is a filamentous fungus which can cause multiple diseases in humans. Allergic broncho-pulmonary aspergillosis (ABPA) is a disease diagnosed primarily in cystic fibrosis patients caused by a severe ...allergic response often to long-term
colonization in the lungs. Mice develop an allergic response to repeated inhalation of
spores; however, no strains have been identified that can survive long-term in the mouse lung and cause ABPA-like disease. We characterized
strain W72310, which was isolated from the expectorated sputum of an ABPA patient, by whole-genome sequencing and
and
viability assays in comparison to a common reference strain, CEA10. W72310 was resistant to leukocyte-mediated killing and persisted in the mouse lung longer than CEA10, a phenotype that correlated with greater resistance to oxidative stressors, hydrogen peroxide, and menadione,
In animals both sensitized and challenged with W72310, conidia, but not hyphae, were viable in the lungs for up to 21 days in association with eosinophilic airway inflammation, airway leakage, serum IgE, and mucus production. W72310-sensitized mice that were recall challenged with conidia had increased inflammation, Th1 and Th2 cytokines, and airway leakage compared to controls. Collectively, our studies demonstrate that a unique strain of
resistant to leukocyte killing can persist in the mouse lung in conidial form and elicit features of ABPA-like disease.
Allergic broncho-pulmonary aspergillosis (ABPA) patients often present with long-term colonization of
Current understanding of ABPA pathogenesis has been complicated by a lack of long-term
fungal persistence models. We have identified a clinical isolate of
, W72310, which persists in the murine lung and causes an ABPA-like disease phenotype. Surprisingly, while viable, W72310 showed little to no growth beyond the conidial stage in the lung. This indicates that it is possible that
can cause allergic disease in the lung without any significant hyphal growth. The identification of this strain of
can be used not only to better understand disease pathogenesis of ABPA and potential antifungal treatments but also to identify features of fungal strains that drive long-term fungal persistence in the lung. Consequently, these observations are a step toward helping resolve the long-standing question of when to utilize antifungal therapies in patients with ABPA and fungal allergic-type diseases.
Microbes expertly manipulate hosts to their advantage, but few completely escape detection. In this issue of Cell Host & Microbe, Takaki et al. (2021) describe how Schistosoma mansoni eggs ...choreograph macrophage behaviors to promote efficient transmission of mature eggs, while immature eggs remain safely hidden in plain sight.
Microbes expertly manipulate hosts to their advantage, but few completely escape detection. In this issue of Cell Host & Microbe, Takaki et al. (2021) describe how Schistosoma mansoni eggs choreograph macrophage behaviors to promote efficient transmission of mature eggs, while immature eggs remain safely hidden in plain sight.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We present an electron-pairs-based method employing a generalized valence bond perfect-pairing (GVB-PP) ansatz that provides a uniformly accurate description of systems where various types of ...electron correlation play a role and the GVB-PP wave function is a suitable reference. In the proposed EERPA-GVB approach, a GVB-PP energy is amended by adding correlation among electron pairs. The latter is achieved by embedding single pairs or couples of pairs in the environment of the other electron fragments and separately accounting for intra- and interfragment correlation effects. For this purpose, we employ truncated extended random phase approximation equations. Application of EERPA-GVB to systems governed by both short-range (energy barriers) and long-range (molecular interactions) correlation effects proves the good accuracy of the method. Moreover, EERPA-GVB is shown to cure a notorious problem of uncorrelated electron-pair models, namely, spatial symmetry breaking in aromatic molecules, using the example of benzene. We have also successfully applied EERPA-GVB to a challenging problem of a phase transition of the boron chain system, where the correlation changes its character along the reaction path. The accuracy and versatility of EERPA-GVB are accompanied by its attractively low computational cost. By truncation of the extended RPA equations and consideration of only at most two-fragment correlation contributions, the cost of computing the EERPA correlation energy is reduced to scale only quadratically with the number of pairs of electrons.
