Pathogen distribution and, consequently, drug susceptibility seem to vary across different geographic regions. Furthermore, protection from invasive zygomycosis for patients on posaconazole prophylaxis is not absolute. Our findings indicate that the use of liposomal amphotericin B as first-line treatment for patients diagnosed with zygomycoses merits further investigation, preferably in the form of a clinical trial.

Increased IFNα production contributes to the pathogenesis of infectious and autoimmune diseases. Plasmacytoid dendritic cells (pDCs) from females produce more IFNα upon TLR7 stimulation than pDCs from males, yet the mechanisms underlying this difference remain unclear. Here, we show that basal levels of interferon regulatory factor 5 (IRF5) in pDCs were significantly higher in females compared to males and positively correlated with the percentage of IFNα-secreting pDCs. Delivery of recombinant IRF5 protein into human primary pDCs increased TLR7-mediated IFNα secretion. In mice, genetic ablation of the estrogen receptor 1 (Esr1) gene in the hematopoietic compartment or DC lineage reduced IRF5 mRNA expression in pDCs and IFNα production. IRF5 mRNA levels furthermore correlated with Esr1 mRNA levels in human pDCs, consistent with IRF5 regulation at the transcriptional level by Esr1. Taken together, these data demonstrate a critical mechanism by which sex differences in basal pDC IRF5 expression lead to higher IFNα production upon TLR7 stimulation in females, and provide novel targets for the modulation of immune responses and inflammation.

Recent studies indicate that murine Tregs highly express the ENTDP1, as well as the 5=-NT and thereby, suppress Teff function by extracellular adenosine production. Furthermore, CD73 seems to play a role as costimulatory molecule for T cell differentiation. In this study, we analyzed the expression of CD73 on peripheral and lymph nodal Teffs and Tregs in a cohort of 95 HIV patients at different stages of disease, including LTNP and ECs. In contrast to murine Tregs, CD73 was only expressed on a small minority (ϳ10%) of peripheral Tregs. In contrast, we see high expression of CD73 on peripheral CD8ϩ T cells. In HIV infection, CD73 is markedly reduced on all Teffs and Tregs, regardless of the memory subtype. On CD8 ϩ T cells, a positive correlation between CD73 expression and CD4 counts (Pϭ0.0003) was detected. CD73 expression on CD8 ϩ T cells negatively correlated with HLA-DR (Ͻ0.0001) and PD1 (Pϭ0.0457) expression. The lower CD73 expression on CD8 ϩ T cells was partially reversible after initiation of ART (Pϭ0.0016). Functionally, we observed that CD8 ϩ CD73 ϩ T cells produce more IL-2 upon HIV-specific and unspecific stimulation than their CD73 Ϫ counterparts and show a higher proliferative capacity. These data indicate that down-regulation of CD73 on CD8ϩ T cells correlates with immune activation and leads to functional deficits in HIV infection.

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