Andrea Mosquera

Bio: Andrea Mosquera is an academic researcher from Universidad de las Américas Puebla. The author has contributed to research in topics: Pharmacogenetics & Medicine. The author has co-authored 1 publications.

The search for molecular mimicry in proteins carried by extracellular vesicles secreted by cells infected with Plasmodium falciparum.

Abstract: Red blood cells infected with Plasmodium falciparum secrete extracellular vesicles in order to facilitate the survival and infection of human cells. Various researchers have studied the composition of these extracellular vesicles and identified the proteins contained inside. In this work, we used that information to detect potential P. falciparum molecules that could be imitating host proteins. We carried out several searches to detect sequences and structural similarities between the parasite and host. Additionally, the possibility of functional mimicry was explored in line with the potential role that each candidate can perform for the parasite inside the host. Lastly, we determined a set of eight sequences (mainly moonlighting proteins) with a remarkable resemblance to human proteins. Due to the resemblance observed, this study proposes the possibility that certain P. falciparum molecules carried by extracellular vesicles could be imitating human proteins to manipulate the host cell's physiology.

An Interactive Pharmacogenetics Lesson Using PharmGKB To Individualize Pharmacotherapy Recommendations

Abstract: PharmGKB is a user‐friendly online pharmacogenomics database that annotates clinical guidelines for optimizing drug therapy based on patient genotypes. The majority of guidelines in PharmGKB are based on the interindividual variability in cytochrome P450 (CYP) enzymes responsible for metabolizing drugs. By individualizing patient therapy according to CYP genotypes, there is potential to improve pharmacotherapy outcomes and minimize the risk of adverse events. Although there is growing interest amongst educators and students to integrate pharmacogenetic content into health science curricula, there is a lack of educational resources that teach students how to utilize resources such as PharmGKB to inform clinical decision making. The purpose of this study was to assess and disseminate a case‐based interactive lesson on pharmacogenetic‐based drug dosing principles that uses PharmGKB. Seventy‐one high school students participated in a two‐hour Zoom session as part of a four‐day Toxicology, Health, and Environmental Disease Program. The lesson was divided into a didactic lecture on pharmacogenetics followed by a group‐based analysis of hypothetical case scenarios. Case questions focused on genetic variation in CYP enzymes in the context of different clinical scenarios. Examples included the use of codeine for analgesia (CYP2D6) and clopidogrel for stroke prevention (CYP2C19). Assessment of student understanding was measured by percent gain in correct answers between pre‐ and post‐lesson polling questions. The first question focused on pharmacology concepts while the last two focused on genetics concepts. Students had high pre‐test scores on the pharmacology question having learned these concepts earlier in the program. For the additional two questions, there was a positive gain (42%) demonstrating an increase in knowledge during the lesson. Seventy‐eight percent of students would be ‘extremely likely’ or ‘very likely’ to recommend this activity. We propose that an interactive, group‐based activity can be used to teach basic principles of pharmacogenetics and empower students and educators to effectively use online drug resources.

Engaging Students in Pharmacogenetics: Patient Case Studies Using the PharmGKB Website.

Abstract: Cytochrome P450 (CYP) enzymes are important regulators of drug efficacy and toxicity. Genetic variation in CYP isoforms can impact how well patients respond to medications or experience unwanted toxicities. PharmGKB is an online pharmacogenomics resource that collates the latest data and clinical guidelines on genetic variation and drug responses. The purpose of this lesson was to develop an interactive, case-based activity that demonstrated how pharmacogenetics can be used to influence the prescribing of medications. This lesson was provided to 71 students during a two-hour online interactive session. The lesson consisted of 1) a didactic lecture on pharmacogenetic principles, 2) an overview of the PharmGKB website by the instructor, and 3) patient cases that used the PharmGKB website to answer questions and make recommendations about drug therapy. Patient cases explored the impact of genetic variation in CYP enzymes on patients prescribed medications for different diseases including depression (citalopram, CYP2C19), pain (codeine, CYP2D6), organ transplantation (tacrolimus, CYP3A5), and viral infection (efavirenz, CYP2B6). Four additional cases are included in this lesson. Students reviewed the patient cases in small groups, used PharmGKB to answer questions and design treatment plans, and presented their recommendations to instructors and other students. Based on pre-/post-lesson assessment questions and student feedback, we conclude that an interactive, group-based activity can be used to teach basic principles of pharmacogenetics and connect students to online resources for drug dosing.