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IJS, KILJ, NUK, PNG, UL, UM
Infection tissue microenvironments are dynamic, complex, and play a critical role in host-microbe interaction outcomes. A crucial parameter of the infection site microenvironment is oxygen. Both host ...and microbial cell physiology is significantly impacted by the availability of oxygen. When oxygen tensions drop to levels that do not meet the metabolic demands of the cell, a hypoxia response ensues. In numerous host-microbe studies, it has now been observed that the host and microbial hypoxia response plays a critical role in disease outcomes. However, in most pathosystems, spatial and temporal oxygen dynamics throughout the infection remain ill defined. Here, we detail a protocol for detecting low oxygen environments in tissue in a murine model of invasive pulmonary aspergillosis. The protocol utilizes mice immune compromised with a high dose of steroid and challenged via the aerosol route with conidia of the major human fungal pathogen Aspergillus fumigatus. Qualitative analysis of oxygen levels at the site of infection in the murine lung is accomplished with pimonidazole-mediated adduct detection via immunohistochemistry. The protocol is adaptable to other host-microbe interaction models.
Pseudomonas aeruginosa strains with loss-of-function mutations in the transcription factor LasR are frequently encountered in the clinic and the environment. Among the characteristics common to ...LasR-defective (LasR−) strains is increased activity of the transcription factor Anr, relative to their LasR+ counterparts, in low-oxygen conditions. One of the Anr-regulated genes found to be highly induced in LasR− strains was PA14_42860 (PA1673), which we named mhr for microoxic hemerythrin. Purified P. aeruginosa Mhr protein contained the predicted di-iron center and bound molecular oxygen with an apparent Kd
of ~1 μM. Both Anr and Mhr were necessary for fitness in lasR+ and lasR mutant strains in colony biofilms grown in microoxic conditions, and the effects were more striking in the lasR mutant. Among genes in the Anr regulon, mhr was most closely coregulated with the Anr-controlled high-affinity cytochrome c oxidase genes. In the absence of high-affinity cytochrome c oxidases, deletion of mhr no longer caused a fitness disadvantage, suggesting that Mhr works in concert with microoxic respiration. We demonstrate that Anr and Mhr contribute to LasR− strain fitness even in biofilms grown in normoxic conditions. Furthermore, metabolomics data indicate that, in a lasR mutant, expression of Anr-regulated mhr leads to differences in metabolism in cells grown on lysogeny broth or artificial sputum medium. We propose that increased Anr activity leads to higher levels of the oxygen-binding protein Mhr, which confers an advantage to lasR mutants in microoxic conditions.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
A
bstract
Isolated photons with high transverse energy have been studied in deep inelastic
ep
scattering with the ZEUS detector at HERA, using an integrated luminosity of 326 pb
−1
in the range of ...exchanged-photon virtuality 10-350 GeV
2
. Outgoing isolated photons with transverse energy 4 <
E
T
γ
< 15 GeV and pseudorapidity − 0.7 <
η
γ
< 0.9 were measured with accompanying jets having transverse energy and pseudorapidity 2.5 <
E
T
jet
< 35 GeV and −1
.
5
< η
jet
<
1
.
8, respectively. Differential cross sections are presented for the following variables: the fraction of the incoming photon energy and momentum that is transferred to the outgoing photon and the leading jet; the fraction of the incoming proton energy transferred to the photon and leading jet; the differences in azimuthal angle and pseudorapidity between the outgoing photon and the leading jet and between the outgoing photon and the scattered electron. Comparisons are made with theoretical predictions: a leading-logarithm Monte Carlo simulation, a next-to-leading-order QCD prediction, and a prediction using the
k
T
-factorisation approach.
Heterogeneity among
isolates results in unique virulence potential and inflammatory responses. How these isolates drive specific immune responses and how this affects fungally induced lung damage and ...disease outcome are unresolved. We demonstrate that the highly virulent CEA10 strain is able to rapidly germinate within the immunocompetent lung environment, inducing greater lung damage, vascular leakage, and interleukin 1α (IL-1α) release than the low-virulence Af293 strain, which germinates with a lower frequency in this environment. Importantly, the clearance of CEA10 was consequently dependent on IL-1α, in contrast to Af293. The release of IL-1α occurred by a caspase 1/11- and P2XR7-independent mechanism but was dependent on calpain activity. Our finding that early fungal conidium germination drives greater lung damage and IL-1α-dependent inflammation is supported by three independent experimental lines. First, pregermination of Af293 prior to
challenge drives greater lung damage and an IL-1α-dependent neutrophil response. Second, the more virulent EVOL20 strain, derived from Af293, is able to germinate in the airways, leading to enhanced lung damage and IL-1α-dependent inflammation and fungal clearance. Third, primary environmental
isolates that rapidly germinate under airway conditions follow the same trend toward IL-1α dependency. Our data support the hypothesis that
phenotypic variation significantly contributes to disease outcomes.
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