Biology subjects

Malloy, M.

Publications and source records attributed to Malloy, M..

3 recordsLinked to original sources

bioRxiv2025

Neonatal Platelets Differentiate Monocytes to a Myeloid Derived Suppressor Cell Phenotype

Adult platelets are relatively enriched in immune related molecules compared to neonatal platelets, but neonatal platelets express some growth factors and enzymes at comparatively higher levels. This makes a prediction of platelet-immune cell interaction outcomes in neonates a challenge, as they are likely dependent on the cell type and tissue environment at the time of injury or infection. Our past studies revealed that the transfusion of adult but not neonatal platelets into thrombocytopenic neonatal mice led to an acute increase in monocyte trafficking. We have now found that neonatal, but not adult platelets, induce monocytes to a Myeloid Derived Suppressor Cell (MDSC) phenotype, typified by increased PD-L1, that limits T-cell activation in vitro and in vivo. Monocytes prior incubated with neonatal, but not adult platelets, or platelet releasates, limited T-cell activation in vitro. Using an in vivo asthma-like model we also found that the treatment of mice with monocytes prior incubated with neonatal platelet releasates limited T-cell activation in a asthma-like model. Platelet-driven effects were dependent on neonatal platelets producing more PGE2 that signaled through monocyte EP4. These studies indicate that neonatal platelets have immune limiting roles in the post-natal period by indirectly limiting T-cell responses, perhaps contributing to the adverse outcomes of platelet transfusions to neonates.

immunology↗

bioRxiv2024

Lung megakaryocytes are long-lived, arise from Flt3-negative bone marrow cells, and contribute to platelet recovery in thrombocytopenia

We previously characterized lung megakaryocytes (Mks) as largely extravascular cells with an immune modulatory phenotype (Pariser et al., 2021). Because bone marrow (BM) Mks are relatively short lived, it is assumed that extravascular lung Mks are constantly seeded from the BM, but there are no experimental data to validate this concept. To investigate lung Mk origin and how their origin may impact lung Mk functions, we developed novel models using CFSE dye delivered oropharyngeal (OP) and biotin labeling to specifically label lung Mks and identify lung Mk derived platelets. Labeled lung Mks were present for up to four months, while BM Mks had a less than 1 week lifespan. In a parabiosis model, lung Mks were only partially replaced by a circulating source over a 1-month time period. Unlike tissue resident lung macrophages, we determined using MDS1-Cre-ERT2 TdTomato mice that lung Mks arise from a hematopoietic stem cell (HSC) source. However, studies with FlkSwitch mTmG mice showed that lung Mks originate from a Flt3-negative cell lineage, that does not go through a multipotent progenitor stage. CFSE labeling of lung cells enabled us to track lung Mk-derived platelets and we found that about 10% of circulating platelets at steady-state are lung resident Mk-derived, but in the context of sterile thrombocytopenia there was a doubling of lung Mk derived platelets (about 20%). Lung-derived platelets were similarly increased in a murine malaria infection model (Plasmodium yoelii) typified by chronic thrombocytopenia. Taken together, our studies indicate that lung Mks arise from a Flt3-negative, HSC-dependent pathway and contribute relatively more platelets during thrombocytopenia.

cell biology↗

bioRxiv2020

Sequence-based prediction of vaccine targets for inducing T cell responses to SARS-CoV-2 utilizing the bioinformatics predictor RECON

BackgroundThe ongoing COVID-19 pandemic has created an urgency to identify novel vaccine targets for protective immunity against SARS-CoV-2. Consistent with observations for SARS-CoV, a closely related coronavirus responsible for the 2003 SARS outbreak, early reports identify a protective role for both humoral and cell-mediated immunity for SARS CoV-2. MethodsIn this study, we leveraged HLA-I and HLA-II T cell epitope prediction tools from RECON(R) (Real-time Epitope Computation for ONcology), our bioinformatic pipeline that was developed using proteomic profiling of individual HLA-I and HLA-II alleles to predict rules for peptide binding to a diverse set of such alleles. We applied these binding predictors to viral genomes from the Coronaviridae family, and specifically to identify SARS-CoV-2 T cell epitopes. ResultsTo test the suitability of these tools to identify viral T cell epitopes, we first validated HLA-I and HLA-II predictions on Coronaviridae family epitopes deposited in the Virus Pathogen Database and Analysis Resource (ViPR) database. We then use our HLA-I and HLA-II predictors to identify 11,776 HLA-I and 7,991 HLA-II candidate binding peptides across all 12 open reading frames (ORFs) of SARS-CoV-2. This extensive list of identified candidate peptides is driven by the length of the ORFs and the significant number of HLA-I and HLA-II alleles that we are able to predict (74 and 83, respectively), providing over 99% coverage for the US, European and Asian populations, for both HLA-I and HLA-II. From our SARS-CoV-2 predicted peptide-HLA-I allele pairs, 368 pairs identically matched previously reported pairs in the ViPR database, originating from other forms of coronaviruses. 320 of these pairs (89.1%) had a positive MHC-binding assay result. This analysis reinforces the validity our predictions. ConclusionsUsing this bioinformatic platform, we identify multiple putative epitopes for CD4+ and CD8+ T cells whose HLA binding properties cover nearly the entire population and thus may be effective when included in prophylactic vaccines against SARS-CoV-2 to induce broad cellular immunity.

bioinformatics↗