Victoriano Mulero

University of Murcia | UM · Department of Cellular Biology and Histology

Acute lymphoblastic leukemia (ALL) is an aggressive hematological malignancy that affects thousands of pediatric and adult patients each year. A major hurdle to developing more effective treatments is a limited understanding of the genes and pathways that drive ALL malignancy, and which are required for continued tumor growth. ALL is often diagnose...

Plasmalogens are glycerophospholipids with a vinyl ether bond that confers unique properties. Recent identification of the gene encoding PEDS1, the desaturase generating the vinyl ether bond, enables evaluation of the role of plasmalogens in health and disease. Here, we report that Peds1-deficient zebrafish larvae display delayed development, incre...

Introduction Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), manifests as persistent and often debilitating symptoms enduring well beyond the initial COVID-19 infection. This disease is especially worrying in children since it can seriously alter their development. Presently, a specific diagnostic test or definitive biomarker set...

Dysbiosis has been linked to the pathogenesis of multiple diseases. Although dozens of publications have associated changes in the nasopharyngeal microbiota to patient's susceptibility to COVID-19, results from these studies are highly variable and contradictory in many cases. Addressing the limitations in previous research responsible for that var...

Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), manifests as persistent and often debilitating symptoms enduring well beyond the initial COVID-19 infection. Presently, a specific diagnostic test or definitive biomarker set for confirming long COVID is lacking, relying instead on the protracted presence of symptoms post-acute infe...

Type I interferonopathies are a heterogenic group of rare diseases associated with an increase in type I interferon (IFN). The main challenge for the study of Type I interferonopathies is the lack of a well-founded animal model to better characterize the phenotype as well as to perform fast and large drug screenings to offer the best treatment opti...

Plasmalogens are glycerophospholipids with a vinyl ether bond that confers unique properties. Recent identification of the gene encoding PEDS1, the desaturase generating the vinyl ether bond, enables evaluation of the role of plasmalogens in health and disease. Here, we report that Peds1-deficient zebrafish larvae display delayed development, incre...

Telomerase RNA (TERC) has a noncanonical function in myelopoiesis binding to a consensus DNA binding sequence and attracting RNA polymerase II (RNA Pol II), thus facilitating myeloid gene expression. The CR4/CR5 domain of TERC is known to play this role, since a mutation of this domain found in dyskeratosis congenita (DC) patients decreases its aff...

Chronic inflammatory diseases are associated with hematopoietic lineage bias, including neutrophilia and anemia. We have recently identified that the canonical inflammasome mediates the cleavage of the master erythroid transcription factor GATA1 in hematopoietic stem and progenitor cells (HSPCs). We report here that genetic inhibition of Nlrp1 resu...

Background Macrophages take center stage in the tumor microenvironment, a niche composed of extracellular matrix and a heterogeneous group of cells, including immune ones. They can evolve during tumor progression and acquire Tumor-Associated Macrophage (TAMs) phenotype. The release of cytokines by tumor and stromal cells, influence the secretion of...

Introduction: Hepsin is a type II transmembrane serine protease and its expression has been linked to greater tumorigenicity and worse prognosis in different tumors. Recently, our group demonstrated that high hepsin levels from primary tumor were associated with a higher risk of metastasis and thrombosis in localized colorectal cancer patients. Thi...

Fish are the most diverse and successful group of vertebrate animals, with about 30,000 species. The study of fish immunity is of great importance for understanding the evolution of vertebrate immunity, as they are the first animals to show both innate and adaptive immune responses. Although fish immunity is similar to that of mammals, there are ob...

Melanoma is the most serious type of skin cancer. Inflammation and oxidative stress play an essential role in the development of several types of cancer, including melanoma. Although oxidative stress promotes tumor growth, once cells escape from the primary tumor, they are subjected to a more hostile environment, with higher levels of oxidative str...

Functional or compositional perturbations of the microbiome can occur at different sites, of the body and this dysbiosis has been linked to various diseases. Changes in the nasopharyngeal microbiome are associated to patient’s susceptibility to multiple viral infections, supporting the idea that the nasopharynx may be playing an important role in h...

The development of novel culture-independent techniques of microbial identification has allowed a rapid progress in the knowledge of the nasopharyngeal microbiota and its role in health and disease. Thus, it has been demonstrated that the nasopharyngeal microbiota defends the host from invading pathogens that enter the body through the upper airway...

One of the most studied defense mechanisms against invading pathogens, including viruses, are Toll-like receptors (TLRs). Among them, TLR3, TLR7, TLR8 and TLR9 detect different forms of viral nucleic acids in endosomal compartments, whereas TLR2 and TLR4 recognize viral structural and nonstructural proteins outside the cell. Although many different...

