Long-term antibiotic exposure promotes mortality after systemic fungal infection by driving lymphocyte dysfunction and systemic escape of commensal bacteria

Absence of Bacteria Permits Fungal Gut-To-Brain Translocation and Invasion in Germfree Mice but Ageing Alone Does Not Drive Pathobiont Expansion in Conventionally Raised Mice

“…Our data shows that disruption of the intestinal environment by antibiotic treatment permits increased fungal colonisation of the intestinal tract, but suggest that short term-antibiotic treatment is not sufficient to promote dissemination to the brain. On the other hand, recent data show that long-term chronic administration of antibiotics can promote systemic dissemination of both fungi and bacteria ( Drummond et al, 2022 ). Advanced age is also associated with changing gut bacterial composition, as well as depleted barrier integrity promoting chronic systemic inflammageing ( Fransen et al, 2017 ; Thevaranjan et al, 2017 ; Parker et al, 2022 ).…”

“…We also found that while short-term antibiotic pre-treatment allowed for increased expansion of C. albicans in colonised SPF mice, compared to PBS pre-treated controls, no fungal cells, either in yeast or hyphal form, were detected in the brains of the colonised mice. Drummond and colleagues ( Drummond et al, 2022 ) have recently shown that chronic exposure to antibiotics (>4 weeks in mice or >7 days in humans) can promote fungal and bacterial dissemination to other organs, however, brains were not assessed for fungal cell staining in the mouse studies so it is unclear whether a longer antibiotic regimen might allow for dissemination into the brain tissues. SPF mice may be resistant to brain infection by C. albicans , as intestinal mucins can inhibit hyphal formation by C. albicans ( Kavanaugh et al, 2014 ) and the mucus layer differs in composition between SPF and germ-free mice ( Johansson et al, 2014 ; Jakobsson et al, 2015 ).…”

A gut-oral microbiome–driven axis controls oropharyngeal candidiasis through retinoic acid

“…Mice and humans lacking IL-17 receptor signaling pathway components are highly susceptible to OPC (9,11). Antibiotic use is also associated with increased susceptibility to candidiasis, including both mucosal but also the more life-threatening systemic form of invasive C. albicans infection (25,68). The last decade has seen an exciting upsurge of our understanding of the composition and influence of the microbiome on immune homeostasis, due in part to more widespread access to gnotobiotic facilities and advances in defining the composition of the bacterial microbiome.…”

“…Gut-associated C. albicans also orchestrates extraintestinal events, including a surprising observation of effects on promoting social behavior (76,77). A recent report shows that long-term antibiotic use, specifically vancomycin that targets SFB, promotes susceptibility to invasive candidiasis in mice, which is linked to reduced Th17 cells and reduced diversity in the microbiome (68).…”

Defective antifungal immunity in patients with COVID-19

“…It is unclear whether this reflects the pathogenesis of COVID-19 creating an environment suited to IFD, if clinical interventions and treatments for COVID-19 increase the risk of IFD or its associated with the presence of pre-existing conditions with established links to IFD within the vast COVID-19 population. On infection, COVID-19 binds to angiotensin-converting enzyme 2 (ACE-2) receptors found on respiratory epithelial cells and leads to transient impairment of ciliary motility, limiting muco-ciliary clearance and innate immune function ( 39 ). Cellular uptake and viral replication instigates a pro-inflammatory immune response and in severe cases generates a cytokine storm characterized by increased inflammatory markers including IFN-α, Interleukin (IL)-1Ra and several type 1 (IFN-γ, IL-12p70), type 2 (IL-4, IL-5) and type 3 cytokines (IL-17A, IL-22) and chemokines that direct leukocyte trafficking (C-C Motif Chemokine Ligand 2 (CCL2), C-X-C Motif Chemokine Ligand 9 (CXCL9)) ( 40 ).…”