Bacterial meningitis

Summary

Bacterial meningitis (MONDO:0006670) is a disease (an umbrella term covering 8 Mondo subtypes) with 6 cohort genes (5 GWAS associations across 3 studies) and 31 clinical trials. Top therapeutic interventions include avibactam, acetaminophen, and glycerin.

At a glance

• Umbrella term: 8 Mondo subtypes
• Cohort genes: 6
• GWAS associations: 5
• Clinical trials: 31

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	bacterial meningitis
Mondo ID	MONDO:0006670
EFO	EFO:1000831
MeSH	D016920
DOID	DOID:9470
ICD-11	684930313
NCIT	C118297
SNOMED CT	95883001
UMLS	C0085437
MedGen	39048
GARD	0005881
MedDRA	10004049
Is cancer (heuristic)	no

Also known as: Bacteria caused infectious meningitis · Bacteria infectious meningitis · meningitis, bacterial

Data availability: 5 GWAS associations (3 studies).

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › encephalomyelitis › meningitis › infectious meningitis › bacterial meningitis

Related subtypes (4): fungal meningitis, viral meningitis, arachnoiditis, meningitis caused by poliovirus

Subtypes (8): haemophilus meningitis, streptococcal meningitis, anaerobic meningitis, meningeal tuberculosis, Escherichia coli meningitis, Listeria meningitis, meningococcal meningitis, bacterial meningitis caused by gram-negative bacteria

Genetics & variants

GWAS landscape

5 GWAS associations across 3 studies. Top hits map to 3 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs12081070	2e-08	UBE2U	A	1.62
rs116264669	4e-08	CCDC33	?
rs3870369	7e-08	RNA5SP224 - RNA5SP225	T	1.27
rs2309554	4e-07	TENM3-AS1	A	1.58
rs72739603	7e-07	ZCCHC7 - LINC01627	A	2.36

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST009085	Lees JA	2019	2,345	345,042	Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.
GCST009083	Lees JA	2019	1,149	4,836	Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.
GCST009088	Lees JA	2019	277	4,836	Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	5

MAF distribution

Bucket	Variants
common (>=0.05)	5
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	4
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs12081070	1	64215092	G>A	0.05	intron_variant	UBE2U	2e-08	Tier 4: intronic/intergenic
rs116264669	15	74309203	G>A,T	0.05	intron_variant	CCDC33	4e-08	Tier 4: intronic/intergenic
rs3870369	6	153261855	T>A,G	0.05	intron_variant	RNA5SP224 - RNA5SP225	7e-08	Tier 4: intronic/intergenic
rs2309554	4	181902651	G>A,C,T	0.05	intron_variant	TENM3-AS1	4e-07	Tier 4: intronic/intergenic
rs72739603	9	37382234	G>A	0.05	intergenic_variant	ZCCHC7 - LINC01627	7e-07	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RORA	Orphanet:528084	Non-specific syndromic intellectual disability
GRHPR	Orphanet:93599	Primary hyperoxaluria type 2

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RORA	HGNC:10258	ENSG00000069667	P35398	Nuclear receptor ROR-alpha	gwas
RGS17	HGNC:14088	ENSG00000091844	Q9UGC6	Regulator of G-protein signaling 17	gwas
ZCCHC7	HGNC:26209	ENSG00000147905	Q8N3Z6	Zinc finger CCHC domain-containing protein 7	gwas
CCDC33	HGNC:26552	ENSG00000140481	Q8N5R6	Coiled-coil domain-containing protein 33	gwas
UBE2U	HGNC:28559	ENSG00000177414	Q5VVX9	Ubiquitin-conjugating enzyme E2 U	gwas
GRHPR	HGNC:4570	ENSG00000137106	Q9UBQ7	Glyoxylate reductase/hydroxypyruvate reductase	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RORA	Nuclear receptor ROR-alpha	Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5’-AGGTCA-3’ preceded by a short A-T-rich sequence.
RGS17	Regulator of G-protein signaling 17	Regulates G protein-coupled receptor signaling cascades, including signaling via muscarinic acetylcholine receptor CHRM2 and dopamine receptor DRD2.
UBE2U	Ubiquitin-conjugating enzyme E2 U	Catalyzes the covalent attachment of ubiquitin to other proteins.
GRHPR	Glyoxylate reductase/hydroxypyruvate reductase	Enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Nuclear receptor	1	64.3×	0.062
Enzyme (other)	2	4.0×	0.166
Transcription factor	1	1.4×	0.719
Other/Unknown	2	0.6×	0.936