Although COVID-19 has only recently appeared, research studies have already developed and implemented many animal models for deciphering the secrets of the disease and provided insights into the biology of SARS-CoV-2. However, there are several major factors that complicate the study of this virus in model organisms, such as the poor infectivity of...

Hepsin is a type II transmembrane serine protease whose expression has been linked to greater tumorigenicity and worse prognosis in different tumors such as prostate and gastric cancer. Recently, our group described hepsin expression in the primary biopsy as a potential biomarker of thrombosis and metastasis in localized colorectal cancer patients....

The coronavirus disease 2019 (COVID-19) pandemic turned the whole world upside down in a short time. One of the main challenges faced has been to understand COVID-19–associated life-threatening hyperinflammation, the so-called cytokine storm syndrome (CSS). We report here the proinflammatory role of Spike (S) proteins from different severe acute re...

Telomere shortening is the main molecular mechanism of aging, but not the only one. The adaptive immune system also ages, and older organisms tend to develop a chronic pro-inflammatory status with low-grade inflammation characterized by chronic activation of the innate immune system, called inflammaging. One of the main stimuli that fuels inflammag...

A retrospective study of 200 psoriasis patients and 100 healthy donors in a Spanish cohort was carried out to study the comorbidities associated with psoriasis and their association with the response to phototherapy. The results showed a higher incidence of psychiatric disease, liver disease, kidney disease, hypertension, heart disease, vascular di...

Prostaglandins (PGs) are highly reactive small lipophilic molecules derived from polyunsaturated fatty acids of the cell membrane and play a key role in the resolution of inflammation processes. 15-deoxy-Δ12,14-PGJ2 (15dPGJ2) is a cyclopentenone PG (CyPG) of the J series with anti-inflammatory, anti-proliferative and pro-apoptotic effects. This CyP...

Silica crystals are potent activators of the inflammasome that cause a fibrotic lung disease, called silicosis, with no effective treatment available. We report here that injection of silica crystals into the hindbrain ventricle of zebrafish embryos led to the initiation of local and systemic immune responses driven through both TLR- and inflammaso...

Understanding the mechanism of virulence of SARS-CoV-2 and host innate immune responses are essential to develop novel therapies. One of the most studied defense mechanisms against invading pathogens, including viruses, are Toll-like receptors (TLRs). Among them, TLR3, TLR7, TLR8 and TLR9 detect different forms of viral nucleic acids in endosomal c...

Melanoma is the deadliest form of skin cancer, and its incidence continues to increase. In the early stages of melanoma, when the malignant cells have not spread to lymph nodes, they can be removed by simple surgery and there is usually low recurrence. Melanoma has a high mortality rate due to its ability to metastasize; once melanoma has spread, i...

Background Functional or compositional perturbations of the microbiome can occur at different sites of the body and this dysbiosis has been linked to various diseases. Changes in the nasopharyngeal microbiome are associated to patient’s susceptibility to multiple viral infections, including COVID-19, supporting the idea that the nasopharynx may be...

Bee pollen is recommended as dietary supplement due to immunostimulating functions including antioxidant, anti-inflammatory and anti-carcinogenic properties. Nevertheless, the effectiveness of such properties is still not well understood. As diet can be associated with animal performance, microbiota modulation and potentially factor for cancer, thi...

Silicosis is a long-term lung disease caused by the inhalation of large amounts of crystalline silica dust. As there is no effective treatment available, patients are provided with supportive care, and some may be considered for lung transplantation. There is therefore an evident need for a better understanding of the disease biology and for identi...

Chronic disease and hematopoietic disorders are associated with dysregulation of the inflammasome. Our group has recently reported the relevance of the inflammasome in the differentiation of hematopoietic stem and progenitor cells. However, the impact of the inflammasome of myeloid cells in the regulation of hematopoiesis is largely unknown. In thi...

The sudden and unexpected appearance of the COVID-19 pandemic turned the whole world upside down in a very short time. One of the main challenges faced has been to understand COVID-19 patient heterogeneity, as a minority develop life-threatening hyperinflammation, the so-called cytokine storm syndrome (CSS). Using the unique advantages of the zebra...

Telomeres are essential for chromosome protection and genomic stability, and telomerase function is critical to organ homeostasis. Zebrafish has become a useful vertebrate model for understanding the cellular and molecular mechanisms of regeneration. The regeneration capacity of the caudal fin of wild-type zebrafish is not affected by repetitive am...

Several studies have revealed a correlation between chronic inflammation and nicotinamide adenine dinucleotide (NAD⁺) metabolism, but the precise mechanism involved is unknown. Here, we report that the genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the salvage pathway of NAD⁺ bi...

