ORCID Profile
0000-0003-4794-1564
Current Organisation
Singapore Immunology Network
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Publisher: Springer Science and Business Media LLC
Date: 14-10-2011
DOI: 10.1038/SREP00118
Publisher: Elsevier BV
Date: 09-2021
Publisher: Cold Spring Harbor Laboratory
Date: 14-02-2021
DOI: 10.1101/2021.02.14.430970
Abstract: Malaria begins when mosquito-borne Plasmodium sporozoites invade hepatocytes and usurp host pathways to support the differentiation and multiplication of erythrocyte-infective merozoite progeny. The deadliest complication of infection, cerebral malaria, accounts for the majority of malarial fatalities. Although our understanding of the cellular and molecular mechanisms underlying the pathology remains incomplete, recent studies support the contribution of systemic and neuroinflammation as the cause of cerebral edema and blood-brain barrier (BBB) dysfunction. All Plasmodium species encode an orthologue of the innate cytokine, Macrophage Migration Inhibitory Factor (MIF), which functions in mammalian biology to regulate innate responses. Plasmodium MIF (PMIF) similarly signals through the host MIF receptor CD74, leading to an enhanced inflammatory response. We investigated the PMIF-CD74 interaction in the onset of experimental cerebral malaria (ECM) using CD74 deficient ( Cd74 −/−) mice, which were found to be protected from ECM. The protection was associated with the inability of brain microvessels from Cd74 −/− hosts to present parasite antigen to sequestered Plasmodium -specific CD8 + T cells. Infection of mice with PMIF-deficient sporozoites ( Pb A mif -) also protected mice from ECM, highlighting the pivotal role of PMIF in the pre-erythrocytic stage of the infection. A novel pharmacologic PMIF-selective antagonist reduced PMIF/CD74 signaling and fully protected mice from ECM. These findings reveal a conserved mechanism for Plasmodium usurpation of host CD74 signaling and suggest a tractable approach for new pharmacologic intervention.
Publisher: Springer Science and Business Media LLC
Date: 18-09-2019
DOI: 10.1038/S41467-019-12017-8
Abstract: Malaria-associated acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are life-threatening manifestations of severe malaria infections. The pathogenic mechanisms that lead to respiratory complications, such as vascular leakage, remain unclear. Here, we confirm that depleting CD8 + T cells with anti-CD8β antibodies in C57BL/6 mice infected with P. berghei ANKA (PbA) prevent pulmonary vascular leakage. When we transfer activated parasite-specific CD8 + T cells into PbA-infected TCRβ −/− mice (devoid of all T-cell populations), pulmonary vascular leakage recapitulates. Additionally, we demonstrate that PbA-infected erythrocyte accumulation leads to lung endothelial cell cross-presentation of parasite antigen to CD8 + T cells in an IFNγ−dependent manner. In conclusion, pulmonary vascular damage in ALI is a consequence of IFNγ-activated lung endothelial cells capturing, processing, and cross-presenting malaria parasite antigen to specific CD8 + T cells induced during infection. The mechanistic understanding of the immunopathogenesis in malaria-associated ARDS and ALI provide the basis for development of adjunct treatments.
Publisher: Springer Science and Business Media LLC
Date: 27-11-2021
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3707283
Publisher: Springer Science and Business Media LLC
Date: 04-11-2019
DOI: 10.1038/S41467-019-13025-4
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Elsevier BV
Date: 06-2023
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.IMMUNI.2019.08.008
Abstract: Human mononuclear phagocytes comprise phenotypically and functionally overlapping subsets of dendritic cells (DCs) and monocytes, but the extent of their heterogeneity and distinct markers for subset identification remains elusive. By integrating high-dimensional single-cell protein and RNA expression data, we identified distinct markers to delineate monocytes from conventional DC2 (cDC2s). Using CD88 and CD89 for monocytes and HLA-DQ and FcεRIα for cDC2s allowed for their specific identification in blood and tissues. We also showed that cDC2s could be sub ided into phenotypically and functionally distinct subsets based on CD5, CD163, and CD14 expression, including a distinct subset of circulating inflammatory CD5
Publisher: Springer Science and Business Media LLC
Date: 30-10-2021
DOI: 10.1007/S10875-021-01142-Z
Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that have become dominant as the pandemic progresses bear the ORF8 mutation together with multiple spike mutations. A 382-nucleotide deletion (Δ382) in the ORF7b and ORF8 regions has been associated with milder disease phenotype and less systemic inflammation in COVID-19 patients. However, its impact on host immunity against SARS-CoV-2 remains undefined. Here, RNA-sequencing was performed to elucidate whole blood transcriptomic profiles and identify contrasting immune signatures between patients infected with either wildtype or Δ382 SARS-CoV-2 variant. Interestingly, the immune landscape of Δ382 SARS-CoV-2 infected patients featured an increased adaptive immune response, evidenced by enrichment of genes related to T cell functionality, a more robust SARS-CoV-2-specific T cell immunity, as well as a more rapid antibody response. At the molecular level, eukaryotic initiation factor 2 signaling was found to be upregulated in patients bearing Δ382, and its associated genes were correlated with systemic levels of T cell-associated and pro-inflammatory cytokines. This study provides more in-depth insight into the host–pathogen interactions of ORF8 with great promise as a therapeutic target to combat SARS-CoV-2 infection.
