited the most potent responses. trans-Aconitic acid and isoorientin were the major compounds in some preparations. Polynomial regression analysis showed the association between the contents of swertiajaponin, swertisin, trans-aconitic, and chicoric acids with the antitumor necrosis factor-α activity of the extracts and fractions. None of the compounds tested alone abolished tumor necrosis factor-α release completely, however, some extracts and fractions reached this result, suggesting a synergistic effect between the constituents. Therefore, it is clearly shown that the species E. grandiflorus has significant in vitro antitumor necrosis factor-α activity, a promising characteristic that deserves further investigations in the search for new anti-inflammatory agents from plants.

Nicorandil is a drug characterized by the coupling of a nitric oxide (NO) donor to nicotinamide. We have previously demonstrated that nicotinamide exhibits activity in different models of pain and inflammation. Now, we investigated the effects induced by per os (p.o.) administration of nicorandil (25, 50 or 100mg/Kg) on neutrophil recruitment in a carrageenan-induced model of pleurisy in mice. Effects induced by nicorandil (100mg/kg) were compared with those induced by equimolar doses of nicotinamide (58mg/kg) and N-(2-hydroxyethyl)-nicotinamide (NHN; 79mg/kg). We also investigated whether effects on the production of inflammatory mediators play a role in the activity of nicorandil. P.o. nicorandil, 0.5h before and 1h after the i.pl. injection of carrageenan, reduced neutrophil recruitment. However, equimolar doses of nicotinamide or NHN failed to induce such effect. Single treatment (previous or late) with nicorandil (100mg/Kg, p.o.) also reduced neutrophils recruitment, although to a lesser extent when compared to the double treatment. Nicorandil reduced the concentrations of interleukin-1β, CXCL-1 and prostaglandin E2 in the pleural exudate. Concluding, we demonstrated the activity of nicorandil in a model of pleurisy induced by carrageenan. This activity was characterized by reduction of the neutrophil accumulation and inhibition of production of inflammatory mediators. The effects induced by nicorandil on the leukocytes recruitment and production of inflammatory mediators contribute to a better understanding of its clinical benefits and indicate that these benefits may be due to its vasodilating and anti-inflammatory activities.

Pain is one of the main symptoms of multiple sclerosis, a demyelinating disease of the central nervous system that affects millions of people worldwide. The experimental autoimmune encephalomyelitis (EAE) is considered an experimental model of multiple sclerosis, and besides motor weakness, hypernociception is one of the clinical signs of animals with EAE. In this study, we investigated the influence of some cytokines in the generation of the hypernociceptive response in a mouse model of EAE using MOG35-55. We measured some cytokines in the dorsal root ganglia (DRG), an important anatomical structure involved in pain. We found increased levels of the cytokines TNF-α, IL-1β, and Kc in DRGs of animals with EAE. We used the antibody IL-1ra to antagonize the effects of IL-1β, and animals presented a decrease in the hypernociceptive response. Thus, our results suggest that hypernociception in this experimental model of EAE may be a consequence of the increase in some cytokines in DRGs, especially IL-1β.

Gout manifests as recurrent episodes of acute joint inflammation and pain due to the deposition of monosodium urate (MSU) crystals within the affected tissue in a process dependent on NLRP3 inflammasome activation. The synthesis, activation, and release of IL-1β are crucial for MSU-induced inflammation. The current study evaluated the mechanism by which TNF-α contributed to MSU-induced inflammation. Male C57BL/6J or transgenic mice were used in this study and inflammation was induced by the injection of MSU crystals into the joint. TNF-α was markedly increased in the joint after the injection of MSU. There was inhibition in the infiltration of neutrophils, production of CXCL1 and IL-1β, and decreased hypernociception in mice deficient for TNF-α or its receptors. Pharmacological blockade of TNF-α with Etanercept or pentoxyfylline produced similar results. Mechanistically, TNF-α blockade resulted in lower amounts of IL-1β protein and pro-IL-1β mRNA transcripts in joints. Gene-modified mice that express only transmembrane TNF-α had an inflammatory response similar to that of WT mice and blockade of soluble TNF-α (XPro™1595) did not decrease MSU-induced inflammation. In conclusion, TNF-α drives expression of pro-IL-1β mRNA and IL-1β protein in experimental gout and that its transmembrane form is sufficient to trigger MSU-induced inflammation in mice.