Bee pollen, a natural resource collected by bees, is rich in many nutrients, therefore it may represent a useful dietary supplement. Different uses of bee pollen are proposed due to its beneficial health properties, which includes the capacity to improve animal performance and promote immunostimulation. Animal nutrition can directly affect adults a...

Ubiquitin-fold modifier 1 (UFM1) is involved in neural and erythroid development, yet its biological roles in these processes are unknown. Here, we generated zebrafish models deficient in Ufm1 and Ufl1 that exhibited telomere shortening associated with developmental delay, impaired hematopoiesis and premature aging. We further report that HeLa cell...

Significance Dyskeratosis congenita (DC) is a rare inherited bone marrow failure and cancer predisposition syndrome caused by mutations in telomerase or telomeric proteins. Although all patients show telomere shortening, the symptoms are highly variable and, therefore, other mechanisms have to be involved. Here, we report that telomerase RNA compon...

Telomerase reverse transcriptase (TERT) maintains telomere homeostasis, thus ensuring chromosome stability and cell proliferation. In addition, several telomere‐independent functions of human TERT have been described. In this study, we report that TERT binds directly to the TCF binding elements (TBE) located upstream of the oncomiR miR500A, and ind...

Apoptosis is the main mechanism by which multicellular organisms eliminate damaged or unwanted cells. To regulate this process, a balance between pro-survival and pro-apoptotic proteins is necessary in order to avoid impaired apoptosis, which is the cause of several pathologies, including cancer. Among the anti-apoptotic proteins, Bcl-xL exhibits a...

Several studies have revealed a correlation between chronic inflammation and NAD ⁺ metabolism but the precise mechanism involved is unknown. Here we report that the genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the salvage pathway of NAD ⁺ biosynthesis, reduced oxidative stress...

Nicotinamide adenine dinucleotide (NAD⁺) is the most important hydrogen carrier in cell redox reactions. It is involved in mitochondrial function and metabolism, circadian rhythm, the immune response and inflammation, DNA repair, cell division, protein-protein signaling, chromatin remodeling and epigenetics. Recently, NAD⁺ has been recognized as th...

Hematopoiesis is a complex process through which immature bone marrow precursor cells mature into all types of blood cells. Although the association of hematopoietic lineage bias (including anemia and neutrophilia) with chronic inflammatory diseases has long been appreciated, the causes involved are obscure. Recently, cytosolic multiprotein inflamm...

Since inflammasomes were discovered in the early 21st century, knowledge about their biology has multiplied exponentially. These cytosolic multiprotein complexes alert the immune system about the presence of infection or tissue damage, and regulate the subsequent inflammatory responses. As inflammasome dysregulation is increasingly associated with...

Prostaglandin E2 (PGE2) plays an important role in immune activities in teleost fish, including seabream. However, receptors involved in PGE2 signaling, as well as the pathways activated downstream, are largely unknown. In this study, one ortholog of mammalian PTGER1, PTGER3 and PTGER4, and two of PTGER2 (Ptger2a and Ptger2b) were identified and ch...

Iron plays a major role in multiple processes involved in cell homeostasis such as metabolism, respiration and DNA synthesis. Cancer cells exhibit pronounced iron retention as compared to healthy counterpart. This phenomenon also occurs in multiple myeloma (MM), a hematological malignancy characterized by terminally differentiated plasma cells (PCs...

Fungi, particularly yeasts, are known essential components of the host microbiota but their functional relevance in development of immunity and physiological processes of fish remains to be elucidated. In this study, we used a transcriptomic approach and a germ-free (GF) fish model to determine the response of newly hatched zebrafish larvae after 2...

Tumor invasion requires efficient cell migration, which is achieved by the generation of persistent and polarized lamellipodia. The generation of lamellipodia is supported by actin dynamics at the leading edge where a complex of proteins known as the WAVE regulatory complex (WRC) promotes the required assembly of actin filaments to push the front o...

The classical activity of telomerase (TERT) is to maintain telomere homeostasis, ensuring chromosome stability and cellular proliferation. However, increasing evidences of telomere-independent human TERT functions have been lastly obtained. We report here that TERT directly binds to the TCF binding elements (TBE) located upstream the oncomiR MIR500...

Psoriasis is a skin inflammatory disorder that affects 3% of the human population. Although several therapies based on the neutralization of proinflammatory cytokines have been used with relative success, additional treatments are required. The in silico analysis of gene expression data of psoriasis lesional skin and an analysis of vitamin B6 metab...

Background: Skin cutaneous melanoma (SKCM) is the most lethal form of skin cancer and while incidence rates are declining for most cancers, they have been steadily rising for SKCM. Serine protease inhibitor, kunitz-type, 1 (SPINT1) is a type II transmembrane serine protease inhibitor that has been shown to be involved in the development of several...