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RORA	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
RGS17	Other/Unknown	no		RGS, RGS_sf, RGS_subdomain_2
ZCCHC7	Transcription factor	no		Znf_CCHC, Znf_CCHC_sf, TRAMP_AT-DNA-binding
CCDC33	Other/Unknown	no		C2_dom, C2_domain_sf, CCD33
UBE2U	Enzyme (other)	yes	2.3.2.23	UBC, UBQ-conjugating_enzyme/RWD, UBQ-conjugating_AS
GRHPR	Enzyme (other)	yes	1.1.1.26	D-isomer_2_OHA_DH_cat_dom, D-isomer_DH_NAD-bd, D-isomer_DH_CS

Expression context

Cohort genes with no expression data: 0.

6 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
tendon of biceps brachii	2
left testis	2
lateral nuclear group of thalamus	1
skin of hip	1
upper leg skin	1
buccal mucosa cell	1
cortical plate	1
calcaneal tendon	1
tendon	1
olfactory segment of nasal mucosa	1
right uterine tube	1
right testis	1
sperm	1
liver	1
right adrenal gland	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RORA	284	ubiquitous	marker	upper leg skin, lateral nuclear group of thalamus, skin of hip
RGS17	227	ubiquitous	marker	cortical plate, buccal mucosa cell, tendon of biceps brachii
ZCCHC7	245	ubiquitous	marker	calcaneal tendon, tendon, tendon of biceps brachii
CCDC33	100	broad	marker	right uterine tube, olfactory segment of nasal mucosa, left testis
UBE2U	105	tissue_specific	marker	sperm, left testis, right testis
GRHPR	292	ubiquitous	marker	right lobe of liver, liver, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GRHPR	2,785
UBE2U	2,232
ZCCHC7	2,085
CCDC33	2,024
RGS17	1,504
RORA	68

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GRHPR	Q9UBQ7	4
RORA	P35398	3
RGS17	Q9UGC6	2
UBE2U	Q5VVX9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CCDC33	Q8N5R6	72.34
ZCCHC7	Q8N3Z6	53.92

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 33. Enrichment computed across 6 evidence-associated genes (5 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters	1	175.7×	0.056	RORA
Glyoxylate metabolism and glycine degradation	1	152.3×	0.056	GRHPR
R-HSA-1368082	1	142.8×	0.056	RORA
The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex	1	142.8×	0.056	RORA
Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes	1	95.2×	0.056	RORA
RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression	1	81.6×	0.056	RORA
R-HSA-400253	1	69.2×	0.056	RORA
SUMOylation of intracellular receptors	1	67.2×	0.056	RORA
Nuclear RNA decay	1	61.7×	0.056	ZCCHC7
Expression of BMAL (ARNTL), CLOCK, and NPAS2	1	58.6×	0.056	RORA
G alpha (z) signalling events	1	46.6×	0.063	RGS17
Heme signaling	1	43.1×	0.063	RORA
Nuclear Receptor transcription pathway	1	40.1×	0.063	RORA
SUMO E3 ligases SUMOylate target proteins	1	35.7×	0.065	RORA
SUMOylation	1	32.6×	0.067	RORA
Regulation of lipid metabolism by PPARalpha	1	28.2×	0.072	RORA
Interleukin-4 and Interleukin-13 signaling	1	20.6×	0.093	RORA
PPARA activates gene expression	1	18.9×	0.095	RORA
Signaling by Interleukins	1	12.8×	0.131	RORA
G alpha (q) signalling events	1	11.5×	0.139	RGS17
Cytokine Signaling in Immune system	1	8.2×	0.177	RORA
G alpha (i) signalling events	1	7.8×	0.177	RGS17
Antigen processing: Ubiquitination & Proteasome degradation	1	7.4×	0.177	UBE2U
Cellular responses to stress	1	7.4×	0.177	RORA
Metabolism of lipids	1	6.3×	0.189	RORA
Cellular responses to stimuli	1	6.3×	0.189	RORA
RNA Polymerase II Transcription	1	4.5×	0.248	RORA
Post-translational protein modification	1	3.8×	0.277	RORA
Gene expression (Transcription)	1	3.6×	0.285	RORA
Generic Transcription Pathway	1	3.0×	0.319	RORA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dicarboxylic acid metabolic process	1	1685.2×	0.005	GRHPR
nuclear mRNA surveillance of mRNA 3’-end processing	1	1685.2×	0.005	ZCCHC7
nuclear polyadenylation-dependent snoRNA catabolic process	1	1685.2×	0.005	ZCCHC7
nuclear polyadenylation-dependent snRNA catabolic process	1	1685.2×	0.005	ZCCHC7
nuclear polyadenylation-dependent CUT catabolic process	1	1685.2×	0.005	ZCCHC7
cGMP metabolic process	1	842.6×	0.007	RORA
cellular response to sterol	1	674.1×	0.007	RORA
carboxylic acid metabolic process	1	561.7×	0.007	GRHPR
glyoxylate metabolic process	1	561.7×	0.007	GRHPR
regulation of steroid metabolic process	1	481.5×	0.007	RORA
nuclear polyadenylation-dependent rRNA catabolic process	1	481.5×	0.007	ZCCHC7
TRAMP-dependent tRNA surveillance pathway	1	481.5×	0.007	ZCCHC7
T-helper 17 cell differentiation	1	481.5×	0.007	RORA
cerebellar granule cell precursor proliferation	1	306.4×	0.010	RORA
regulation of macrophage activation	1	259.3×	0.011	RORA
positive regulation of circadian rhythm	1	240.7×	0.011	RORA
cerebellar Purkinje cell differentiation	1	210.7×	0.012	RORA
intracellular receptor signaling pathway	1	198.3×	0.012	RORA
muscle cell differentiation	1	168.5×	0.014	RORA
nitric oxide biosynthetic process	1	140.4×	0.016	RORA
regulation of smoothened signaling pathway	1	124.8×	0.017	RORA
regulation of glucose metabolic process	1	112.3×	0.018	RORA
response to amphetamine	1	99.1×	0.018	RGS17
positive regulation of vascular endothelial growth factor production	1	99.1×	0.018	RORA
triglyceride homeostasis	1	96.3×	0.018	RORA
negative regulation of signal transduction	1	74.9×	0.022	RGS17
negative regulation of fat cell differentiation	1	62.4×	0.026	RORA
cellular response to interleukin-1	1	56.2×	0.028	RORA
circadian regulation of gene expression	1	46.8×	0.032	RORA
negative regulation of canonical NF-kappaB signal transduction	1	34.4×	0.042	RORA