The leaves of Hancornia speciosa Gomes (Apocynaceae), a medicinal species found in the Brazilian cerrado biome, are traditionally used to treat wounds and inflammatory disorders. The goal of the present study was to investigate the in vitro wound healing properties of ethanolic extract of H. speciosa leaves and its isolated compounds, using the scratch assay, and to evaluate their effects on the release of the pro-inflammatory cytokine tumor necrosis factor (TNF-α) by lipopolysaccharide (LPS)-stimulated human acute monocytic (THP-1) cells. H. speciosa ethanolic extract significantly increased (42.8% ± 5.4 at 25 µg/mL) cell migration and proliferation of fibroblasts compared with control cells, as well as the isolated compounds bornesitol (80.8% ± 5.1) and quinic acid (69.1% ± 6.2), both assayed at 50 μM. TNF-α release by LPS-stimulated THP-1 cells was significantly reduced by the ethanolic extract (62.9% ± 8.2, i.e. 1791.1 ± 394.7 pg/mL) at 10 µg/mL, bornesitol (48.9% ± 0.9, i.e. 2461.6 ± 43.1 pg/mL) at 50 μM, and quinic acid (90.2% ± 3.4, i.e. 473.5 ± 164.4 pg/mL) and rutin (82.4% ± 5.6, i.e. 847.0 ± 271.8 pg/mL) at 10 μM. These results provided evidences to support the traditional use of H. speciosa leaves to treat wounds and inflammatory disorders. Copyright © 2015 John Wiley & Sons, Ltd.

Paracoccidioidomycosis (PCM) is a public health concern in Latin America and South America that when not correctly treated can lead to patient death. In this study, the influence of melanin produced by Paracoccidioides spp. on the effects of treatment with antimicrobial photodynamic inhibition (aPI) and antifungal drugs was evaluated. aPI was performed using toluidine blue (TBO) as a photosensitizer and a 630-nm light-emitting diode (LED) light. The antifungals tested were itraconazole and amphotericin B. We evaluated the effects of each approach, aPI or antifungals, against nonmelanized and melanized yeast cells by performing susceptibility tests and by quantifying oxidative and nitrosative bursts during the experiments. aPI reduced nonmelanized cells by 3.0 log units and melanized cells by 1.3 log units. The results showed that melanization protects the fungal cell, probably by acting as a scavenger of nitric oxide and reactive oxygen species, but not of peroxynitrite. Melanin also increased the MICs of itraconazole and amphotericin B, and the drugs were fungicidal for nonmelanized and fungistatic for melanized yeast cells. Our study shows that melanin production by Paracoccidioides yeast cells serves a protective function during aPI and treatment with itraconazole and amphotericin B. The results suggest that melanin binds to the drugs, changing their antifungal activities, and also acts as a scavenger of reactive oxygen species and nitric oxide, but not of peroxynitrite, indicating that peroxynitrite is the main radical that is responsible for fungal death after aPI.

Zika virus (ZIKV) has recently caused a worldwide outbreak of infections associated with severe neurological complications, including microcephaly in infants born from infected mothers. ZIKV exhibits high neurotropism and promotes neuroinflammation and neuronal cell death. We have recently demonstrated that N-methyl-D-aspartate receptor (NMDAR) blockade by memantine prevents ZIKV-induced neuronal cell death. Here we show that ZIKV induces apoptosis in a non-cell autonomous manner, triggering cell death of uninfected neurons by releasing cytotoxic factors. Neuronal cultures infected with ZIKV exhibit increased levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and glutamate. Moreover, infected neurons exhibit increased expression of GluN2B and augmented intracellular Ca2+ concentration. Blockade of GluN2B-containing NMDAR by ifenprodil normalizes Ca2+ levels and rescues neuronal cell death. Notably, TNF-α and IL-1β blockade decreases ZIKV-induced Ca2+ flux through GluN2B-containing NMDARs and reduces neuronal cell death, indicating that these cytokines might contribute to NMDAR sensitization and neurotoxicity. In addition, ZIKV infected cultures treated with ifenprodil exhibits increased activation of the neuroprotective pathway including extracellular signal-regulated kinase (ERK) and cAMP response element binding protein (CREB), which may underlie ifenprodil-mediated neuroprotection. Together, our data shed some light on the neurotoxic mechanisms triggered by ZIKV and begin to elucidate how GluN2B-containing NMDAR blockade can prevent neurotoxicity.

