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Resolving the temporal and spatial splenic proteome during fungal infection for putative dual perspective biomarker discovery

ABSTRACT: Fungal pathogens are emerging threats to global health and the rise of incidence is associated with climate change and increased geographical distribution; factors also influencing host susceptibility to infection. Accurate detection and diagnosis of fungal infections is paramount to align options for rapid and effective therapeutic treatments. For improved diagnostics, the discovery and development of biomarkers presents a promising avenue; however, this approach requires a priori knowledge of markers of infection. To uncover putative novel biomarkers of disease, profiling of the host immune response and pathogen virulence factor production is indispensable. In this study, we use mass spectrometry-based proteomics to resolve the temporal and spatial proteomes of Cryptococcus neoformans infection of the spleen following a murine model of infection. Dual perspective proteome profiling defines global remodeling of the host over a time course of infection, confirming activation of immune associated proteins connected to fungal infections. Conversely, pathogen proteomes detect well-characterized C. neoformans virulence determinants, along with novel mapped patterns of pathogenesis during progression of disease. Together, our systematic approach confirms immune protection against fungal pathogens and explores the discovery of putative biomarkers from complementary biological systems for monitoring the presence and progression of cryptococcal disease.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spleen

DISEASE(S): Cryptococcosis

SUBMITTER: Benjamin Muselius

LAB HEAD: Jennifer Geddes-McAlister

PROVIDER: PXD040868 | Pride | 2023-05-23

REPOSITORIES: Pride

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			Action	DRS
	OxidationM-Sites.txt	Txt
	RD166_220815_Spleen_A1.raw	Raw
	RD166_220815_Spleen_A2.raw	Raw
	RD166_220815_Spleen_A3.raw	Raw
	RD166_220815_Spleen_A4.raw	Raw

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Project description:Minerals are essential for proper cell function. In infectious processes where both cells of the causative agent and the host itself are involved, competition for their acquisition is necessary. In this context, pathogenic fungi have developed machinery to ensure the acquisition of minerals and at the same time have perfected strategies that protect them from intoxication by excess of them. In eukaryotic cells, minerals are involved both in the respiratory chain and in cellular metabolisms, which in microorganisms are related to the expression of virulence factors, while in the host, they are related to the activation and regulation of the immune system In the activation of phagocytic cells, in addition, the host can regulate the availability of minerals, which has been called nutritional immunity. Cryptococcosis is an opportunistic mycosis, acquired by inhaling fungal propagules present in the environment; it is a potentially fatal infection that affects the lungs and the central nervous system, both in immunosuppressed and immunocompetent people. The infection is caused by two species, namely: Cryptococcus neoformans (var. grubii (serotype A), var. neoformans (serotype D) and a hybrid corresponding to serotype AD) and Cryptococcus gattii (serotypes B and C). These species present phenotypic, genotypic and epidemiological differences, as well as in their geographical distribution. In recent years, mechanisms for the acquisition of iron and copper, among other micronutrients, have been described in C. neoformans, as well as their relationship, both with the expression of genes associated with virulence factors, the interaction with different intracellular signaling pathways. , especially in routes involved in adaptation to environmental changes and stress conditions. The regulation of the acquisition of these minerals is mediated by several signaling pathways, as the Rim 101 pathway in C. neoformans is essential in adapting to the change in pH and is particular to fungal cells. Iron and copper have been related to the induction of virulence through the production of melanin, capsules and the formation of titan cells, as well as enzymes related to oxidation-reduction phenomena and other virulence factors, which can be regulated by the factor of RIM101 transcription, this pathway induces the expression of genes that encode an iron transporter and a permease (SIT1 and CFT1, respectively) and a copper transporter (CTR4). This enables the yeast to survive in the host because it can rapidly transition from a slightly acidic environment in the phagolysosome to a slightly alkaline environment such as cerebrospinal fluid and serum. For mycoses in general, alternative therapies have been proposed, where the regulation of the acquisition of minerals in the tissue environment during the establishment of the mycosis could be a mechanism to control the growth of the fungus. Therefore, the compression of the signaling networks will allow exploring new alternatives for the development of novel antifungal drugs as well as biological biomarkers, both for the diagnosis and for possible combined therapies at the nutritional immunology level that help prevent and anticipate management. Taking these antecedents into account, we consider it important to evaluate the effect of iron and copper in Colombian clinical isolates of C. neoformans for the prediction of new antifungal targets.

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Resolving the temporal and spatial splenic proteome during fungal infection for putative dual perspective biomarker discovery

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