Infections caused by the fungal pathogen Aspergillus fumigatus are increasingly resistant to first-line azole antifungal drugs. However, despite its clinical importance, little is known about how susceptible patients acquire infection from drug-resistant genotypes in the environment. Here, we present a population genomic analysis of 218 A. fumigatus isolates from across the UK and Ireland (comprising 153 clinical isolates from 143 patients and 65 environmental isolates). First, phylogenomic analysis shows strong genetic structuring into two clades (A and B) with little interclade recombination and the majority of environmental azole resistance found within clade A. Second, we show occurrences where azole-resistant isolates of near-identical genotypes were obtained from both environmental and clinical sources, indicating with high confidence the infection of patients with resistant isolates transmitted from the environment. Third, genome-wide scans identified selective sweeps across multiple regions indicating a polygenic basis to the trait in some genetic backgrounds. These signatures of positive selection are seen for loci containing the canonical genes encoding fungicide resistance in the ergosterol biosynthetic pathway, while other regions under selection have no defined function. Lastly, pan-genome analysis identified genes linked to azole resistance and previously unknown resistance mechanisms. Understanding the environmental drivers and genetic basis of evolving fungal drug resistance needs urgent attention, especially in light of increasing numbers of patients with severe viral respiratory tract infections who are susceptible to opportunistic fungal superinfections.

We investigated whether plants imported to Ireland from the Netherlands might harbor triazole-resistant Aspergillus fumigatus. Samples of plant bulbs were positive for triazole-resistant A. fumigatus with CYP51A mutations. We hypothesize that this represents a route for intercountry transfer of an emerging resistance mechanism in a major opportunistic mold pathogen.

This study provides a rationale for the therapeutic effect of itraconazole and implied that the therapeutic potential of vitamin D supplementation in preventing ABPA is only feasible with concurrent elimination of A. fumigatus to permit VDR expression and its positive functional consequences.

SUMMARY The clinical features and outcome of idiopathic acute transverse myelopathy were reviewed for 21 children aged between seven months and 14 years. Pain, most commonly in the back, was the initial symptom for 12 patients; for another six it was weakness and for two urinary retention. All patients had weakness of the legs, and 11 had arm weakness as well. Five patients had very acute onset of severe weakness and were unable to walk within three hours of onset of symptoms. Two children made no significant recovery; for the remainder onset of recovery was evident within two to 17 days. 12 patients later were normal or had only minimal neurological deficit, but nine had a poor outcome with major disturbance of motor or sphincter function. Only one of the five with very acute onset had a good outcome. Over–all, the prognosis after acute transverse myelopathy in childhood is a little better than that reported for adults. RÉSUMÉ Myélopathie transverse aigue de l'enfance Les caractéristiques cliniques et le devenir de la myélopathie transverse aigue myélopathique ont été précisées chez 21 enfants âgés de sept mois á 14 ans. La douleur, le plus fréquemment au niveau du dos, a été le symptome initial chez 12 sujets. Ce fut une faiblesse chez six sujets et une rétention urinaire chez deux sujets. Tous les sujets présentaient des faiblesses des jambes, associées chez 11 d'entre eux á des faiblesses des bras. Un début par faiblesse trés sévere de caractére trés aigu est survenu chez cinq sujets qui ont été incapables de marcher dans les trois heures du début des Symptômes. II n'y a pas eu de ré cupération significative chez deux enfants; pour les autres, le début de la récupé ration a étéévident aprés deux á 17 jours. Chez 12 sujets, le devenir ultérieur a été normal ou marqué seulement par un déficit neurologique minime, mais l'évolution a été mauvaise dans neuf cas avec troubles graves des fonctions motrices ou sphinctériennes. Un seul parmi les cinq enfants avec début brutal a eu un bon devenir. Globalement, le pronostic de la myélopathie transverse de I'enfance est un peu meilleur que ce qui a été rapporté chez les adultes. ZUSAMMENFASSUNG Akute Querschnittsmyelopathie im Kindesalter Bei 21 Kindern im Alter zwischen sieben Monaten und 14 Jahren wurden die klinischen Merkmale und Endbefunde der akuten idiopathischen Querschnittsmyelopathie zusammengestellt. Bei 12 Patienten war der Schmerz, meistens im Rücken, das erste Symptom: weitere sechs gaben Schwache und zwei eine Harnverhaltung an. Alle Patienten gaben Schwache in den Beine an und 11 klagten zusätzlich über Schwäche in den Armen. Fünf Patienten hatten einen sehr akuten Beginn mit hochgradiger Schwäche und konnten innerhalb von drei Stunden nicht mehr laufen. Zwei Kinder hatten sich nicht wesentlich gebessert; bei den restlichen stelite sich nach zwei bis 17 Tagen eine Besserung ein. 12 Patienten waren später gesund und hatten nur geringfügige neurologische Befunde, aber neun hatten ein schlechtes Endergebnis mit einer deutlichen Störung der motorischen‐oder...