Infection with Plasmodium falciparum may result in severe disease affecting various organs, including liver, spleen, and brain, resulting in high morbidity and mortality. Plasmodium berghei Anka infection of mice recapitulates many features of severe human malaria. The aryl hydrocarbon receptor (AhR) is an intracellular receptor activated by ligands important in the modulation of the inflammatory response. We found that AhR-knockout (KO) mice infected with P. berghei Anka displayed increased parasitemia, earlier mortality, enhanced leukocyte-endothelial cell interactions in the brain microvasculature, and increased inflammation in brain (interleukin-17 [IL-17] and IL-6) and liver (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]) compared to infected wild-type (WT) mice. Infected AhR-KO mice also displayed a reduction in cytokines required for host resistance, including TNF-α, IL-1β, and IFN-γ, in the brain and spleen. Infection of AhR-KO mice resulted in an increase in T regulatory cells and transforming growth factor β, IL-6, and IL-17 in the brain. AhR modulated the basal expression of SOCS3 in spleen and brain, and P. berghei Anka infection resulted in enhanced expression of SOCS3 in brain, which was absent in infected AhR-KO mice. These data suggest that AhR-mediated control of SOCS3 expression is probably involved in the phenotype seen in infected AhR-KO mice. This is, to our knowledge, the first demonstration of a role for AhR in the pathogenesis of malaria.

Chagas disease, caused by Trypanosoma cruzi (Tc), is an important cause of heart disease. Resistance to Tc infection is multifactorial and associated with Th1 response. IL-18 plays an important role in regulation of IFN-γ production/development of Th1 response. However, the role of IL-18 in the setting of Tc infection remains unclear. Therefore, we investigated the role of IL-18 in the modulation of immune response and myocarditis in Tc infection. C57BL/6 and IL-18 KO mice were infected with Tc (Y or Colombian strain) and parasitemia, immune response and pathology were evaluated. Y strain infection of IL-18 KO did not alter any parameters when compared with C57BL/6 mice. However, during the acute phase (20 and 40 days post infection-dpi), Colombian strain infected-IL-18 KO mice displayed higher serum levels of IL-12 and IFN-γ, respectively, and at the chronic phase (100 dpi) an increase in splenic IFN-γ-producing CD4(+) and CD8(+) T memory cells. There was an IL-10, FOXP3 and CD4(+)CD25(+) cells reduction during acute infection in spleen. Additionally, there was a significant reduction in leukocyte infiltration and parasite load in myocardium of chronically infected IL-18 KO mice. Collectively, these data indicate that IL-18 contributes to the pathogenesis of Tc-induced myocarditis when infected with Colombian but not Y strain. These observations also underscore that parasite and host strain differences are important in evaluation of experimental Tc infection pathogenesis.

Trichophyton rubrum is the main etiological agent of dermatophytosis, an infection of the skin that affects millions of people worldwide. In this study, we developed a murine model of the dermatophytosis caused by T. rubrum in which C57BL/6 wild-type, interleukin (IL)-12(-/-), and interferon-gamma (IFN-γ(-/-)) mice were inoculated with 1 × 10(6) conidia/animal. The fungal burden, myeloperoxidase and N-acetylglucosaminidase activities, cytokine and chemokine profiles, and histopathology of the skin were evaluated on the seventh and fourteenth days post infection. Phagocytic indices, intracellular proliferation rates, and oxidative bursts generated by macrophages from WT and IFN-γ(-/-) mice were determined. On day 7 post infection, higher fungal burdens were observed comparison with burdens on day 14 post infection. The IL-12(-/-) and IFN-γ(-/-) mice showed higher fungal burdens on the skin and lower levels of IL-1β. Conversely, the WT mice showed lower fungal burdens with higher production of TNF-α, IL-1β, and chemokine ligand 1/keratinocyte chemoattractant (CXCL1/KC). The macrophages from WT mice proved to be more efficient at engulfing and killing T. rubrum conidia through the production of reactive oxygen species. The results show that our model is a useful tool for understanding the pathogenesis of dermatophytosis caused by T. rubrum and that IL-12 and IFN-γ are pivotal in controlling the infection through the recruitment and activation of neutrophils and macrophages.

