Cerebrospinal fluid transcriptional analyses reveals upregulation of IL-17, Type 1 interferon transcriptional pathways and neutrophil persistence genes associated with increased mortality from pneumococcal meningitis in adults

Wall, E. C.; Guerra-Assuncao, J. A.; Pollara, G.; Venturini, C.; Mlowzowa, V.; Allain, T.; Lalloo, D.; Noursadeghi, M.; Brown, J. S.; Heyderman, R.

doi:10.1101/490045

bioRxiv · 10.1101/490045

Cerebrospinal fluid transcriptional analyses reveals upregulation of IL-17, Type 1 interferon transcriptional pathways and neutrophil persistence genes associated with increased mortality from pneumococcal meningitis in adults

Wall, E. C.·Guerra-Assuncao, J. A.·Pollara, G.·Venturini, C.·Mlowzowa, V.·Allain, T.·Lalloo, D.·Noursadeghi, M.·Brown, J. S.·Heyderman, R.

View original source ↗Export metadata ↓

Abstract

BackgroundImproving outcomes from pneumococcal meningitis (PM), particularly in populations with high HIV prevalence, requires better understanding of host inflammatory responses to infection.\n\nMethodsWe compared the transcriptome in pre-antibiotic cerebrospinal fluid (CSF) and blood from Malawian adults with PM using RNA sequencing. We used network analyses and cellular/process deconvolution of the transcriptome to identify important patho-physiological associations with outcome.\n\nFindingsBlood transcriptional profiles were obtained in 28 patients (21 HIV co-infected; median age 33 years [26-66]; median CSF WCC 28 cells/mm3 [0-3660]; median bacterial load 4.7x106 copies/ml CSF [671-2x109]; in-hospital mortality 64%), paired CSF profiles were obtained in 13. Marked differences in gene expression by outcome were confined to the CSF. In non-survivors, differentially expressed genes in the CSF were co-correlated in a network of pro-inflammatory gene-clusters enriched for collagen degradation and platelet degranulation. In contrast, CSF gene expression networks from surviving patients were dominated by DNA repair, transcriptional regulation and immunological signalling. CSF expression of gene response-modules for IL-17, Type 1 interferons and IL-10 were enriched in non-survivors, expression of cell-specific response-modules did not differ by outcome. However, genes for neutrophil chemotaxis and persistence were highly over-expressed in non-survivors.\n\nInterpretationThese data suggest poor outcome in PM is associated with over-expression of IL-17 and T1-IFN associated pro-inflammatory responses in the CSF and suggest a role for neutrophil-mediated inflammation. These responses are unlikely to be effected by current adjunctive treatments. Improving poor outcomes from PM will require better-targeted interventions.\n\nFundingAcademy of Medical Sciences (UK), Wellcome Trust (UK) (089671/B/09/Z)

Explore related subjects

immunology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Wall, E. C., Guerra-Assuncao, J. A., Pollara, G., Venturini, C., Mlowzowa, V., Allain, T., Lalloo, D., Noursadeghi, M., Brown, J. S., Heyderman, R.. 2018-12-07. Cerebrospinal fluid transcriptional analyses reveals upregulation of IL-17, Type 1 interferon transcriptional pathways and neutrophil persistence genes associated with increased mortality from pneumococcal meningitis in adults. https://doi.org/10.1101/490045

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

γδ T cell-derived IL-17A aggravates experimental epidermolysis bullosa acquisita in response to IL-1β

Epidermolysis bullosa acquisita (EBA) is a mucocutaneous autoimmune blistering disorder mediated by autoantibodies against type VII collagen and subsequent splitting of the dermal-epidermal junction. Interleukin (IL)-17A promotes the production of chemokines and cytokines involved in neutrophil recruitment and activation, suggesting that IL-17A may contribute to EBA pathogenesis. We aimed to clarify the role of IL-17A in experimental EBA. Using an antibody transfer-induced EBA mouse model, we demonstrate that IL-17A promotes disease development, as pharmacological blockade of IL-17A with a neutralizing antibody ameliorated skin lesions. Gamma-delta ({gamma}{delta}) T cells were identified as the predominant cellular source of IL-17A, supported by the attenuated disease phenotype observed in {gamma}{delta}TCR-deficient mice. In addition, CD4+ T cells and neutrophils contributed to IL-17A production in experimental EBA. Mechanistically, IL-1-beta, rather than IL-23, was identified as a critical mediator of IL-17A production by {gamma}{delta} T cells in vitro, consistent with our in vivo findings. Whereas EBA severity was not reduced in IL-23p19-deficient mice, disease was markedly attenuated in IL-1R-deficient animals. Together, our study provides the first evidence that {gamma}{delta} T cell-derived IL-17A plays a pivotal role in experimental EBA and identifies a previously unrecognized IL-1{beta}/{gamma}{delta} T cell/IL-17A axis that expands current understanding of EBA immunopathogenesis.

immunology↗

bioRxiv2026

A mammalian fibroblast zoo reveals barriers to cross-species virus replication and differential regulation of antiviral immunity

Virus zoonosis represents a continual threat to humans. Viruses emerge in humans directly or indirectly through interactions with mammals. However, our understanding of virus-host susceptibility across the diversity of mammals is limited and experimental model systems are restricted to a very small set of model organisms. Mammals are highly diverse and different habitats, lifestyles, diets, and exposures to different pathogens have driven substantial genetic diversity. We generated a library of primary fibroblasts across 86 mammalian species and used these cells to build an atlas of virus-host susceptibility across a panel of arboviruses that infect diverse mammals including humans. Perturbing the innate immune system revealed some virus-host pairs where restriction is controlled by the immune system and others where there is an incompatibility with host factors. Transcriptomic profiling of the library in response to virus sensing mimicked by poly(I:C) or antiviral signaling with type I interferon reveals a core set of conserved genes that respond as well as substantial species- and order-specific responses. Together these data provide a comparative atlas of innate immune responses across mammals and offer a window into how these systems have evolved across animals.

immunology↗

bioRxiv2026

A reporter mouse model to map RIG-I expression and function in vivo

The cytosolic RNA sensor RIG-I is a critical component of the innate immune response to RNA viruses, yet few tools exist to track RIG-I in vivo. Herein, we report the development of a RIG-I reporter mouse, termed RIG-ImScar, that enables fluorescence imaging and tractable immunoprecipitation of RIG-I in vivo. These mice revealed enrichment of RIG-I expression in circulatory, lymphoid, and mucosal tissues and broad expression across immune cell types. RIG-I itself is upregulated in response to IFN. To distinguish RIG-I sentinel cells, which are programmed to express RIG-I at steady state, from IFN-responder cells, we crossed RIG-ImScar mice with Mx1GFP mice. Blocking IFNAR with a monoclonal antibody showed that basal RIG-I expression in immune cells was largely independent of type I IFN signaling, although Ly6Chi monocytes required IFNAR for RIG-I expression. To probe functional responses in vivo, we intranasally administered a RIG-I-specific agonist, SLR14. Mapping RIG-I expression across the lung identified alveolar macrophages as a critical RIG-I sensor cell population, and depletion of alveolar macrophages, but not neutrophils, slightly impaired lung IFN responses. Together, these findings support the use of the RIG-ImScar model to probe RIG-I dynamics in vivo and predict functional sensor cell populations across tissues.

immunology↗