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γδ T cells expressing the Vδ1 TCR are expanded in patients with HIV infection. We show in this article that circulating Vδ1 T cell numbers are particularly high in patients with HIV and candidiasis, and that these cells expand and produce IL-17 in response to Candida albicans in vitro. Although C. albicans could directly stimulate IL-17 production by a subset of Vδ1 T cells, fungus-treated dendritic cells (DCs) were required to expand C. albicans–responsive Vδ1 T cells to generate sufficient numbers of cells to release IL-17 at levels detectable by ELISA. C. albicans induced the release of IL-1β, IL-6, and IL-23 by DCs, but addition of these cytokines or supernatants of C. albicans–treated DCs to Vδ1 T cells was not sufficient to induce proliferation. We found that direct contact with DCs was required for Vδ1 T cell proliferation, whereas IL-23R–blocking studies showed that IL-23 was required for optimal C. albicans–induced IL-17 production. Because IL-17 affords protection against both HIV and C. albicans, and because Vδ1 T cells are not depleted by HIV, these cells are likely to be an important source of IL-17 in HIV-infected patients with candidiasis, in whom CD4+ Th17 responses are impaired. These data show that C. albicans stimulates proliferation and IL-17 production by Vδ1 T cells by a mechanism that involves IL-23 release by DCs.

Infections caused by opportunistic fungal pathogens are increasingly resistant to first-line azole antifungal drugs. However, despite its clinical importance, little is known about the extent to which susceptible patients acquire infection from drug resistant genotypes in the environment. Here, we present a population genomic analysis of the mould Aspergillus fumigatus from across the United Kingdom and Republic of Ireland. First, we show occurrences where azole resistant isolates of near identical genotypes were obtained from both environmental and clinical sources, indicating with high confidence the infection of patients with resistant isolates transmitted from the environment. Second, we find that the fungus is structured into two clades ('A' and 'B') with little interclade recombination and the majority of environmental azole resistance genetically clustered inside Clade A. Genome-scans show the impact of selective sweeps across multiple regions of the genome. These signatures of positive selection are seen in regions containing canonical genes encoding fungicide resistance in the ergosterol biosynthetic pathway, whilst other regions under selection have no defined function. Phenotyping identified genes in these regions that could act as modifiers of resistance showing the utility of reverse genetic approaches to dissect the complex genomic architecture of fungal drug resistance. Understanding the environmental drivers and genetic basis of evolving fungal drug resistance needs urgent attention, especially in light of increasing numbers of patients with severe viral respiratory tract infections who are susceptible to opportunistic fungal superinfections.

Human γδ T cells expressing the Vδ1 T cell receptor (TCR) recognize self and microbial antigens and stress-inducible molecules in a major histocompatibility complex-unrestricted manner and are an important source of innate interleukin (IL)-17. Vδ1 T cells are expanded in the circulation and intestines of patients with human immunodeficiency virus (HIV) infection. In this study, we show that patients with HIV have elevated frequencies, but not absolute numbers, of circulating Vδ1 T cells compared to control subjects. This increase was most striking in the patients with Candida albicans co-infection. Using flow cytometry and confocal microscopy, we identify two populations of Vδ1 T cells, based on low and high expression of the ε chain of the CD3 protein complex responsible for transducing TCR-mediated signals (denoted CD3εlo and CD3εhi Vδ1 T cells). Both Vδ1 T cell populations expressed the CD3 ζ-chain, also used for TCR signaling. Using lines of Vδ1 T cells generated from healthy donors, we show that CD3ε can be transiently downregulated by activation but that its expression is restored over time in culture in the presence of exogenous IL-2. Compared to CD3εhi Vδ1 T cells, CD3εlo Vδ1 T cells more frequently expressed terminally differentiated phenotypes and the negative regulator of T cell activation, programmed death-1 (PD-1), but not lymphocyte-activation gene 3, and upon stimulation in vitro, only the CD3εhi subset of Vδ1 T cells, produced IL-17. Thus, while HIV can infect and kill IL-17-producing CD4+ T cells, Vδ1 T cells are another source of IL-17, but many of them exist in a state of exhaustion, mediated either by the induction of PD-1 or by downregulation of CD3ε expression.