Publisher: Cold Spring Harbor Laboratory
Date: 23-10-2020
DOI: 10.1101/2020.10.23.351726
Abstract: Gastric cancer (GC) tumors are highly heterogenous with different subpopulations of epithelial cells. We employed single cell RNA sequencing (scRNA-seq) to dissect the heterogeneity and identified subpopulations of cancer cells with stem-like properties. We further investigated their resistance to oxaliplatin chemotherapy and their contribution to gastric cancer outcome. We performed scRNA-seq on FACS sorted epithelial and immune cells from paired s les of GC tumors and normal adjacent tissues. We identified two epithelial subpopulations (STMN1 + IQGAP3 + and STMN1 + IQGAP3 − ) with stem-like properties. We characterized and compared them to known healthy gastric stem cell populations. We also cultivated GC derived organoids to study the chemoresistance of similarly marked populations. Lastly, we employed immunohistochemistry (IHC) staining to ascertain the predicted immunosuppressive interactions. The STMN1 + IQGAP3 + subpopulation showed a higher tumor mutation burden, upregulated proliferative pathways and transcriptomically resembled proliferative healthy gastric isthmus stem cells. The STMN1 + IQGAP3 − subpopulation were comparatively quiescent and transcriptomically resembled enteroendocrine cells. Both transcriptomic signatures were associated with worse mortality than other epithelial subpopulations with the quiescent being associated with the poorest patient survival. GC tissue derived organoids were dominated by STMN1 + IQGAP3 + cells but the STMN1 + IQGAP3 − compartment was more resistant to chemotherapy. We also verified the likely suppression of CD8 T cell cytotoxicity by STMN1 + IQGAP3 + cells through the NECTIN2/TIGIT interaction. Cancer cells with stem-like characteristics are associated with poor survival through chemoresistance and immunosuppression. Reactivating the immune system through checkpoint blockade is an opportunity to eliminate these cells. Multiple gastric stem cell populations have been identified and linked to tumor initiation in rodent-based studies. However, none of them have been conclusively proven in human tumors. Isolating and characterizing tumor cells with stem-like properties will help shed light on their possible origin and possible mitigation strategies. Here we identified two sets of stem-like gastric cancer cells that are associated with poorer patient prognosis. One set is highly proliferative and exhibits oxaliplatin susceptibility. It also engages in immunosuppressive interactions such as NECTIN2/TIGIT. The other set is quiescent and highly resistant to oxaliplatin. The transcriptome signatures of the identified stem-like cells can aid in patient prognosis and identify patients who can benefit from checkpoint blockade therapy to reactivate their immune response towards gastric cancer cells.
Publisher: eLife Sciences Publications, Ltd
Date: 18-02-2020
DOI: 10.7554/ELIFE.51546
Abstract: In malaria, rosetting is described as a phenomenon where an infected erythrocyte (IRBC) is attached to uninfected erythrocytes (URBC). In some studies, rosetting has been associated with malaria pathogenesis. Here, we have identified a new type of rosetting. Using a step-by-step approach, we identified IGFBP7, a protein secreted by monocytes in response to parasite stimulation, as a rosette-stimulator for Plasmodium falciparum- and P. vivax-IRBC. IGFBP7-mediated rosette-stimulation was rapid yet reversible. Unlike type I rosetting that involves direct interaction of rosetting ligands on IRBC and receptors on URBC, the IGFBP7-mediated, type II rosetting requires two additional serum factors, namely von Willebrand factor and thrombospondin-1. These two factors interact with IGFBP7 to mediate rosette formation by the IRBC. Importantly, the IGFBP7-induced type II rosetting h ers phagocytosis of IRBC by host phagocytes.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 23-12-2022
DOI: 10.1126/SCIIMMUNOL.ADD3330
Abstract: Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase (MAPK) pathway activation. LCH cells may trigger destructive pathology yet remain in a precarious state finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well known and may offer targets for intervention. Here, we used single-cell RNA-seq and protein analysis to dissect LCH lesions, assessing LCH cell heterogeneity and comparing LCH cells with normal mononuclear phagocytes within lesions. We found LCH discriminatory signatures pointing to senescence and escape from tumor immune surveillance. We also uncovered two major lineages of LCH with DC2- and DC3/monocyte-like phenotypes and validated them in multiple pathological tissue sites by high-content imaging. Receptor-ligand analyses and lineage tracing in vitro revealed Notch-dependent cooperativity between DC2 and DC3/monocyte lineages during expression of the pathognomonic LCH program. Our results present a convergent dual origin model of LCH with MAPK pathway activation occurring before fate commitment to DC2 and DC3/monocyte lineages and Notch-dependent cooperativity between lineages driving the development of LCH cells.
Publisher: Elsevier BV
Date: 08-2006
DOI: 10.1016/J.PEP.2006.01.026
Abstract: NY-ESO-1 is a highly immunogenic tumor antigen and a promising vaccine candidate in cancer immunotherapy. Access to purified protein both for vaccine formulations and for monitoring antigen-specific immune responses is vital to vaccine development. Currently available recombinant Escherichia coli-derived NY-ESO-1 is isolated from inclusion bodies as a complex protein mixture and efforts to improve the purity of this antigen are required, especially for later-stage clinical trials. Using yeast cell surface display and fluorescence activated cell sorting techniques, we have engineered an NY-ESO-1 variant (NY-ESO-L5 C(75)A C(76)A C(78)A L(153)H) with a 100x improved display level on yeast compared to the wild-type protein. This mutant can be effectively produced as an Aga2p-fusion and purified in soluble form directly from the yeast cell wall. In the process, we have identified the epitope recognized by anti-NY-ESO-1 mAb E978 (79-87, GARGPESRL). The availability of an alternative expression host for this important antigen will help avoid artifactual false positive tests of patient immune response due to reaction against expression-host-specific contaminants.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Springer Science and Business Media LLC
Date: 22-07-2021
DOI: 10.1038/S41564-021-00939-3
Abstract: More than one-third of the world's population is exposed to Plasmodium vivax malaria, mainly in Asia
No related grants have been discovered for Shanshan Howland.