Sialylated N ‐glycans mediate monocyte uptake of extracellular vesicles secreted from Plasmodium falciparum ‐infected red blood cells

Abstract: Glycoconjugates on extracellular vesicles (EVs) play a vital role in internalization and mediate interaction as well as regulation of the host immune system by viruses, bacteria, and parasites. During their intraerythrocytic life-cycle stages, malaria parasites, Plasmodium falciparum (Pf) mediate the secretion of EVs by infected red blood cells (RBCs) that carry a diverse range of parasitic and host-derived molecules. These molecules facilitate parasite-parasite and parasite-host interactions to ensure parasite survival. To date, the number of identified Pf genes associated with glycan synthesis and the repertoire of expressed glycoconjugates is relatively low. Moreover, the role of Pf glycans in pathogenesis is mostly unclear and poorly understood. As a result, the expression of glycoconjugates on Pf-derived EVs or their involvement in the parasite life-cycle has yet to be reported. Herein, we show that EVs secreted by Pf-infected RBCs carry significantly higher sialylated complex N-glycans than EVs derived from healthy RBCs. Furthermore, we reveal that EV uptake by host monocytes depends on N-glycoproteins and demonstrate that terminal sialic acid on the N-glycans is essential for uptake by human monocytes. Our results provide the first evidence that Pf exploits host sialylated N-glycans to mediate EV uptake by the human immune system cells.

Proteome-wide comparison of tertiary protein structures reveals molecular mimicry in Plasmodium-human interactions

Abstract: Introduction Molecular mimicry is a strategy used by parasites to evade the host’s immune system and facilitate transmission to a new host. To date, high-throughput examples of molecular mimicry have been limited to comparing protein sequences. However, recent advances in the prediction of tertiary structural models, led by Deepmind’s AlphaFold, enable the comparison of thousands of proteins from parasites and their hosts at the structural level, allowing for the identification of more mimics. Here, we present the first proteome-level search for tertiary structure similarity between proteins from Plasmodium falciparum, a malaria-causing parasite, and humans. Methods We assembled a database of experimentally-characterized protein tertiary structures (from the Protein Data Bank) and AlphaFold-generated protein tertiary structures from P. falciparum, human, and 15 negative control species, i.e., species not infected by P. falciparum. We aligned human and control structures to the parasite structures using Foldseek. Results We identified molecular mimicry in three proteins that have been previously proposed as mediators of Plasmodium-human interactions. By extending this approach to all P. falciparum proteins, we identified an additional 41 potential mimics that are supported by additional experimental data. Discussion Our findings demonstrate a valuable application of AlphaFold-derived tertiary structural models, and we discuss key considerations for its effective use in other host-parasite systems.

Proteome-wide comparison of tertiary protein structures reveal extensive molecular mimicry in Plasmodium-human interactions

Abstract: Molecular mimicry is a strategy used by parasites to escape the host immune system and successfully transmit to a new host. To date, high-throughput examples of molecular mimicry have been limited to comparing protein sequences. However, with advances in the prediction of tertiary structural models, led by Deepmind’s AlphaFold, it is now possible to compare the tertiary structures of thousands of proteins from parasites and their hosts, to identify more subtle mimics. Here, we present the first proteome-level search for tertiary structure similarity between the proteins from Plasmodium falciparum and human. Of 206 P. falciparum proteins that have previously been proposed as mediators of Plasmodium-human interactions, we propose that seven evolved to molecularly mimic a human protein. By expanding the approach to all P. falciparum proteins, we identified a further 386 potential mimics, with 51 proteins corroborated by additional biological data. These findings demonstrate a valuable application of AlphaFold-derived tertiary structural models, and we discuss key considerations for its effective use in other host-parasite systems.