Therapeutics

Drugs indicated or in trials for this disease

1 approved drug — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Status
Meropenem	Approved (phase 4)

3 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Acetaminophen	Phase 3
Glycerin	Phase 3
Ceftazidime	Phase 2

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 4

Druggability breadth: 3 of 6 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
RORA	TRETINOIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RORA	2	4
RGS17	2	2
ZCCHC7	0	0
CCDC33	0	0
UBE2U	0	0
GRHPR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TRETINOIN	4	RORA
SANGUINARIUM	2	RGS17
SANGUINARIUM CHLORIDE	2	RGS17
CINTIRORGON	1	RORA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RORA	115	Binding:111, Functional:3, Unclassified:1
RGS17	20	Binding:20
GRHPR	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
UBE2U	2.3.2.23	E2 ubiquitin-conjugating enzyme
GRHPR	1.1.1.26, 1.1.1.79, 1.1.1.81	glyoxylate reductase, glyoxylate reductase (NADP+), hydroxypyruvate reductase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
RORA	115

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

4 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
TRETINOIN	4	RORA
SANGUINARIUM	2	RGS17
SANGUINARIUM CHLORIDE	2	RGS17
CINTIRORGON	1	RORA

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RORA
B	Phased (≥1) drug, not yet approved	1	RGS17
C	Druggable family + PDB, no drug	2	UBE2U, GRHPR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ZCCHC7, CCDC33

