bioRxiv Science⌕ Search

Biology subjects

Hellstrom, M.

Publications and source records attributed to Hellstrom, M..

5 recordsLinked to original sources

Migration patterns and hybridization within the Asian stonechat complex in response to a major geographical barrier

Long-distance avian migration is thought to be under strong natural selection. Facing geographical barriers, migrants display various patterns considered to be adaptive. For example, they may detour along either side around the barrier or cross it, requiring specialized behavioral adaptations. Variations within closely related taxa are excellent sources for understanding the evolutionary background of migration and how barriers are shaping migration routes. In Asia, some species are assumed to have a migratory divide in response to the major geographical barrier, the Qinghai-Tibet Plateau (QTP), including the stonechat taxa (Siberian Stonechat Saxicola maurus maurus and Amur Stonechat S. stejnegeri). As they detour along either side of the QTP, these taxa are believed to disfavor a crossing over the highland. However, the more southernly distributed Tibetan Stonechat (S. m. przewalskii) breeds on the QTP, suggesting adaptation to high elevation. To investigate migration patterns and the potentially associated genetic differences, we studied migration routes and population genetics of four populations around the assumed migratory divide in Russia and Mongolia, and of one from the QTP in China. Our results confirmed the existence of a migratory divide between maurus and stejnegeri, albeit with extensive hybridization. We observed both the hypothesized western and eastern routes, but also found individuals employing intermediate routes crossing the QTP, of which two-thirds were clear hybrids. Meanwhile, przewalskii followed a highland-crossing route and was genetically differentiated from maurus and stejnegeri. The diverse migration routes among Asian stonechats show differential responses towards the geographical barrier. The intermediate route may be associated with hybridization, and its conditional viability may facilitate gene flow between maurus and stejnegeri. The Asian stonechat complex thus offers great opportunities for novel research of the genetics and evolution of migration. The specific evolutionary background associated with inhabiting and crossing the QTP can offer new perspectives in this field. Teaser textMigratory divides can arise in birds because alternative routes around migratory barriers would select for behaviors to restrict hybridization. Hybrids of parental types that employ alternative routes are hypothesized to embark on intermediate routes that would expose them to suboptimal conditions, resulting in post-zygotic reproductive isolation. However, this hypothesis is challenged when a sister taxon actually breeds on the geographical barrier. This is the case in the Asian stonechat complex that breeds near or on the Qinghai-Tibet Plateau (QTP), the roof of the world. We demonstrated a migratory divide in central Siberia to Mongolia for race maurus and stejnegeri, yet showed also evidence for extensive hybridization. Hybrids migrated along a newly discovered intermediate route, seemingly viable and overlaps with the migration trajectory of race przewalskii over the eastern part of the QTP. The Asian migratory divide relative to the QTP thus provided new insights to the evolution of landbird migration.

evolutionary biology↗

Brain tumor induce immunoregulatory dendritic cells in tumor draining lymph nodes that can be targeted by OX40

Brain tumors and metastases have a poor prognosis due to the unique characteristics of the central nervous system (CNS) and tumor immune microenvironment (TIME). CNS tumors exhibit limited infiltration and activation of dendritic cells (DCs) in tumor tissue and tumor-draining lymph nodes (TdLN), which regulate immune responses influenced by factors in the TIME. The immune response in the brain is significantly different from the rest of the body, and although DC subtypes have been identified in mice and humans with brain tumors or metastases, little is known how they affect the response to immunotherapy. We investigated the immunoregulatory function of cervical DCs (DC-c) compared to peripheral DCs (DC-p) in TdLN. Our analysis revealed that DC-c have unique phenotypes and promoted regulatory T cell expansion and poorly cytotoxic CD8 T cells compared to DC-p. Furthermore, we identified OX40 as a modulator of immunoregulatory DC-c function, and Batf3 knockout confirmed the essential role of DC-c in mounting an immune response to brain tumors. Additionally, the expression of markers associated with mature regulatory DCs (mregDC) in TdLN was associated with immune regulation in the CNS and the response to OX40. Our findings highlight that immunotherapy interventions can modulate DC-cs immunoregulatory function, offering an innovative approach for optimized immunotherapy against CNS malignancies.

immunology↗

Deep immune profiling reveals targetable mechanisms of immune evasion in checkpoint blockade-refractory glioblastoma

