Data di Pubblicazione:
2021
Citazione:
TACKLING BIOFILM-RELATED OPPORTUNISTIC FUNGAL INFECTIONS / E. Ottaviano ; tutor: E. Borghi ; coordinatore: M. Samaja. Dipartimento di Scienze della Salute, 2021 Jan 21. 33. ciclo, Anno Accademico 2020. [10.13130/ottaviano-emerenziana_phd2021-01-21].
Abstract:
More than 1.5 million people/year die for a biofilm-related fungal
infection. The ability to develop biofilms is widespread among
human opportunistic pathogens, among them fungi. Biofilms are a
community of microorganisms with the ability to attach to surfaces
biotic or abiotic, surrounded by a self-produced extracellular
polymeric matrix. The pathogen clearance and the general
overcoming of the infection are complicated by biofilm presence as
it confers tolerance to antimicrobial treatments. Compromised or
altered immune response and an inflammatory milieu can
exacerbate the pathogenesis and prolong the resolution of the
infection. Candida albicans, between yeasts, and Aspergillus
fumigatus between molds, are pathobionts considered the most
common agents of opportunistic fungi mediated. In our study we
assessed different strategies to eradicate biofilms and counteract
biofilm-related infections, targeting both pathogens and host
immune response. We investigated the efficacy of urinary fractions
after cranberry extract intake by healthy volunteers against C.
albicans biofilm. By mass spectrometry analyses, we identified two
metabolites picking in the most active urine fractions, 5-(3′,4′-
dihydroxy phenyl)-γ-valerolactone and 4-hydroxybenzoic acid,
which revealed a strong inhibitory effect on C. albicans adhesion
and biofilm formation. Both compounds were also able to
downregulate the expression of key genes involved in early phases
of biofilm formation. Due to the spread of the use of catheters or
prostheses in the medical field, the possibility to develop
biomaterials with biofilm inhibitory activity could represent a good
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strategy to control nosocomial infections. We thus investigated
newly synthesized hydrogels and demonstrated their ability to
prevent C. albicans growth.
To target both pathogen virulence and host immune response, we
conducted two different studies, the first on C. albicans systemic
candidiasis and the second on A. fumigatus infection in cystic
fibrosis patients.
We investigated the possible dual action of pilocarpine, a
muscarinic receptor agonist, in vitro and in vivo using the model
host Galleria mellonella. Pilocarpine showed a direct effect in
inhibiting C. albicans biofilm biomass and metabolic activity, and its
administration to infected larvae increased larval survival. Because
of the different behavior of pilocarpine compared to acetylcholine in
the modulation of larva immune response, we concluded that the
antifungal activity of pilocarpine might rely on muscarinic-like
receptor activation on C. albicans, whereas the strong
immunomodulatory effect of acetylcholine (but not of pilocarpine)
might imply the engagement of nicotinic receptors. A similar
approach, aimed at targeting both infection and inflammation, was
used to investigate A. fumigatus persistence in CF patient lungs.
Indeed, CF monocytes are characterized by altered intracellular
lipid accumulation, that compromise pathogen clearance, and the
infection resolution. We demonstrated that the treatment of patient
monocytes with Myriocin, by inhibiting the synthesis of sphingolipids
and hampering CF inflammation, ameliorate the A. fumigatus
conidia internalization and clearance. On the host side, Myriocin
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was able to reduce the over expression of genes encoding for proinflammatory
cytokines and at the same time to increase the
expression of gene encoding for pathogen recognizing receptors,
crucial for its clearance.
Our results indicate that, despite we are still far from clinical
practice, exploring alternative anti-biofilm strategies could pave the
way to new target discovery and to integrated approaches able to
promote the infection resolution.
Tipologia IRIS:
Tesi di dottorato
Elenco autori:
E. Ottaviano
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