Biology subjects

Libri, V.

Publications and source records attributed to Libri, V..

7 recordsLinked to original sources

bioRxiv2025

NK cells undergo transcriptional and functional reprogramming following Streptococcus pneumoniae infection

Natural Killer (NK) cells are cytotoxic lymphocytes and key mediators of innate immunity, essential for combating viral infections and cancer. Notably, they exhibit immunological memory, generating a stronger response upon re-exposure to the same stimulus. While NK cell memory holds promise for infection control, its role in bacterial infections remains poorly understood. Previously, we demonstrated that Streptococcus pneumoniae induces long-term, specific, and protective NK cell memory. In this study, we performed single-cell RNA-seq to uncover how NK cells respond to S. pneumoniae infection. Our findings reveal that challenged Memory (cMemory) NK cells undergo transcriptional reprogramming following S. pneumoniae infection and have a differential transcriptional response upon reinfection. In addition, we identified distinct cMemory NK cell subpopulations, with responding cMemory NK cells displaying a general enhanced activation, proliferation, and cytotoxic activity. These findings support a novel role for NK cells in the context of bacterial infections, thereby opening avenues for harnessing the potential of innate immune memory for therapeutic applications.

immunology↗

bioRxiv2024

Host and rabies virus gene expression is shaped by human brain cell type and reveals a preexisting pro-viral transcriptional state in astrocytes

How virus-host cell interactions and innate immune antagonism shape neurotropic infection dynamics across diverse brain cell types are largely unknown. To "unmask" and study how innate immune inhibition affects cell type-specific transcriptional regulation of the human and viral genome, we performed single-cell RNA sequencing of human brain cell co-cultures, comparing an isolate of rabies virus (RABV) to its mutant incapable of antagonizing interferon- and NF-{kappa}B-dependent responses. RABV gene expression was shaped by host cell type. RABV induced small-scale, cell-type conserved transcriptional programs that likely support infection by 1) hijacking negative transcriptional feedback of pro-viral factors while 2) reducing anti-viral RNAs. Unexpectedly, disinhibited innate immune signaling increased RABV transcription, most strikingly in an infection-independent "pro-viral" astrocyte subpopulation. Further analysis suggested that "pro-viral"-like astrocytes are a rare subtype in the human brain and are primed to protect the brain during viral infection in concert with interferon-sensitive microglia recalcitrant to infection.

neuroscience↗

bioRxiv2024

Accurate evaluation of live-virus microneutralisation for SARS-CoV-2 variant JN.1

Emerging SARS-CoV-2 variants require rapid assessments of pathogenicity and evasion of existing immunity to inform policy. A crucial component of these assessments is accurate estimation of serum neutralising antibody titres using cultured live virus isolates. Here, we report our updated culture methods for Omicron sub-variant JN.1 using Caco-2 cells and the subsequent evaluation of neutralising antibody titres (nAbTs) in recipients of BNT162b2-XBB.1.5 monovalent and the Ancestral/BA.5 containing bivalent vaccines. We compared culture of JN.1 in either Vero V1 cells or Caco-2 cells, finding culture in Vero V1 either resulted in low-titre stocks or induced crucial mutations at the Spike furin cleavage site. Using the sequence-clean culture stocks generated in Caco-2 cells, we assessed serum samples from 71 healthy adults eligible for a COVID-19 vaccination given as a 5th dose booster: all participants had detectable nAbs against JN.1 prior to vaccination, with baseline/pre-existing nAbTs between both vaccine groups comparable (p = 0.240). However, nAbTs against JN.1 post-vaccination were 2.6-fold higher for recipients of the monovalent XBB1.5 vaccine than the BA.4/5 bivalent vaccine (p<0.001). Regular re-appraisal of methods involved in the evaluation of new variants is required to ensure robust data are used to underpin crucial severity assessments as variants arise and vaccine strain selection decisions.

microbiology↗

bioRxiv2024

Differential predictive value of resident memory CD8+T cell subpopulations in non-small-cell lung cancer patients treated by immunotherapy

A high density of resident memory T cells (TRM) in tumors correlates with improved clinical outcomes in immunotherapy-treated patients. However, in preclinical models, only some subpopulations of TRM are associated with cancer vaccine efficacy. We identified two main TRM subpopulations in tumor-infiltrating lymphocytes derived from non-small cell lung cancer (NSCLC) patients: one co-expressing CD103 and CD49a (DP), and the other expressing only CD49a (MP); both exhibiting additional TRM surface markers like CD69. DP TRM exhibited greater functionality compared to MP TRM. Analysis of T-cell receptor (TCR) repertoire and of the stemness marker TCF-1 revealed shared TCRs between populations, with the MP subset appearing more progenitor-like phenotype. In two NSCLC patient cohorts, only DP TRM predicted PD-1 blockade response. Multivariate analysis, including various biomarkers (CD8, TCF1+CD8+T cells, and PD-L1) associated with responses to anti-PD(L)1, showed that only intra-tumoral infiltration by DP TRM remained significant. This study highlights the non-equivalence of TRM populations and emphasizes the importance of distinguishing between them to better define their role in antitumor immunity and as a biomarker of response to immunotherapy.

