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Extracellular vesicles proteomic profile in anti-TNF immunosuppressed mice: insights into protein dysregulation during Leishmania infantum infection

ABSTRACT: Visceral leishmaniasis (VL) is most frequent in immunosuppressed patients, especially among those receiving immunosuppressive therapy for autoimmune diseases, being TNF antagonist (anti-TNF) one of the main immunosuppressants used. Under these conditions, VL is most severe, with lower response to traditional leishmanicidal treatments such as antimonials (Sb) and a higher risk of relapse. Extracellular vesicles (EVs) are a great source of biological molecules, including proteins, capable of modulating immune-mediated cells and virulence factors. To identify proteins involved in the clinic of VL under anti-TNF immunosuppression, the proteomic profile of EVs from the serum of BALB/c mice was analysed using a label-free quantification (LFQ) proteomics approach. In infected mice with Leishmania infantum a comparison was made between immunosuppression with anti-TNF at clinical doses and non-immunosuppressed conditions, before and after treatment with Sb. Proteomics analysis revealed 271 dysregulated proteins in the pre-treatment groups, the majority of which were downregulated in the anti-TNF samples. On the other hand, 216 proteins were identified in the treated groups, being most of them enriched in the anti-TNF treated (anti-TNF+Sb) samples. The gene ontology (GO) analysis of these proteins revealed altered pathways related to the immune system, liver regeneration, or ion transport. Our results show dysregulated proteins associated with anti-TNF immunosuppression, which could have an impact on the greatest severity of the VL infection experienced in this situation. This study is an important step in the understanding of the clinical management of these VL pharmacologically immunosuppressed cases.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Plasma

DISEASE(S): Leishmaniasis

SUBMITTER: Ana Montero Calle

LAB HEAD: Rodrigo Barderas

PROVIDER: PXD060935 | Pride | 2025-07-22

REPOSITORIES: Pride

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			Action	DRS
	Exos_leish_Mouse_A_R1.raw	Raw
	Exos_leish_Mouse_A_R2.raw	Raw
	Exos_leish_Mouse_A_R3.raw	Raw
	Exos_leish_Mouse_A_R4.raw	Raw
	Exos_leish_Mouse_B_R1.raw	Raw

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Project description:Leishmania is an intracellular protozoan parasite and the etiological agent of a vector-borne disease known as leishmaniasis. This neglected tropical disease exhibits high morbidity and mortality. It is endemic in 97 countries and 700.000–1.000.000 new cases are estimated to occur each year. Leishmania-HIV co-infection has been an emergent public health problem in the last twenty years and has been reported in 35 endemic countries. HIV-infected people are especially vulnerable to visceral leishmaniasis (VL), and VL accelerates HIV replication and advancement to AIDS. In the context of HIV co-infection, the challenges associated with VL disease management are very significant. Disease presentation is often atypical and therapeutical responses are limited with recurrent relapses. A better understanding of the disease and also new biomarkers for infection detection, treatment prognosis and relapse are needed. Extracellular Vesicles (EVs), are considered a resource with great potential for generating a higher understanding of complex biological processes and also as a potential source of biomarkers. To evaluate the potential of plasma EVs in the context of VL and to find new possible molecules of interest for disease management in the context of HIV/VL coinfection, EVs were recovered from the plasma of an HIV+VL+ patient over a two-year period, and compared to age and sex-matched HIV and HIV-VL- controls. The approach selected for plasma EVs recovery was Size-Exclusion Chromatography followed by fraction selection using common EVs markers and proteomic analysis of fractions of interest by MS. The proteomic analysis performed confirmed the identification of common EVs biomarkers. The capacity to detect Leishmania proteins was limited with no identifications with more than one UP existed. Moreover no Leishmania protein identification was common between time points. Concernng human proteins, several proteins were detected with distinct abundance in the patient compared to both control groups. Using GO approach, the proteins were associated with specific biological processes, like MHC-I that provide a complementary overview of the patient immunological condition. Among the proteins detected, we highlighted the Macrophage receptor with collagenous structure (MARCO). This protein was detected in the patient in 4 out of 5 time points. Significantly, MARCO was also detected in plasma EVs from 5 other VL patients that were analysed. The presence of MARCO in the plasma EVs preparations was also confirmed by Western Blot. In conclusion, it was demonstrated that EVs analysis in the context of VL can contribute to understand the ongoing pathological process. Moreover, these EV are a source of possible biomarkers for VL monitoring. MARCO was a protein of interest being only identified in the VL patients. Ultimately, further studies need to be performed to generate a critical mass of data on EVs in the context of this and other infections to generate improvements in the clinical management of these vulnerable populations.

Project description:Among the most central questions in Leishmania research is why some species remain in the skin dermis at the site of infection by the sand fly vector whereas other species migrate to visceral organs where they cause fatal visceral leishmaniasis. Although L. donovani is the species typically responsible for visceral leishmaniasis, an atypical L. donovani strain is the etiologic agent for cutaneous leishmaniasis in Sri Lanka. To identify molecular determinants for visceral disease, we have analysed the phenotype and genotype of two L. donovani clinical isolates from Sri Lanka where one isolate was derived from a cutaneous leishmaniasis patient (CL) and the other from a visceral leishmaniasis patient (VL). These isolates cause dramatically different pathology when introduced into mice; notably the CL isolate has lost the ability to survive in visceral organs while the VL isolate was highly virulent in visceral organs of BALB/c mice. Whole genome sequencing of the CL and VL isolates revealed that these genomes were very similar as there were no gene deletions and few individual gene amplifications. Indels resulting in frame shifts and loss/gain of stop codons resulted in 13 distinct pseudogenes present in each of the CL and VL isolates. There were 154 non-synonymous SNPs specific to the CL isolate and 193 non-synonymous SNPs specific to the VL isolate. Genome wide gene expression analysis revealed several transcript level differences, including the A2 virulence gene resulting in higher expression of A2 proteins in the VL isolate than in the CL isolate. Genotypic variations relevant to pathology and tropism in Leishmania can be interrogated by reverse genetics. Experimentally increasing A2 expression in the CL isolate through gene transfer significantly increased itM-bM-^@M-^Ys ability to survive in the spleen of BALB/c mice and conversely, down-regulating A2 expression in the VL isolate abrogated attenuated its survival in BALB/c mice. These observations reveal that there are relatively few genetic differences between the CL and VL isolates apart from the A2 genes, but collectively these have profound effects on human disease and experimentally infected mice. 6 Samples in total, 3 each from VL and CL causing isolates were analyzed by Splice Leader RNASeq. These three samples from each of the isolates were grown to form one of the following three lifestages, Promastigotes, Macrophage derived Amastigotes, Axenic Amastigotes.

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Extracellular vesicles proteomic profile in anti-TNF immunosuppressed mice: insights into protein dysregulation during Leishmania infantum infection

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