Key genes and pathways in measles and their interaction with environmental chemicals

Abstract

The aim of the present study was to explore key genes that may have a role in the pathology of measles virus infection and to clarify the interaction networks between environmental factors and differentially expressed genes (DEGs). After screening the database of the Gene Expression Omnibus of the National Center for Biotechnology Information, the dataset GSE5808 was downloaded and analyzed. A global normalization method was performed to minimize data inconsistencies and heterogeneity. DEGs during different stages of measles virus infection were explored using R software (v3.4.0). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the DEGs were performed using Cytoscape 3.4.0 software. A protein-protein interaction (PPI) network of the DEGs was obtained from the STRING database v9.05. A total of 43 DEGs were obtained from four analyzed sample groups, including 10 highly expressed genes and 33 genes with decreased expression. The most enriched pathways based on KEGG analysis were fatty acid elongation, cytokine-cytokine receptor interaction and RNA degradation. The genes mentioned in the PPI network were mainly associated with protein binding and chemokine activity. A total of 219 chemicals were identified that may, jointly or on their own, interact with the 6 DEGs between the control group and patients with measles (at hospital entry), including benzo(a)pyrene (BaP) and tetrachlorodibenzodioxin (TCDD). In conclusion, the present study revealed that chemokines and environmental chemicals, e.g. BaP and TCDD, may affect the development of measles.

Keywords: and measles; differentially expressed genes; environmental risk factors.

Figure 1.

Distribution features of the expression data after normalization of all samples. The volatility of the data after normalization was greatly reduced and the median of expression values of all the genes are on the same line, which provided more reliable data and information for subsequent analyses.

Figure 2.

Heat map of differentially expressed genes between peripheral blood mononuclear cell samples of measles-infected and control subjects (C, Control; E, at hospital entry; D, at discharge; F, 1 month following discharge). Compared with the controls, 33 genes exhibited a decreased expression when patients entered hospital, reached a minimum value at discharge and then increased, while 10 genes displayed the opposite trend. Green represents low expression and red high expression. Each row represents a single gene and each column represents a sample.

Figure 3.

Profiles containing a cluster of multiple genes that have similar expression patterns were identified by gene-cloud of biotechnology information (0, control; 1, admission; 2, discharge; 3, 1 month after discharge). Of these clusters, profiles 3, 5 and 21 are statistically significant (The three Ps refer to profiles 3, 5 and 21<0.05). Clusters 3 and 5 were comprised of genes that were downregulated in patients with measles, but when the patients were discharged, the genes in cluster 3 had the lowest expression. Cluster 21 was comprised of genes that were clearly upregulated in patients with measles when they were admitted to hospital and discharged. The gene SPOP is included in profiles 3 and 5, indicating that SPOP is co-expressed in these profiles. SPOP, speckle-type POZ protein.

Figure 4.

PPI network (confidence, ≥0.70; PPI enrichment P=4.28×10⁻¹¹) of 38 coding proteins of the 43 DEGs generated with STRING. The network was expanded by including 20 additional partner proteins (CCR1 and CCR5, C-C motif chemokine receptor; CUL3, Cullin 3; LSM2, LSM3, LSM4, LSM5, LSM6 and LSM7, LSMs homolog, mRNA degradation associated; MAP3K5, mitogen-activated protein kinase kinase kinase 5; NDUFA12, Ubiquinone oxidoreductase subunit A12; NDUFB9, Ubiquinone oxidoreductase subunit B9; NDUFC2, Ubiquinone oxidoreductase subunit C2; PATL1, PAT1 homolog 1, processing body mRNA decay factor; RNPS1, RNA binding protein with serine rich domain 1; TGFB1, transforming growth factor beta 1; TGFB3, transforming growth factor beta 3; TGFBR1, transforming growth factor beta receptor 1; TXNIP, thioredoxin interacting protein; TXNRD1, thioredoxin reductase 1) that share similar physiological functions to the included DEGs. The genes with names are mainly associated with protein binding and chemokine activity. PPI, Protein-protein interaction; DEG, Differentially expressed gene. SPOP, Speckle-type POZ protein.

Figure 5.

Volcano plot of the differentially expressed genes (orange squares in the circle) between control group and patients with measles when they entered hospital (GTPase IMAP family members 1–5 included).