BackgroundGlioblastoma (GBM) is refractory to checkpoint blockade immunotherapy (CPI). We sought to determine to what extent this immune evasion is due to intrinsic properties of the tumor cells versus the specialized immune context of the brain, and if it can be reversed. MethodsWe used CyTOF mass cytometry to compare the tumor immune microenvironments (TIME) of human tumors that are generally CPI-refractory (GBM and sarcoma) or CPI-responsive (renal cell carcinoma), as well as mouse models of GBM that are CPI-responsive (GL261) or CPI-refractory (SB28). We further compared SB28 tumors grown intracerebrally versus subcutaneously to determine how tumor site affects TIME and responsiveness to dual CTLA-4/PD-1 blockade. Informed by these data, we explored rational immunotherapeutic combinations. ResultsCPI-sensitivity in human and mouse tumors was associated with increased T cells and dendritic cells, and fewer myeloid cells, in particular PD-L1+ tumor associated macrophages. The SB28 mouse model of GBM responded to CPI when grown subcutaneously but not intracerebrally, providing a system to explore mechanisms underlying CPI resistance in GBM. The response to CPI in the subcutaneous SB28 model required CD4 T cells and NK cells, but not CD8 T cells. Recombinant FLT3L expanded dendritic cells, improved antigen-specific T cell priming, and prolonged survival of mice with intracerebral SB28 tumors, but at the cost of increased Tregs. Targeting PD-L1 also prolonged survival, especially when combined with stereotactic radiation. ConclusionsOur data suggest that a major obstacle for effective immunotherapy of GBM is the low antigenicity of the tumor cells coupled with poor antigen presentation in the brain, rather than intrinsic immunosuppressive properties of GBM tumor cells. Deep immune profiling identified dendritic cells and PD-L1+ tumor-associated macrophages as promising targetable cell populations, which was confirmed using therapeutic interventions in vivo. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/404939v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@bdd0e4org.highwire.dtl.DTLVardef@1dd335forg.highwire.dtl.DTLVardef@157bfa6org.highwire.dtl.DTLVardef@1e76151_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefIn mice and humans, tumors that were sensitive to checkpoint blockade had consistent immunological features. A mouse model of glioma that is refractory to checkpoint blockade was sensitized by increasing antigen presentation through a variety of approaches.

cancer biology↗

Paladin is a PI(4,5)P2 phosphoinositide phosphatase that regulates endosomal signaling and angiogenesis

Cell signaling governs cellular behavior and is therefore subject to tight spatiotemporal regulation. Signaling output is regulated by specialized cell membranes and vesicles which contain unique combinations of lipids and proteins. The phospholipid phosphatidylinositol 4,5-bisphosphate, (PI(4,5)P2), an important component of the plasma membrane as well as other subcellular membranes, is involved in multiple processes, including signaling. However, which enzymes drive the formation and degradation of non-plasma membrane PI(4,5)P2, and their impact on cell signaling and function at the organismal level are unknown. Here we show in a mouse model that Paladin is a vascular PI(4,5)P2 phosphatase that regulates endosomal signaling and angiogenesis. Paladin was localized to the endosomal and Golgi compartments, and interacted with vascular endothelial growth factor receptor 2 (VEGFR2) in vitro and in vivo. Loss of Paladin resulted in increased internalization of the receptor, over-activation of extracellular regulated kinase, and hypersprouting of endothelial cells in the developing retina of mice. These findings suggest that inhibition of Paladin, or other endosomal PI(4,5)P2 phosphatases, could be exploited to modulate VEGFR2 signaling and angiogenesis, when direct and full inhibition of the receptor is not desirable.

cell biology↗

Using environmental DNA for the detection of Schistosoma mansoni: toward improved environmental surveillance of schistosomiasis

Schistosomiasis is a waterborne, infectious disease with high morbidity and significant economic burdens affecting more than 250 million people globally. Disease control has, with notable success, for decades focused on drug treatment of infected human populations, but a recent paradigm shift now entails moving from control to elimination. To achieve this ambitious goal more sensitive diagnostic tools are needed to monitor progress towards transmission interruption in the environment, especially in low-intensity infection areas. We report on the development of an environmental DNA (eDNA) based tool to efficiently detect DNA traces of the parasite Schistosoma mansoni directly in the aquatic environment, where the non-human part of the parasite life cycle occurs. To our knowledge, this is the first report of the successful detection of S. mansoni in freshwater samples using aquatic eDNA. True eDNA was detected in as few as 10 cercariae/L water in laboratory experiments. The field applicability of the method was tested at known transmission sites in Kenya, where comparison of schistosome detection by conventional snail surveys (snail collection and cercariae shedding) with eDNA (water samples) showed 71% agreement between the methods. The eDNA method furthermore detected schistosome presence at two additional sites where snail shedding failed, demonstrating a higher sensitivity of eDNA sampling. We conclude that eDNA provides a promising new tool to significantly improve the environmental surveillance of S. mansoni. Given the proper method and guideline development, eDNA could become an essential future component of the schistosomiasis control tool box needed to achieve the goal of elimination. SignificanceAccurate detection and delineation of schistosomiasis transmission sites will be vital in on-going efforts to control and ultimately eliminate one of the most neglected tropical parasitic diseases affecting more than 250 million people worldwide. Conventional methods to detect parasites in the environment are cumbersome and have low sensitivity. We therefore developed an environmental DNA (eDNA) based method for schistosome detection in aquatic environments. Aquatic eDNA showed higher sensitivity than conventional snail surveys. We conclude that eDNA is a promising non-invasive and sensitive tool for environmental surveillance of schistosomiasis transmission. As the efforts and aims to control the disease are transitioning towards complete transmission interruption, this could be the robust and cost-effective surveillance tool needed in the "end game" of schistosomiasis.

microbiology↗