The zebrafish has become an excellent model for the study of inflammation and immunity. Its unique advantages for in vivo imaging and gene and drug screening have allowed the visualization of dual oxidase 1 (Duox1)-derived hydrogen peroxide (H2O2) tissue gradients and its crosstalk with neutrophil infiltration to inflamed tissue. Thus, it has been...

Genetic studies using knockout mouse models provide strong evidence for the essential role of the ubiquitin-like protein UFM1 for hematopoiesis, especially erythroid development, yet its biological roles in this process are largely unknown. Here we have identified a UFL1-dependent UFMylation of the MRE11 nuclease on the K281 and K282 residues. We s...

In mammals, recombination activating gene 1 (RAG1) plays a crucial role in adaptive immunity, generating a vast range of immunoglobulins. Rag1−/− zebrafish (Danio rerio) are viable and reach adulthood without obvious signs of infectious disease in standard nonsterile conditions, suggesting that innate immunity could be enhanced to compensate for th...

Inflammasomes are pivotal cytosolic molecular platforms involved in infection resistance. As multiprotein complexes, they consist of NOD-like receptors (NLRs), the adaptor proteins apoptosis-associated speck-like protein containing a CARD (ASC) and the effector molecules caspase-1 and caspase-11, whose assembly and activation depends on homotypic i...

Significance Many pathogens exploit the olfactory route to gain entry into the host. Olfactory sensory neurons (OSNs) are responsible for the detection of chemical stimuli in the environment but are also continuously exposed to microorganisms. Here, we report the interaction between crypt neurons (unique OSNs present in fish) and fish rhabdoviruses...

Chronic inflammatory diseases are associated with altered hematopoiesis that could result in neutrophilia and anemia. Here we report that genetic or chemical manipulation of different inflammasome components altered the differentiation of hematopoietic stem and progenitor cells (HSPC) in zebrafish. Although the inflammasome was dispensable for the...

Skin cutaneous melanoma (SKCM) is the deadliest form of skin cancer and while incidence rates are declining for most cancers, they have been steadily rising for SKCM worldwide. Serine protease inhibitor, kunitz-type, 1 (SPINT1) is a type II transmembrane serine protease inhibitor that has been shown to be involved in the development of several type...

The zebrafish has unique advantages for understanding the evolution of vertebrate immunity and to model human diseases. In this review, we will firstly give an overview of the current knowledge on vertebrate innate immune receptors with special emphasis on the inflammasome and then summarize the main contribution of the zebrafish model to this fiel...

Executive Summary Background Cost-effective commercial production of marine fish larvae is still a bottleneck in European aquaculture. The high and unpredictable mortality (sometimes more than 80%) in the first weeks after hatching remains a challenging problem that needs to be solved. The severity of the problem differs between species, but cannot...

A key goal of a successful vaccine formulation is the strong induction of persistent protective immune responses without producing side-effects. Adjuvants have been proved to be successful in several species at inducing increased immune responses against poorly immunogenic antigens. Fish are not the exception and promising results of adjuvanted vac...

Mucormycosis is a life-threatening fungal infection caused by various ubiquitous filamentous fungi of the Mucorales order, although Rhizopus spp. and Mucor spp. are the most prevalent causal agents. The limited therapeutic options available together with a rapid progression of the infection and a difficult early diagnosis produce high mortality. He...

Establishment of the early-life gut microbiota has a large influence on host development and succession of microbial composition in later life stages. The effect of commensal yeasts - which are known to create a conducive environment for beneficial bacteria - on the structure and diversity of fish gut microbiota still remains unexplored. The presen...

It is well accepted that estrogens, the primary female sex hormones, play a key role in modulating different aspects of the immune response. Moreover, estrogens have been linked with the sexual dimorphism observed in some immune disorders, such as chronic inflammatory and autoimmune diseases. Nevertheless, their effects are often controversial and...

Vertebrate olfactory sensory neurons (OSNs) are located in direct contact with the external environment and therefore they directly exposed to microorganisms such as viruses. Teleost fish have four types of OSNs, including crypt neurons, a cell type with enigmatic function. Crypt neurons express tyrosine receptor kinase A (TrkA)-like molecule and O...

Vertebrate olfactory sensory neurons (OSNs) are located in direct contact with the external environment and therefore they directly exposed to microorganisms such as viruses. Teleost fish have four types of OSNs, including crypt neurons, a cell type with enigmatic function. Crypt neurons express tyrosine receptor kinase A (TrkA)-like molecule and O...

Although Aluminum salts (Alum) have been extensively used in human vaccination for decades, its mechanism of action is controversial. In fish, the use of Alum as a vaccine adjuvant is scarce and there are no studies aimed at identifying its mechanism of action. In the present study we report that Alum is a powerful adjuvant in the gilthead seabream...