Trypanosoma cruzi genome: Organization, multi-gene families, transcription, and biological implications

Chagas disease caused by the parasite Trypanosoma cruzi affects millions of people. Although its first genome dates from 2005, its complexity hindered a complete assembly and annotation. However, the new sequencing methods have improved genome annotation of some strains elucidating the broad genetic diversity and complexity of this parasite. Here, we reviewed the genomic structure and regulation, the genetic diversity, and the analysis of the principal multi-gene families of the recent genomes for several strains. The telomeric and sub-telomeric regions are sites with high recombination events, the genome displays two different compartments, the core and the disruptive, and the genome plasticity seems to play a key role in the survival and the infection process. Trypanosoma cruzi (T. cruzi) genome is composed mainly of multi-gene families as the trans-sialidases, mucins, and mucin-associated surface proteins. Trans-sialidases are the most abundant genes in the genome and show an important role in the effectiveness of the infection and the parasite survival. Mucins and MASPs are also important glycosylated proteins of the surface of the parasite that play a major biological role in both insect and mammal-dwelling stages. Altogether, these studies confirm the complexity of T. cruzi genome revealing relevant concepts to better understand Chagas diseaseSAF2016-75988-R, PGC2018-096132-B-I00, S2017/BMD-367

TCFL5 deficiency impairs the pachytene to diplotene transition during spermatogenesis in the mouse

Spermatogenesis is a complex, multistep process during which spermatogonia give rise to spermatozoa. Transcription Factor Like 5 (TCFL5) is a transcription factor that has been described expressed during spermatogenesis. In order to decipher the role of TCFL5 during in vivo spermatogenesis, we generated two mouse models. Ubiquitous removal of TCFL5 generated by breeding TCFL5fl/fl with SOX2-Cre mice resulted in sterile males being unable to produce spermatozoa due to a dramatic alteration of the testis architecture presenting meiosis arrest and lack of spermatids. SYCP3, SYCP1 and H1T expression analysis showed that TCFL5 deficiency causes alterations during pachytene/diplotene transition resulting in a meiotic arrest in a diplotene-like stage. Even more, TCFL5 deficient pachytene showed alterations in the number of MLH1 foci and the condensation of the sexual body. In addition, tamoxifen-inducible TCFL5 knockout mice showed, besides meiosis phenotype, alterations in the spermatids elongation process resulting in aberrant spermatids. Furthermore, TCFL5 deficiency increased spermatogonia maintenance genes (Dalz, Sox2, and Dmrt1) but also increased meiosis genes (Syce1, Stag3, and Morc2a) suggesting that the synaptonemal complex forms well, but cannot separate and meiosis does not proceed. TCFL5 is able to bind to the promoter of Syce1, Stag3, Dmrt1, and Syce1 suggesting a direct control of their expression. In conclusion, TCFL5 plays an essential role in spermatogenesis progression being indispensable for meiosis resolution and spermatids maturatio

Dextran sulfate from Leuconostoc mesenteroides B512F exerts potent antiviral activity against SARS-CoV-2 in vitro and in vivo

The emergent human coronavirus SARS-CoV-2 and its resistance to current drugs makes the need for new potent treatments for COVID-19 patients strongly necessary. Dextran sulfate (DS) polysaccharides have long demonstrated antiviral activity against different enveloped viruses in vitro. However, their poor bioavailability has led to their abandonment as antiviral candidates. Here, we report for the first time the broad-spectrum antiviral activity of a DS-based extrapolymeric substance produced by the lactic acid bacterium Leuconostoc mesenteroides B512F. Time of addition assays with SARS-CoV-2 pseudoviruses in in vitro models confirm the inhibitory activity of DSs in the early stages of viral infection (viral entry). In addition, this exopolysaccharide substance also reports broad-spectrum antiviral activity against several enveloped viruses such as SARS-CoV-2, HCoV229E, HSV-1, in in vitro models and in human lung tissue. The toxicity and antiviral capacity of DS from L. mesenteroides was tested in vivo in mouse models which are susceptible to SARS-CoV-2 infection. The described DS, administered by inhalation, a new route of administration for these types of polymers, shows strong inhibition of SARS-CoV-2 infection in vivo, significantly reducing animal mortality and morbidity at non-toxic doses. Therefore, we suggest that it may be considered as a potential candidate for antiviral therapy against SARS-CoV-2Financial support for the study was provided by the REACT-EU 2021 grant from Comunidad de Madrid to the Project COVTRAVI19-CM, Plataformas y modelos preclínicos para el abordaje multidisciplinar en COVID-19 y en respuesta a futuras pandemia

Isoform-specific effects of transcription factor TCFL5 on the pluripotency-related genes SOX2 and KLF4 in colorectal cancer development

Colorectal cancer (CRC) is a very common life-threatening malignancy. Transcription factor-like 5 (TCFL5) has been suggested to be involved in CRC. Here, we describe the expression of four alternative transcripts of TCFL5 and their relevance in CRC. Complete deletion of all isoforms drastically decreased pro-tumoural properties such as spheroids formation and in vivo tumour growth, although increased migration in CRC cell lines. Overexpression of the two main isoforms, TCFL5_E8 and CHA, had opposite effects: TCFL5_E8 reduced proliferation and spheroids formation, while CHA increased them. TCFL5_E8 reduced in vivo tumour formation, while CHA had no effect. In addition, TCFL5_E8 and CHA have different roles in the regulation of the pluripotency-related genes SOX2 and KLF4. Both isoforms bind directly to their promoters; however, TCFL5_E8 induced SOX2 and reduced KLF4 mRNA levels, whereas CHA did the opposite. Together, our results show that TCFL5 plays an important role in the development of CRC, being however isoform-specific. This work also points to the need to analyse separately TCFL5 isoforms in cancer, due to their different and opposite functionsMinisterio de Ciencia e Innovación’ (SAF2016-75988-R and PID2019-104760RB-I00) ‘Comunidad de Madrid (S2017/BMD-3671. INFLAMUNE-CM), Fondo de Investigaciones Sanitarias’ (BIOIMID) to MF and Institutional grants from ‘Fundación Ramón Areces’ and ‘Banco de Santande