The extensive genetic diversity of HIV-1 is a major challenge for the prevention and treatment of HIV-1 infections. Subtype C accounts for most of the HIV-1 infections in the world but has been ...mainly localized in Southern Africa, Ethiopia and India. For elusive reasons, South Brazil harbors the largest HIV-1 subtype C epidemic in the American continent that is elsewhere dominated by subtype B. To investigate this topic, we collected clinical data and viral sequences from 2611 treatment-naïve patients diagnosed with HIV-1 in Brazil. Molecular epidemiology analysis supported 35 well-delimited transmission clusters of subtype C highlighting transmission within South Brazil but also from the South to all other Brazilian regions and internationally. Individuals infected with subtype C had lower probability to be deficient in CD4
T cells when compared to subtype B. The HIV-1 epidemics in the South was characterized by high female-to-male infection ratios and women-to-child transmission. Our results suggest that HIV-1 subtype C probably takes advantage of longer asymptomatic periods to maximize transmission and is unlikely to outcompete subtype B in settings where the infection of women is relatively less relevant. This study contributes to elucidate factors possibly underlying the geographical distribution and expansion patterns of the most spread HIV-1 subtypes.
Cytokinesis is the last step of cell division that physically partitions the mother cell into two daughter cells. Cytokinesis requires the assembly and constriction of a contractile ring, a ...circumferential array of filamentous actin (F-actin), non-muscle myosin II motors (myosin), and actin-binding proteins that forms at the cell equator. Cytokinesis is accompanied by long-range cortical flows from regions of relaxation toward regions of compression. In the
C. elegans
one-cell embryo, it has been suggested that anterior-directed cortical flows are the main driver of contractile ring assembly. Here, we use embryos co-expressing motor-dead and wild-type myosin to show that cortical flows can be severely reduced without major effects on contractile ring assembly and timely completion of cytokinesis. Fluorescence recovery after photobleaching in the ingressing furrow reveals that myosin recruitment kinetics are also unaffected by the absence of cortical flows. We find that myosin cooperates with the F-actin crosslinker plastin to align and compact F-actin bundles at the cell equator, and that this cross-talk is essential for cytokinesis. Our results thus argue against the idea that cortical flows are a major determinant of contractile ring assembly. Instead, we propose that contractile ring assembly requires localized concerted action of motor-competent myosin and plastin at the cell equator.
The dry season is a major challenge for Plasmodium falciparum parasites in many malaria endemic regions, where water availability limits mosquito vectors to only part of the year. How P. falciparum ...bridges two transmission seasons months apart, without being cleared by the human host or compromising host survival, is poorly understood. Here we show that low levels of P. falciparum parasites persist in the blood of asymptomatic Malian individuals during the 5- to 6-month dry season, rarely causing symptoms and minimally affecting the host immune response. Parasites isolated during the dry season are transcriptionally distinct from those of individuals with febrile malaria in the transmission season, coinciding with longer circulation within each replicative cycle of parasitized erythrocytes without adhering to the vascular endothelium. Low parasite levels during the dry season are not due to impaired replication but rather to increased splenic clearance of longer-circulating infected erythrocytes, which likely maintain parasitemias below clinical and immunological radar. We propose that P. falciparum virulence in areas of seasonal malaria transmission is regulated so that the parasite decreases its endothelial binding capacity, allowing increased splenic clearance and enabling several months of subclinical parasite persistence.
The success of antiretroviral treatment (ART) is threatened by the emergence of drug resistance mutations (DRM). Since Brazil presents the largest number of people living with HIV (PLWH) in South ...America we aimed at understanding the dynamics of DRM in this country. We analyzed a total of 20,226 HIV-1 sequences collected from PLWH undergoing ART between 2008–2017. Results show a mild decline of DRM over the years but an increase of the K65R reverse transcriptase mutation from 2.23% to 12.11%. This increase gradually occurred following alterations in the ART regimens replacing zidovudine (AZT) with tenofovir (TDF). PLWH harboring the K65R had significantly higher viral loads than those without this mutation (p < 0.001). Among the two most prevalent HIV-1 subtypes (B and C) there was a significant (p < 0.001) association of K65R with subtype C (11.26%) when compared with subtype B (9.27%). Nonetheless, evidence for K65R transmission in Brazil was found both for C and B subtypes. Additionally, artificial neural network-based immunoinformatic predictions suggest that K65R could enhance viral recognition by HLA-B27 that has relatively low prevalence in the Brazilian population. Overall, the results suggest that tenofovir-based regimens need to be carefully monitored particularly in settings with subtype C and specific HLA profiles.
