Biology subjects

Lopez-Verges, S.

Publications and source records attributed to Lopez-Verges, S..

3 recordsLinked to original sources

bioRxiv2025

Zika virus induces persistent phenotypic changes in natural killer cells distinct from dengue virus infection

Zika virus (ZIKV) is a mosquito-borne orthoflavivirus of global concern due to its ability to cause congenital neurological defects in infants. Natural killer (NK) cells are innate lymphocytes that can directly kill virus-infected cells. It is thought that NK cells are protective against ZIKV, although the mechanisms by which NK cells detect and respond to ZIKV are not well understood. Here, we evaluated NK cell receptor expression on isolated NK cells from a Panamanian cohort of ZIKV-infected participants, and corresponding NK receptor ligand expression on participant PBMCs and ZIKV-infected cells in vitro using mass cytometry. We found that during acute ZIKV infection, NK cells express high levels of activation markers, proliferative markers, and cytotoxic effector proteins, indicating that NK cells are mounting a response to ZIKV. Interestingly, many markers elevated during acute infection remain elevated post-acute infection, suggesting ZIKV infection may have potential long-term effects on NK cell function. Analysis of NK receptor ligand expression on ZIKV-infected participant PBMCs and ZIKV-infected cells in vitro did not identify a cellular source of NK cell activation, suggesting that either soluble or tissue-specific factors are responsible for modulating NK cell activity during ZIKV infection. Comparison of the NK cell receptor expression with a previously characterized cohort of dengue-infected participants revealed both common and virus-specific changes in NK cell phenotype during acute infection. This work improves our understanding of the NK cell response to orthoflavivirus infection, which will aid in the development of vaccines and therapeutics.

immunology↗

bioRxiv2020

Mass cytometry analysis of the NK cell receptor-ligand repertoire reveals unique differences between dengue-infected children and adults

Dengue virus (DENV) is a significant cause of morbidity in many regions of the world, with children at the greatest risk of developing severe dengue. Natural killer (NK) cells, characterized by their ability to rapidly recognize and kill virally infected cells, are activated during acute DENV infection. However, their role in viral clearance versus pathogenesis has not been fully elucidated. Our goal was to profile the NK cell receptor-ligand repertoire to provide further insight into the function of NK cells during pediatric and adult DENV infection. We used mass cytometry (CyTOF) to phenotype isolated NK cells and peripheral blood mononuclear cells (PBMCs) from a cohort of DENV-infected children and adults. Using unsupervised clustering, we found that pediatric DENV infection leads to a decrease in total NK cell frequency with a reduction in the percentage of CD56dimCD38bright NK cells and an increase in the percentage of CD56dimperforinbright NK cells. No such changes were observed in adults. Next, we identified markers predictive of DENV infection using a differential state test. In adults, NK cell expression of activation markers, including CD69, perforin, and Fas-L, and myeloid cell expression of activating NK cell ligands, namely Fas, were predictive of infection. In contrast, NK cell expression of the maturation marker CD57 and increased myeloid cell expression of inhibitory ligands, such as HLA class I molecules, were predictive of pediatric DENV infection. These findings suggest that acute pediatric DENV infection may result in diminished NK cell activation, which could contribute to enhanced pathogenesis and disease severity.

immunology↗

bioRxiv2019

HLA upregulation during dengue virus infection suppresses the natural killer cell response

Dengue virus (DENV) is the most prevalent mosquito-borne virus in the world and a major cause of morbidity in the tropics and subtropics. Upregulation of HLA class I molecules has long been considered a feature of DENV infection, yet this has not been evaluated in the setting of natural infection. Natural killer (NK) cells, an innate immune cell subset critical for mounting an early response to viral infection, are inhibited by self HLA class I, suggesting that upregulation of HLA class I during DENV infection could dampen the NK cell response. Here we addressed whether upregulation of HLA class I molecules occurs during in vivo DENV infection and, if so, whether this suppresses the NK cell response. We found that HLA class I expression was indeed upregulated during acute DENV infection across multiple cell lineages in vivo. To better understand the role of HLA class I upregulation, we infected primary human monocytes, a major target of DENV infection, in vitro. Upregulation of total HLA class I is dependent on active viral replication and is mediated in part by cytokines and other soluble factors induced by infection, while upregulation of HLA-E occurs in the presence of replication-incompetent virus. Importantly, blocking DENV-infected monocytes with a pan-HLA class I Fab nearly doubles the frequency of degranulating NK cells, while blocking HLA-E does not significantly improve the NK cell response. These findings demonstrate that upregulation of HLA class I during DENV infection suppresses the NK cell response, potentially contributing to disease pathogenesis.

immunology↗