Objective The role of platelet-activating factor (PAF) on diet-induced inflammatory and metabolic dysfunction is unknown. The effects of diet-induced metabolic and inflammatory dysfunction in mice with deletion of the PAF receptor (PAFR−/−) were evaluated in this study. Methods Wild-type and PAFR−/− mice were fed chow (WT-C and PAFR−/−-C) or high-refined carbohydrate-containing diet (WT-HC and PAFR−/−-HC). PAFR−/−- Results HC mice gained more weight and adiposity than PAFR−/−-C and WT-HC mice. Lipogenesis increased and hormone-sensitive lipase expression decreased in PAFR−/−-HC compared to WT-HC mice. WT-HC mice had impaired glucose tolerance and insulin sensitivity compared to WT-C mice. In contrast, glucose tolerance and insulin sensitivity in PAFR−/−-HC mice were similar to that of lean littermates. PAFR−/−-HC mice expressed significantly more peroxisome proliferator-activator receptor gamma (PPARγ) than PAFR−/−-C and WT-C mice. Resistin increased in WT-HC mice compared to WT-C mice. However, the levels of resistin were 35% lower in PAFR−/−-HC mice than WT-HC mice. PAFR−/− presented with less HC diet-induced adipose tissue inflammation than WT mice. Adipocytes isolated from PAFR−/− mice incubated in media containing normal or high levels of glucose secreted less interleukin-6 and tumor necrosis factor alpha and presented lower rate of lipolysis than WT mice. Conclusion PAFR deficiency resulted in less inflammation in adipose tissue and improvement in glucose homeostasis when fed the HC diet. The higher adiposity observed in PAFR−/− mice fed HC diet could be owing to the maintenance of insulin sensitivity, decreased adipocyte lipolysis rate, high lipogenesis and PPARγ expression, and lower inflammatory milieu in adipose tissue.

Lithothamnion muelleri (Hapalidiaceae) is a marine red alga, which is a member of a group of algae with anti-inflammatory, antitumor, and immunomodulatory properties. The present study evaluated the effects of treatment with Lithothamnion muelleri extract (LM) in a model of acute graft-versus-host disease (GVHD), using a model of adoptive splenocyte transfer from C57BL/6 donors into B6D2F1 recipient mice. Mice treated with LM showed reduced clinical signs of disease and mortality when compared with untreated mice. LM-treated mice had reduced tissue injury, less bacterial translocation, and decreased levels of proinflammatory cytokines and chemokines (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 3 (CCL3) and chemokine (C-C motif) ligand 5 (CCL5)). The polysaccharide-rich fraction derived from LM could inhibit leukocyte rolling and adhesion in intestinal venules, as assessed by intravital microscopy. LM treatment did not impair the beneficial effects of graft-versus-leukaemia (GVL). Altogether, our studies suggest that treatment with Lithothamnion muelleri has a potential therapeutic application in GVHD treatment.

Dengue disease is a mosquito-borne viral disease of expanding geographical range and incidence. Infection by one of the four serotypes of dengue virus induces a spectrum of disease manifestations, ranging from asymptomatic to life-threatening Dengue hemorrhagic fever/dengue shock syndrome. Many efforts have been made to elucidate several aspects of dengue virus–induced disease, but the pathogenesis of disease is complex and remains unclear. Understanding the mechanisms involved in the early stages of infection is crucial to determine and develop safe therapeutics to prevent the severe outcomes of disease without interfering with control of infection. In this review, we discuss the dual role of the innate and inflammatory pathways activated during dengue disease in mediating both protection and exacerbation of disease. We show that some mediators involved in each of these responses differ substantially, suggesting that interfering in disease-associated immune pathways may represent a potential therapeutic opportunity for the treatment of severe dengue.

Objective: The effects of high-refined carbohydrate-containing diet (HC) on inflammatory parameters and metabolic disarrangement of adipose tissue are poorly understood. The aim of this study was to evaluate the timing and progression of metabolic and inflammatory dysfunction induced by HC diet in mice. Design and Methods: BALB/c mice were fed chow or HC diet for 1 and 3 days, 1, 2, 4, 6, 8, 10, and 12 weeks. Results: Animals given HC diet exhibited acute and sustained increase in visceral adiposity, glucose intolerance, low insulin sensitivity, hyperlipemia, acute increase in mRNA expression of ACC, LPL, PPARc, SREBP-1, and ChREBP and altered circulating levels of adiponectin, resistin, and leptin. There was leucocyte rolling and adhesion on adipose tissue microvessels already at 3 days and until 8 weeks of HC diet. Adipose tissue of mice had increased number of macrophages (M1 and M2), lymphocytes (CD8 þ and CD4 þ Foxp3 þ ), and neutrophils (GR1 þ ) already at 3 days after initiation of HC diet. Overall, concentration of cytokines and chemokines, TNF-a, IL-6, IL-10, TGF-b1, CCL2, and CXCL1, in adipose tissue was elevated throughout the experimental period. Levels of IL-10 and TGF-b1 tended to reach baseline levels at 12 weeks of HC diet. Conclusions: We describe a novel murine model of fat pad expansion induced by HC diet that is characterized by early onset and sustained adipose tissue inflammation and metabolic disarrangement. The acute inflammatory response in adipose tissue occurs very early and is sustained, suggesting that adipose tissue inflammation is a homeostatic mechanism to regulate nutrient overload and adipose expansion.

