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Abstract Malaria, caused by Plasmodium parasites, imposes a significant health burden and live-attenuated parasites are being pursued as vaccines. Here, we report on the creation of a genetically attenuated parasite by the deletion of Plasmodium LINUP, encoding a liver stage nuclear protein. In the rodent parasite Plasmodium yoelii, LINUP expression was restricted to liver stage nuclei after the onset of liver stage schizogony. Compared to wildtype P. yoelii, P. yoelii LINUP gene deletion parasites (linup —) exhibited no phenotype in blood stages and mosquito stages but suffered developmental arrest late in liver stage schizogony with a pronounced defect in exo-erythrocytic merozoite formation. This defect caused severe attenuation of the liver stage-to-blood stage transition and immunization of mice with linup — parasites conferred robust protection against infectious sporozoite challenge. LINUP gene deletion in the human parasite Plasmodium falciparum also caused a severe defect in late liver stage differentiation. Importantly, P. falciparum linup — liver stages completely failed to transition from the liver stage to a viable blood stage infection in a humanized mouse model. These results suggest that P. falciparum LINUP is an ideal target for late liver stage attenuation that can be incorporated into a late liver stage-arresting replication competent whole parasite vaccine.

Objetivo: Identificar la prevalencia, causas y evolución clínica de las pacientes con reintervención quirúrgica por complicaciones durante la cesárea. Material y métodos: Se revisó el archivo de la Unidad de Toco-Quirúrgica del Hospital Ginecobstetricia No. 3 del Centro Médico Nacional “La Raza” Instituto Mexicano del Seguro Social para conocer el total de pacientes sometidas a cesárea desde enero hasta diciembre de 2019 y se seleccionaron los casos con reintervención por complicaciones durante la cesárea. Se estudiaron sus datos generales, la causa de reintervención, estancia en la Unidad de Cuidados Intensivos (UCI), estancia en hospital y la mortalidad. Los datos se analizaron con estadística descriptiva utilizando el programa estadístico SPSS versión 20. Resultados: Se encontró que 3371 pacientes fueron sometidas a cesárea de las cuales 1.60% (54 casos) se reintervinieron por las siguientes causas: desempaquetamiento 27.79%, hemorragia obstétrica 20.37%, sangrado por atonía uterina 20.37%, hematoma de la comisura de histerotomía 18.52%, infiltración uterina 3.70%, lesión vascular 3.70%, lesión vesical 3.70% y lesión colónica 1.85%. La estancia en UCI fue 3.79 ± 2.03 días, estancia en hospital 13.67 ± 11.16 días y mortalidad 1.85%. Conclusión: La prevalencia de reintervención fue reducida, el sangrado fue la principal causa y la evolución clínica resultó satisfactoria con baja mortalidad.

Abstract Vaccine-induced sterilizing protection from infection by Plasmodium parasites, the pathogens that cause malaria, will be essential in the fight against malaria as it would prevent both malaria-related disease and transmission. Stopping the relatively small number of parasites injected by the mosquito before they can migrate from the skin to the liver is an attractive means to this goal. Antibody-eliciting vaccines have been used to pursue this objective by targeting the major parasite surface protein present during this stage, the circumsporozoite protein (CSP). While CSP-based vaccines have recently had encouraging success in disease reduction, this was only achieved with extremely high antibody titers and appeared less effective for a complete block of infection (i.e., sterile protection). While such disease reduction is important, these and other results indicate that strategies focusing on CSP alone may not achieve the high levels of sterile protection needed for malaria eradication. Here, we show that monoclonal antibodies (mAbs) recognizing another sporozoite protein, TRAP/SSP2, exhibit a range of inhibitory activity and that these mAbs may augment CSP-based protection despite conferring no sterile protection on their own. Therefore, pursuing a multivalent subunit vaccine immunization is a promising strategy for improving infection-blocking malaria vaccines.

Abstract Following their inoculation by the bite of an infected Anopheles mosquito, the malaria parasite sporozoite forms travel from the bite site in the skin into the bloodstream, which transports them to the liver. The thrombospondin-related anonymous protein (TRAP) is a type 1 transmembrane protein that is released from secretory organelles and relocalized on the sporozoite plasma membrane. TRAP is required for sporozoite motility and host infection, and its extracellular portion contains adhesive domains that are predicted to engage host receptors. Here, we identified the human platelet-derived growth factor receptor β (hPDGFRβ) as one such protein receptor. Deletion constructs showed that the von Willebrand factor type A and thrombospondin repeat domains of TRAP are both required for optimal binding to hPDGFRβ-expressing cells. We also demonstrate that this interaction is conserved in the human-infective parasite Plasmodium vivax, but not the rodent-infective parasite Plasmodium yoelii. We observed expression of hPDGFRβ mainly in cells associated with the vasculature suggesting that TRAP:hPDGFRβ interaction may play a role in the recognition of blood vessels by invading sporozoites.

Within the liver, Plasmodium sporozoites traverse cells searching for a “suitable” hepatocyte, invading these cells through a process that results in the formation of a parasitophorous vacuole (PV), within which the parasite undergoes intracellular replication as a liver stage. It was previously established that two members of the Plasmodium s48/45 protein family, P36 and P52, are essential for productive invasion of host hepatocytes by sporozoites as their simultaneous deletion results in growth-arrested parasites that lack a PV. Recent studies point toward a pathway of entry possibly involving the interaction of P36 with hepatocyte receptors EphA2, CD81, and SR-B1. However, the relationship between P36 and P52 during sporozoite invasion remains unknown. Here we show that parasites with a single P52 or P36 gene deletion each lack a PV after hepatocyte invasion, thereby pheno-copying the lack of a PV observed for the P52/P36 dual gene deletion parasite line. This indicates that both proteins are equally important in the establishment of a PV and act in the same pathway. We created a Plasmodium yoelii P36mCherry tagged parasite line that allowed us to visualize the subcellular localization of P36 and found that it partially co-localizes with P52 in the sporozoite secretory microneme organelles. Furthermore, through co-immunoprecipitation studies in vivo, we determined that P36 and P52 form a protein complex in sporozoites, indicating a concerted function for both proteins within the PV formation pathway. However, upon sporozoite stimulation, only P36 was released as a secreted protein while P52 was not. Our results support a model in which the putatively glycosylphosphatidylinositol (GPI)-anchored P52 may serve as a scaffold to facilitate the interaction of secreted P36 with the host cell during sporozoite invasion of hepatocytes.

El plan de desarrollo de 2012-2015 denominado “Medellín un hogar para la vida” hace énfasis en la Alianza Antioquia-Medellín y establece unos principios fundamentales entre los que se destacan la equidad regional y la sostenibilidad como fundamentos del actuar de la Alianza. Sin embargo, la revisión del plan desde sus diferentes enfoques, líneas y componentes genera algunos interrogantes frente al territorio rural de Medellín, el cual es desconocido desde el momento mismo de la planeación y no se evidencia una política clara para lo rural como territorio, sino como una asociación del término a la oferta eco-sistémica para lo urbano, lo cual hace que los territorios rurales pierdan por completo su identidad e incluso su vocación económica. Se hace un análisis de los elementos del plan desarrollo “Medellín un hogar para la vida”, a través de la ejecución de los programas que lo componen y que apuntan a la sostenibilidad del territorio en el corregimiento de San Cristóbal, una zona considerada rural, de tradición agrícola y que ha soportado un conflicto social importante en los últimos años. Se identificaron e interpretaron algunos elementos del plan de desarrollo Medellín 2012-2015, que contribuyen a la sostenibilidad del corregimiento seleccionado como territorio rural