immunology↗

bioRxiv2023

Dichotomy of neutralizing antibody, B cell and T cell responses to SARS-CoV-2 vaccination and protection in healthy adults

Heterogeneity in SARS-CoV-2 vaccine responses is not understood. Here, we identify four patterns of live-virus neutralizing antibody responses: individuals with hybrid immunity (with confirmed prior infection); rare individuals with low responses (paucity of S1-binding antibodies); and surprisingly, two further groups with distinct serological repertoires. One group - broad responders - neutralize a range of SARS-CoV-2 variants, whereas the other - narrow responders - neutralize fewer, less divergent variants. This heterogeneity does not correlate with Ancestral S1-binding antibody, rather the quality of the serological response. Furthermore, IgDlowCD27-CD137+ B cells and CCR6+ CD4+ T cells are enriched in broad responders before dose 3. Notably, broad responders have significantly longer infection-free time after their third dose. Understanding the control and persistence of these serological profiles could allow personalized approaches to enhance serological breadth after vaccination.

immunology↗

bioRxiv2022

Environmental and genetic drivers of population differences in SARS-CoV-2 immune responses

Humans display vast clinical variability upon SARS-CoV-2 infection1-3, partly due to genetic and immunological factors4. However, the magnitude of population differences in immune responses to SARS-CoV-2 and the mechanisms underlying such variation remain unknown. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells from 222 healthy donors of various ancestries stimulated with SARS-CoV-2 or influenza A virus. We show that SARS-CoV-2 induces a weaker, but more heterogeneous interferon-stimulated gene activity than influenza A virus, and a unique pro-inflammatory signature in myeloid cells. We observe marked population differences in transcriptional responses to viral exposure that reflect environmentally induced cellular heterogeneity, as illustrated by higher rates of cytomegalovirus infection, affecting lymphoid cells, in African-descent individuals. Expression quantitative trait loci and mediation analyses reveal a broad effect of cell proportions on population differences in immune responses, with genetic variants having a narrower but stronger effect on specific loci. Additionally, natural selection has increased immune response differentiation across populations, particularly for variants associated with SARS-CoV-2 responses in East Asians. We document the cellular and molecular mechanisms through which Neanderthal introgression has altered immune functions, such as its impact on the myeloid response in Europeans. Finally, colocalization analyses reveal an overlap between the genetic architecture of immune responses to SARS-CoV-2 and COVID-19 severity. Collectively, these findings suggest that adaptive evolution targeting immunity has also contributed to current disparities in COVID-19 risk.

genomics↗

bioRxiv2020

Basal Expression of Interferon-Stimulated Genes Drives Population Differences in Monocyte Susceptibility to Influenza Infection

There is considerable inter-individual and inter-population variability in response to viruses. The potential of monocytes to elicit type-I interferon responses has attracted attention to their role in viral infections. Here, we use an ex vivo model to characterize the role of cellular heterogeneity in human variation of monocyte responses to influenza A virus (IAV) exposure. Using single-cell RNA-sequencing, we show widespread inter-individual variability in the percentage of IAV-infected monocytes. We show that cells escaping viral infection display increased mRNA expression of type-I interferon stimulated genes and decreased expression of ribosomal genes, relative to both infected cells and those never exposed to IAV. While this host defense strategy is shared between CD16+/CD16- monocytes, we also uncover CD16+-specific mRNA expression of IL6 and TNF in response to IAV, and a stronger resistance of CD16+ monocytes to IAV infection. Notably, individuals with high cellular susceptibility to IAV are characterized by a lower activation at basal state of an IRF/STAT-induced transcriptional network, which includes antiviral genes such as IFITM3, MX1, and OAS3. Finally, using flow cytometry and bulk RNA-sequencing across 200 individuals of African and European ancestry, we observe a higher number of CD16+ monocytes and lower susceptibility to IAV infection among monocytes from individuals of African-descent. Collectively, our results reveal the effects of IAV infection on the transcriptional landscape of human monocytes and highlight previously unappreciated differences in cellular susceptibility to IAV infection between individuals of African and European ancestry, which may account for the greater susceptibility of Africans to severe influenza. Significance StatementMonocytes may play a critical role during severe viral infections. Our study tackles how heterogeneity in monocyte subsets and activation contributes to shape individual differences in the transcriptional response to viral infections. Using single-cell RNA-sequencing, we reveal heterogeneity in monocyte susceptibility to IAV infection, both between CD16+/CD16- monocytes and across individuals, driven by differences in basal activation of an IRF/STAT-induced antiviral program. Furthermore, we show a decreased ability of IAV to infect and replicate in monocytes from African-ancestry individuals, with possible implications for antigen presentation and lymphocyte activation. These results highlight the importance of early cellular activation in determining an individuals innate immune response to viral infection.

genomics↗