Biology subjects

Pikarsky, E.

Publications and source records attributed to Pikarsky, E..

3 recordsLinked to original sources

bioRxiv2022

RORc expressing immune cells support pro-tumorigenic functions of tertiary lymphoid structures

Tertiary lymphoid structures (TLSs) are formed in many cancer types and have been correlated with better prognosis and response to immunotherapy. In liver cancer, TLSs have been reported to be pro-tumorigenic as they harbor tumor progenitor cells and nurture their growth. The processes involved in TLS development and the acquisition of a pro- or anti-tumorigenic phenotype in cancer are largely unknown. RORc expressing immune cells have been previously implicated in TLS formation, however we find that they are not necessary for TLS neogenesis in the context of inflammation-associated liver cancer. On the contrary, RORc expressing cells negatively regulate TLS formation, since in their absence TLSs form in excess. CD4 cells are essential for liver TLS formation whereas B cells are required for TLS formation specifically in the absence of RORc expressing cells. Importantly, in chronically inflamed livers lacking RORc expressing cells, TLSs become anti-tumorigenic, resulting in reduced tumor load. Comparing liver pro- and anti-tumorigenic TLSs by transcriptional, proteomic and immunohistochemical analyses, revealed enrichment of exhausted CD8 cells that retained effector functions as well as germinal center B cells and plasma cells in anti-tumorigenic TLSs. Cell depletion experiments revealed a role mainly for B cells in limiting tumor development, possibly via tumor directed antibodies. Thus, RORc expressing cells negatively regulate B cell responses, and facilitate the pro-tumorigenic functions of hepatic TLSs. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/498540v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@385067org.highwire.dtl.DTLVardef@126c45corg.highwire.dtl.DTLVardef@25ad06org.highwire.dtl.DTLVardef@1829326_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

2-hydroxyglutarate controls centromere and heterochromatin conformation and function in the male germline

2-hydroxyglutarate (2HG) is recognized as an epigenetic regulator in cancer and some transient biological processes. Of all organs, the testis harbors the highest baseline physiological levels of 2HG, yet its putative functions in germ cell biology are unknown. Here we show that 2HG is generated in specific stages of spermatogenesis by the testis specific lactate dehydrogenase C (LDHC), beginning at the last stages of prophase I. Unexpectedly LDHC enters nuclei and concentrates in centromeres. LDHC-generated L-2HG controls centromere condensation and pericentromeric heterochromatin organization through multiple effects including clustering of chromocenters, centromere and chromocenter condensation and expression of satellite RNAs. These effects are rapid and specific to L but not D-2HG. In vivo depletion of L-2HG causes centromere malfunction and activation of the spindle assembly checkpoint. Our findings reveal that 2HG can directly affect centromere and pericentromeric heterochromatin conformation and function and is necessary for licensing chromosome segregation.

cell biology↗

bioRxiv2021

Human nasal and lung tissues infected ex vivo with SARS-CoV-2 provide insights into differential tissue-specific and virus-specific innate immune responses in the upper and lower respiratory tract

The nasal-mucosa constitutes the primary entry site for respiratory viruses including SARS-CoV-2. While the imbalanced innate immune response of end-stage COVID-19 has been extensively studied, the earliest stages of SARS-CoV-2 infection at the mucosal entry site have remained unexplored. Here we employed SARS-CoV-2 and influenza virus infection in native multi-cell-type human nasal turbinate and lung tissues ex vivo, coupled with genome-wide transcriptional analysis, to investigate viral susceptibility and early patterns of local-mucosal innate immune response in the authentic milieu of the human respiratory tract. SARS-CoV-2 productively infected the nasal turbinate tissues, predominantly targeting respiratory epithelial cells, with rapid increase in tissue-associated viral sub-genomic mRNA, and secretion of infectious viral progeny. Importantly, SARS-CoV-2 infection triggered robust antiviral and inflammatory innate immune responses in the nasal mucosa. The upregulation of interferon stimulated genes, cytokines and chemokines, related to interferon signaling and immune-cell activation pathways, was broader than that triggered by influenza virus infection. Conversely, lung tissues exhibited a restricted innate immune response to SARS-CoV-2, with a conspicuous lack of type I and III interferon upregulation, contrasting with their vigorous innate immune response to influenza virus. Our findings reveal differential tissue-specific innate immune responses in the upper and lower respiratory tract, that are distinct to SARS-CoV-2. The studies shed light on the role of the nasal-mucosa in active viral transmission and immune defense, implying a window of opportunity for early interventions, whereas the restricted innate immune response in early-SARS-CoV-2-infected lung tissues could underlie the unique uncontrolled late-phase lung damage of advanced COVID-19. IMPORTANCEIn order to reduce the late-phase morbidity and mortality of COVID-19, there is a need to better understand and target the earliest stages of SARS-CoV-2 infection in the human respiratory tract. Here we have studied the initial steps of SARS-CoV-2 infection and the consequent innate immune responses within the natural multicellular complexity of human nasal-mucosal and lung tissues. Comparing the global innate response patterns of nasal and lung tissues, infected in parallel with SARS-CoV-2 and influenza virus, we have revealed distinct virus-host interactions in the upper and lower respiratory tract, which could determine the outcome and unique pathogenesis of SARS-CoV-2 infection. Studies in the nasal-mucosal infection model can be employed to assess the impact of viral evolutionary changes, and evaluate new therapeutic and preventive measures against SARS-CoV-2 and other human respiratory pathogens.

microbiology↗