Since long-term corticosteroid treatment is associated with emerging opportunistic fungal infections causing high morbidity and mortality in immune-suppressed individuals, here we characterized the impact of dexamethasone (Dex) treatment on Aspergillus fumigatus-related immune modulation. We found by high content screening and flow cytometric analyses that during monocyte-to-macrophage differentiation, as little as 0.1 µg/mL Dex resulted in a shift in macrophage polarization from M1 to M2-like macrophages. This macrophage repolarization mediated via Dex was characterized by significant upregulation of the M2 marker CD163 and downmodulation of M1 markers CD40 and CD86 as well as changes in phenotypic properties and adherence. These Dex-mediated phenotypic alterations were furthermore associated with a metabolic switch in macrophages orchestrated via PKM2. Such treated macrophages lost their ability to prevent Aspergillus fumigatus germination, which was correlated with accelerated fungal growth, destruction of macrophages, and induction of an anti-inflammatory cytokine profile. Taken together, repolarization of macrophages following corticosteroid treatment and concomitant switch to an anti-inflammatory phenotype might play a prominent role in triggering invasive aspergillosis (IA) due to suppression of innate immunological responses necessary to combat extensive fungal outgrowth.

Lung immunity and susceptibility to infections is subject to interactions between the epithelial layer and immune cells residing in the pulmonary space. Aspergillus (A.) fumigatus, the most prevalent pathogenic fungus, affects both upper and lower respiratory tracts of immunocompromised hosts. Several reports implicate corticosteroids as a major risk factor due to their anti-inflammatory and immunosuppressive effects, which are exacerbated by long-term treatment regimens. Here we demonstrate for the first time the influence of dexamethasone when it comes to germination and hyphae formation of A. fumigatus in the presence of macrophages within a highly differentiated air–liquid interphase (ALI) epithelial/immune lung model. We illustrate suppressed mucus production within the highly differentiated 3D respiratory model as well as significantly decreased cilia beat frequencies by dexamethasone treatment. This goes along with corticosteroid-mediated macrophage M2 polarization within the epithelial/immune microenvironment. Therefore, we here showed that corticosteroids promote enhanced fungal growth and invasion A. fumigatus by creating a suppressive environment affecting both epithelial as well as immune cells.

Hati hii imetayarishwa kushughulikia maswala ya ustawi wa mifugo nchini Kenya na kuongezeka kwa ujuzi wa wafanyikazi wa mstari wa mbele kuhusiana na swala la viwango na sheria zinazoongoza ustawi wa wanyama. Lengo kuu lilikuwa kutathmini vipengele vya utunzaji wa wanyama, matibabu na ujuzi wa ustawi wa wanyama miongoni mwa wakulima nchini Kenya. Tuligundua ya kwamba wakulima wengi hawaelewi kimsingi ustawi wa wanyama kwa kuwa wengi wao hawajapata mafunzo maalum na wengi wao hawajui sheria zilizopo kuhusu mada hiyo. Wadau wengine walitathminiwa pia kwa madhumuni ya kulinganisha na madaktari wa mifugo na kama ilivyotarajiwa walikuwa na ujuzi zaidi kuhusu ustawi wa wanyama na desturi zinazoikuza. Hata hivyo, kadhaa walionelea kwamba serikali haikuweka juhudi za kutosha katika kukuza ufahamu wa umma au hata kuhamasisha jamii dhidi ya ukatili wa wanyama. Kulingana na maelezo yaliyopatikana, hati hii iliundwa ili kutoa suluhisho ya vitendo linapohusu swala la kuongeza ustawi wa wanyama nchini Kenya. Mapendekezo haya ni pamoja na kuishinikiza serikali kuanzisha sera madhubuti dhidi ya ukatili wa wanyama, kuwahimiza maafisa wa sheria kutekeleza sheria za sasa kwa kutumia mifumo ambayo tayari iko na kuhimiza mazungumzo ya jamii na ushiriki wa moja kwa moja wa watu walio mstari wa mbele.