In response to infection, macrophages adapt their metabolism rapidly to enhance glycolysis and fuel specialized antimicrobial effector functions. Here we show that fungal melanin is an essential ...molecule required for the metabolic rewiring of macrophages during infection with the fungal pathogen Aspergillus fumigatus. Using pharmacological and genetic tools, we reveal a molecular link between calcium sequestration by melanin inside the phagosome and induction of glycolysis required for efficient innate immune responses. By remodeling the intracellular calcium machinery and impairing signaling via calmodulin, melanin drives an immunometabolic signaling axis towards glycolysis with activation of hypoxia-inducible factor 1 subunit alpha (HIF-1α) and phagosomal recruitment of mammalian target of rapamycin (mTOR). These data demonstrate a pivotal mechanism in the immunometabolic regulation of macrophages during fungal infection and highlight the metabolic repurposing of immune cells as a potential therapeutic strategy.
The accumulation of adipose tissue macrophages (ATMs) in obesity has been associated with hepatic injury. However, the ATMs contribution to hepatic fibrosis in non-alcoholic fatty liver disease ...(NAFLD) remains to be elucidated. Herein, we investigate the relationship between ATMs and liver fibrosis in NAFLD patients and evaluate the impact of ATMs modulation over hepatic fibrosis in an experimental NASH model.
Adipose tissue and liver biopsies from 42 NAFLD patients with different fibrosis stages were collected. ATMs were characterized by immunohistochemistry and flow cytometry and correlation between ATMs and liver fibrosis stages was assessed. Selective modulation of ATMs phenotype was achieved by ip administration of dextran coupled with dexamethasone in diet induced obese and NASH murine models. Chronic administration effects were evaluated by histology and gene expression analysis in adipose tissue and liver samples. In vitro crosstalk between human ATMs and hepatic stellate cells (HSC) and liver spheroids was performed.
NAFLD patients presented an increased accumulation of pro-inflammatory ATMs that correlated with hepatic fibrosis. Long term modulation of ATMs significantly reduced pro-inflammatory phenotype and ameliorated adipose tissue inflammation. Moreover, ATMs modulation was associated with an improvement in steatosis and hepatic inflammation and significantly reduced fibrosis progression in an experimental NASH model. In vitro, the reduction of the pro-inflammatory phenotype of human ATMs with dextran-dexamethasone treatment reduced the secretion of inflammatory chemokines and directly attenuated the pro-fibrogenic response in HSC and liver spheroids.
Pro-inflammatory ATMs increase in parallel with fibrosis degree in NAFLD patients and their modulation in an experimental NASH model improves liver fibrosis, uncovering the potential of ATMs as a therapeutic target to mitigate liver fibrosis in NAFLD.
We report that human adipose tissue pro-inflammatory macrophages correlate with hepatic fibrosis in NAFLD. Furthermore, the modulation of adipose tissue macrophages by dextran-nanocarrier conjugated with dexamethasone shifts the pro-inflammatory phenotype of ATM to an anti-inflammatory phenotype in an experimental murine model of NASH. This shift ameliorates adipose tissue inflammation, hepatic inflammation and fibrosis. Our results highlight the relevance of adipose tissue in NAFLD pathophysiology and unveil ATMs as a potential target for NAFLD.
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•Pro-inflammatory ATMs are associated with fibrosis in NAFLD patients.•Dextran coupled with dexamethasone administrated ip selective target ATMs•Long term ATMs modulation reduces their pro-inflammatory phenotype in obese and NASH mice•Modulation of ATMs reduces hepatic fibrosis by attenuating hepatic stellate cells activation
The European rabbit (Oryctolagus cuniculus) populations of the Iberian Peninsula have been severely affected by the emergence of the rabbit haemorrhagic disease virus (RHDV) Lagovirus europaeus/GI.2 ...(RHDV2/b). Bushflies and blowflies (Muscidae and Calliphoridae families, respectively) are important RHDV vectors in Oceania, but their epidemiological role is unknown in the native range of the European rabbit. In this study, scavenging flies were collected between June 2018 and February 2019 in baited traps at one site in southern Portugal, alongside a longitudinal capture-mark-recapture study of a wild European rabbit population, aiming to provide evidence of mechanical transmission of GI.2 by flies. Fly abundance, particularly from Calliphoridae and Muscidae families, peaked in October 2018 and in February 2019. By employing molecular tools, we were able to detect the presence of GI.2 in flies belonging to the families Calliphoridae, Muscidae, Fanniidae and Drosophilidae. The positive samples were detected during an RHD outbreak and absent in samples collected when no evidence of viral circulation in the local rabbit population was found. We were able to sequence a short viral genomic fragment, confirming its identity as RHDV GI.2. The results suggest that scavenging flies may act as mechanical vectors of GI.2 in the native range of the southwestern Iberian subspecies O. cuniculus algirus. Future studies should better assess their potential in the epidemiology of RHD and as a tool for monitoring viral circulation in the field.
