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

Clonally Convergent Tph/Tfh-like CD4+ T Cells are Shared Across Recovery and Recurrence in Experimental Periodontitis

Periodontitis is a chronic inflammatory disease of the tooth-supporting structures (periodontium) that requires life-long maintenance to prevent progression. Using a sensitized model of recurrent periodontitis in mice (SeRPD), in which regulatory breakdown was induced by temporary Treg depletion concurrent with disease, we mapped the gingival T cell imprint across each disease phase. Transient regulatory breakdown left a durable mucosal imprint after clinical recovery, characterized by enrichment of local and regional CD4 T cells. Paired single-cell RNA and TCR sequencing of gingival immune cells identified a convergent clonotype expanded from recovery into recurrence that carried a Tfh/Tph-like transcriptional identity. An analogous CD4 T cell population was detected in human periodontitis lesions by single-cell transcriptomics. Together, these findings support a paradigm in which clinical recovery does not ensure a local T cell repertoire reset; instead, a reservoir of antigen-experienced, tissue-adapted CD4 T cells persist in the mucosa and participate in recurrence.

immunology↗

bioRxiv2026

Robust T and B cell activation is associated with rapid clearance of infectious SARS-CoV-2

The immunologic correlates of rapid clearance of SARS-CoV-2 shedding are not well understood, partly due to challenges of collecting samples early after infection and the fact that most studies do not measure infectious virus. Here, we performed mass cytometry profiling of peripheral blood cells collected from people 4-6 days after onset of symptoms from acute SARS-CoV-2 infection who underwent daily nasopharyngeal testing for SARS-CoV-2 culture positivity. We identified broad and coordinated activation of innate and adaptive immune cells in unvaccinated individuals with primary infection. Faster clearance of infectious virus shedding was associated with robust adaptive immune cell activation and proliferation, namely among cytotoxic CD8+, CD4+, and {gamma}{delta} T cells and plasmablasts. In contrast, vaccinated individuals who rapidly cleared breakthrough infection showed minimal cellular immune activation. Our findings identify early immune correlates of rapid clearance of infectious SARS-CoV-2 shedding that may inform future prevention and therapeutic approaches to reduce disease burden and transmission.

immunology↗

bioRxiv2026

HIV-1 Vpu complements HLA-A downregulation by Nef and impairs TCR-mediated recognition of HIV-infected cells through distinct mechanisms

Many viruses, including HIV-1, target the human leukocyte antigen (HLA) class I molecules HLA-A, HLA-B, and HLA-C to evade immune surveillance. HIV-1 Nef selectively downregulates HLA-A and HLA-B, whereas Vpu variants from primary strains reduce cell-surface HLA-C expression. Whether HIV-1 also uses Vpu to target other HLA molecules has remained unclear. Here, we show that Vpu from primary strains reduces HLA-A, including the globally prevalent HLA-A2, on infected cells. Although Nef is the principal modulator of these molecules, Vpu acts independently of Nef and impairs TCR-mediated recognition of infected cells in co-culture systems. However, the reduction in TCR signaling is also dependent on the presence of BST2/tetherin, a restriction factor that retains nascent virions and targets them for degradation. HLA-A2-restricted, HIV-specific CTL responses were lowest when both Nef and Vpu were present. Vpu variants from chronic and transmitted/founder strains, but not from the prototypical recombinant strain NL4.3, were sufficient to reduce cell-surface HLA-A2, although activity varied widely among variants and appears to have arisen independently in different hosts. Coimmunoprecipitation and immunofluorescence analyses showed that Vpu interacts with HLA-A2 and redirects it to a perinuclear compartment which is probably the trans-Golgi network through a mechanism governed by the Vpu N-terminus/transmembrane domain. Overall, our findings reveal a previously unrecognized function of Vpu and show how HIV-1 uses Nef and Vpu to limit HLA-A-mediated viral antigen presentation and promote immune evasion.

immunology↗