Dengue virus (DENV), a mosquito-borne flavivirus, is a public health problem in many tropical countries. IL-22 and IL-17A are key cytokines in several infectious and inflammatory diseases. We have assessed the contribution of IL-22 and IL-17A in the pathogenesis of experimental dengue infection using a mouse-adapted DENV serotype 2 strain (P23085) that causes a disease that resembles severe dengue in humans. We show that IL-22 and IL-17A are produced upon DENV-2 infection in immune-competent mice. Infected IL-22(-/-) mice had increased lethality, neutrophil accumulation and pro-inflammatory cytokines in tissues, notably IL-17A. Viral load was increased in spleen and liver of infected IL-22(-/-) mice. There was also more severe liver injury, as seen by increased transaminases levels and tissue histopathology. γδ T cells and NK cells are sources of IL-17A and IL-22, respectively, in liver and spleen. We also show that DENV-infected HepG2 cells treated with rhIL-22 had reduced cell death and decreased IL-6 production. IL-17RA(-/-) mice were protected upon infection and IL-17A-neutralizing-Ab-treatment partially reversed the phenotype observed in IL-22(-/-) -infected mice. We suggest that disrupting the balance between IL-22 and IL-17A levels may represent an important strategy to reduce inflammation and tissue injury associated with severe dengue infection.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in controlling several aspects of immune responses, including the activation and differentiation of specific T cell subsets and antigen-presenting cells, thought to be relevant in the context of experimental Trypanosoma cruzi infection. The relevance of AhR for the outcome of T. cruzi infection is not known and was investigated here. We infected wild-type (WT) mice and AhR knockout (AhR KO) mice with T. cruzi (Y strain) and determined levels of parasitemia, myocardial inflammation and fibrosis, expression of AhR/cytokines/suppressor of cytokine signaling (SOCS) (spleen/heart), and production of nitric oxide (NO), reactive oxygen species (ROS), and peroxynitrite (ONOO − ) (spleen). AhR expression was increased in the heart of infected WT mice. Infected AhR KO mice displayed significantly reduced parasitemia, inflammation, and fibrosis of the myocardium. This was associated with an anticipated increased immune response characterized by increased levels of inflammatory cytokines and reduced expression of SOCS2 and SOCS3 in the heart. In vitro , AhR deficiency caused impairment in parasite replication and decreased levels of ROS production. In conclusion, AhR influences the development of murine Chagas disease by modulating ROS production and regulating the expression of key physiological regulators of inflammation, SOCS1 to -3, associated with the production of cytokines during experimental T. cruzi infection.

The indigenous intestinal microbiota is frequently considered an additional major organ of the human body and exerts profound immunomodulating activities. Germ-free (GF) mice display a significantly different inflammatory responsiveness pattern compared with conventional (CV) mice, and this was dubbed a “hyporesponsive phenotype.” Taking into account that the deposition of immune complexes is a major event in acute inflammation and that GF mice have a distinct Ig repertoire and B cell activity, we aimed to evaluate whether this altered Ig repertoire interferes with the inflammatory responsiveness of GF mice. We found that serum transfer from CV naive mice was capable of reversing the inflammatory hyporesponsiveness of GF mice in sterile inflammatory injury induced by intestinal ischemia and reperfusion, as well as in a model of lung infection by Klebsiella pneumoniae. Transferring serum from Ig-deficient mice to GF animals did not alter their response to inflammatory insult; however, injecting purified Abs from CV animals restored inflammatory responsiveness in GF mice, suggesting that natural Abs present in serum were responsible for altering GF responsiveness. Mechanistically, injection of serum and Ig from CV mice into GF animals restored IgG deposition, leukocyte influx, NF-κB activation, and proinflammatory gene expression in inflamed tissues and concomitantly downregulated annexin-1 and IL-10 production. Thus, our data show that microbiota-induced natural Abs are pivotal for host inflammatory responsiveness to sterile and infectious insults.