Epidemiological evidence on the health risks of sulfur dioxide (
) is more limited compared with other pollutants, and doubts remain on several aspects, such as the form of the exposure-response ...relationship, the potential role of copollutants, as well as the actual risk at low concentrations and possible temporal variation in risks.
Our aim was to assess the short-term association between exposure to
and daily mortality in a large multilocation data set, using advanced study designs and statistical techniques.
The analysis included 43,729,018 deaths that occurred in 399 cities within 23 countries between 1980 and 2018. A two-stage design was applied to assess the association between the daily concentration of
and mortality counts, including first-stage time-series regressions and second-stage multilevel random-effect meta-analyses. Secondary analyses assessed the exposure-response shape and the lag structure using spline terms and distributed lag models, respectively, and temporal variations in risk using a longitudinal meta-regression. Bi-pollutant models were applied to examine confounding effects of particulate matter with an aerodynamic diameter of
(
) and
(
), ozone, nitrogen dioxide, and carbon monoxide. Associations were reported as relative risks (RRs) and fractions of excess deaths.
The average daily concentration of
across the 399 cities was
, with 4.7% of days above the World Health Organization (WHO) guideline limit (
, 24-h average), although the exceedances occurred predominantly in specific locations. Exposure levels decreased considerably during the study period, from an average concentration of
in 1980-1989 to
in 2010-2018. For all locations combined, a
increase in daily
was associated with an RR of mortality of 1.0045 95% confidence interval (CI): 1.0019, 1.0070, with the risk being stable over time but with substantial between-country heterogeneity. Short-term exposure to
was associated with an excess mortality fraction of 0.50% 95% empirical CI (eCI): 0.42%, 0.57% in the 399 cities, although decreasing from 0.74% (0.61%, 0.85%) in 1980-1989 to 0.37% (0.27%, 0.47%) in 2010-2018. There was some evidence of nonlinearity, with a steep exposure-response relationship at low concentrations and the risk attenuating at higher levels. The relevant lag window was 0-3 d. Significant positive associations remained after controlling for other pollutants.
The analysis revealed independent mortality risks associated with short-term exposure to
, with no evidence of a threshold. Levels below the current WHO guidelines for 24-h averages were still associated with substantial excess mortality, indicating the potential benefits of stricter air quality standards. https://doi.org/10.1289/EHP11112.
HIV-1 subtypes associate with differences in transmission and disease progression. Thus, the existence of geographic hotspots of subtype diversity deepens the complexity of HIV-1/AIDS control. The ...already high subtype diversity in Portugal seems to be increasing due to infections with sub-subtype A1 virus. We performed phylogenetic analysis of 65 A1 sequences newly obtained from 14 Portuguese hospitals and 425 closely related database sequences. 80% of the A1 Portuguese isolates gathered in a main phylogenetic clade (MA1). Six transmission clusters were identified in MA1, encompassing isolates from Portugal, Spain, France, and United Kingdom. The most common transmission route identified was men who have sex with men. The origin of the MA1 was linked to Greece, with the first introduction to Portugal dating back to 1996 (95% HPD: 1993.6-1999.2). Individuals infected with MA1 virus revealed lower viral loads and higher CD4
T-cell counts in comparison with those infected by subtype B. The expanding A1 clusters in Portugal are connected to other European countries and share a recent common ancestor with the Greek A1 outbreak. The recent expansion of this HIV-1 subtype might be related to a slower disease progression leading to a population level delay in its diagnostic.
The extracellular matrix (ECM) plays an undisputable role in tissue homeostasis and its deregulation leads to altered mechanical and biochemical cues that impact cancer development and progression. ...Herein, we undertook a novel approach to address the role of gastric ECM in tumorigenesis, which remained largely unexplored. By combining decellularization techniques with a high-throughput quantitative proteomics approach, we have performed an extensive characterization of human gastric mucosa, uncovering its composition and distribution among tumor, normal adjacent and normal distant mucosa. Our results revealed a common ECM signature composed of 142 proteins and indicated that gastric carcinogenesis encompasses ECM remodeling through alterations in the abundance of 24 components, mainly basement membrane proteins. Indeed, we could only identify one
tumor-specific protein, the collagen alpha-1(X) chain (COL10A1). Functional analysis of the data demonstrated that gastric ECM remodeling favors tumor progression by activating ECM receptors and cellular processes involved in angiogenesis and cell-extrinsic metabolic regulation. By analyzing mRNA expression in an independent GC cohort available at the TGCA, we validated the expression profile of 12 differentially expressed ECM proteins. Importantly, the expression of COL1A2, LOX and LTBP2 significantly correlated with high tumor stage, with LOX and LTBP2 further impacting patient overall survival. These findings contribute for a better understanding of GC biology and highlight the role of core ECM components in gastric carcinogenesis and their clinical relevance as biomarkers of disease prognosis.
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