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ZCCHC7	0	—
CCDC33	0	—
UBE2U	0	—
GRHPR	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 31.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	20
PHASE3	6
PHASE4	2
EARLY_PHASE1	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00774631	PHASE4	TERMINATED	IHPOTOTAM : Induced HyPOthermia TO Treat Adult Meningitis
NCT01540838	PHASE4	COMPLETED	Slow Initial β-lactam Infusion With High-dose Paracetamol to Improve the Outcomes of Childhood Bacterial Meningitis
NCT00619203	PHASE3	COMPLETED	Oral Glycerol and High-Dose Rectal Paracetamol to Improve the Prognosis of Childhood Bacterial Meningitis
NCT01410474	PHASE3	COMPLETED	Immunogenicity and Safety of Meningococcal ACWY Conjugate Vaccine in Healthy Subjects From 2 to 18 Years in Taiwan
NCT01547715	PHASE3	COMPLETED	Immunogenicity and Safety of Meningococcal ACWY Conjugate Vaccine in Healthy Subjects From 2 to 75 Years of Age in India
NCT01589289	PHASE3	COMPLETED	Rapid Diagnostic Tests and Clinical/Laboratory Predictors of Tropical Diseases in Neurological Disorders in DRC
NCT02274285	PHASE3	COMPLETED	DTaP-IPV/Hib Vaccine Primary & Booster Vaccinations Versus Co-administration of DTaP-IPV and Hib Vaccine in Japanese Infants
NCT03891758	PHASE3	COMPLETED	Confirmatory Study of BK1310 in Healthy Infants
NCT07431307	PHASE2	NOT_YET_RECRUITING	Safety, Pharmacokinetics and Efficacy of BV100 Plus Low Dose Polymyxin B Plus Ceftazidime/Avibactam, or Plus Cefiderocol in Patients With Pulmonary and Extrapulmonary Infections Due to Carbapenem-resistant Acinetobacter Baumannii-calcoaceticus Complex
NCT03630250	EARLY_PHASE1	COMPLETED	Challenge of the Nasopharynx With Neisseria Lactamica Expressing the Meningococcal Protein Neisseria Adhesin A (NadA)
NCT03633474	EARLY_PHASE1	COMPLETED	Defining the Immune Response to Nasopharyngeal Colonisation by the Commensal Neisseria Lactamica
NCT02979951	Not specified	RECRUITING	Fosfomycin I.v. for Treatment of Severely Infected Patients
NCT03418441	Not specified	RECRUITING	Central Nervous System Infections in Denmark
NCT07027475	Not specified	RECRUITING	Acute Treatment and Long-term Assessment of Adult Infectious Meningitis
NCT07134751	Not specified	RECRUITING	Febrile Infants Swedish Study
NCT07410624	Not specified	RECRUITING	Augmented Renal Clearance in Neurocritical Care
NCT07432113	Not specified	NOT_YET_RECRUITING	Prediction of Infectious Agents in the Biofire® FilmArray bioMérieux Meningitis/Encephalitis Panel Based on Clinical Syndrome and Cerebrospinal Fluid Parameters: a Diagnostic Stewardship Proposal.
NCT07495150	Not specified	NOT_YET_RECRUITING	Intracalvariosseous Plus Intravenous Antibiotics for Moderate-to-Severe Bacterial Meningitis
NCT01431326	Not specified	COMPLETED	Pharmacokinetics of Understudied Drugs Administered to Children Per Standard of Care
NCT01730690	Not specified	COMPLETED	Bacterial Meningitis in Adults: Analysis of the Determinants of Mortality and Neurosensory Sequelae
NCT01747369	Not specified	UNKNOWN	Surveillance of Hospitalised Pneumonia and Bacterial Meningitis in Tône District, Togo, 2010-2013
NCT02467309	Not specified	UNKNOWN	Vitamin d Levels in Children With Bacterial Meningitis
NCT02972281	Not specified	COMPLETED	Systematic Search for Primary Immunodeficiency in Adults With Infections
NCT03226379	Not specified	COMPLETED	Driving Reduced AIDS-associated Meningo-encephalitis Mortality
NCT03252028	Not specified	UNKNOWN	Rapid Test for Detection of the Focus of Infection in Post Neurosurgical Patients.
NCT03499652	Not specified	UNKNOWN	Neonatal Bacterial Meningitis Cohort
NCT03595761	Not specified	COMPLETED	Meningitis With Cerebral Vasculitis in Children
NCT04135053	Not specified	UNKNOWN	A Controlled Study to Assess Safety, Colonisation and Immunogenicity of Reconstituted Lyophilised Neisseria Lactamica
NCT04196192	Not specified	COMPLETED	Febrile Infants - Diagnostic Assessment and Outcome
NCT04771884	Not specified	UNKNOWN	Population Pharmacokinetics of Commonly Used Antimicrobial Agents in Children of Bacterial Meningitis With Augmented Renal Clearance
NCT05146570	Not specified	UNKNOWN	Early Diagnosis of Native and Device-associated Meningitis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AVIBACTAM	4	2
ACETAMINOPHEN	4	1
GLYCERIN	4	1
POLYMYXIN B	4	1
TIGECYCLINE	4	1
D-LACTIC ACID	3	1
CHEMBL2397513	0	1
CHEMBL373756	0	1
CHEMBL3989738	0	1
CHEMBL4636958	0	1
CHEMBL5281080	0	1