Association of interleukin-6 (174 G/C) and interleukin-12B (1188 A/C) gene polymorphism with expression and risk of Japanese encephalitis disease in North Indian population
Graphical abstract
Introduction
Japanese encephalitis virus (JEV) is one of the most important causes of acute and uncontrolled inflammatory disease of the central nervous system (CNS) in humans, especially affecting children. It is annually causing an estimated 35,000–50,000 encephalitis cases and 10,000–15,000 deaths in Asia (Wang and Deubel, 2011). Nonspecific febrile illness to a poliomyelitis-like flaccid paralysis or a severe meningoencephalitis symptom appear only in a small proportion of JEV infected patients. Up to one-fourth of patients die, and 50% survivors with permanent neurological sequelae in Japanese encephalitis (JE) disease (Baluni et al., 2018). Japanese encephalitis is mosquito borne viral disease caused by JEV (genus flavivirus and family Flaviviridae). JEV is transmitted by Culex species in zoonotic cycle including wild aquatic bird reservoirs and pigs as amplifying hosts. JEV is enveloped virus with a genome of single-stranded positive RNA approximately 11 kb in size. Symptoms arise in JEV infected patients after an incubation period of 5–15 days. JE virus exists and proliferates in host leucocytes throughout incubation period which plays vital role in pathogenesis of JEV. JEV disrupts the blood-brain barrier (BBB) and induced inflammation which play a role in disease severity by inducing neuronal cell death (Lannes et al., 2017; Wang and Deubel, 2011). JEV-induced inflammation, promote alteration in cytokine/chemokine production as well as activation and migration of cells. Uncontrolled overactivation of microglial cells discharge a high level of proinflammatory cytokines such as interleukin 6 (IL-6), TNF- α, monocytes chemoattractant protein 1 (MCP-1) and RANTES. Previous studies proved that various immune related protein such as complimentary factor or cytokines like interferon (IFN)-a, tumor necrosis factor (TNF), interleukin IL-6, IL-8, and RANTES are association with the severity of JE disease (Singh et al., 2017; Zhang et al., 2011).
Interleukin IL-6 is a proinflammatory cytokine produced in response to a number of inflammatory stimuli such as IL-1, tumor necrosis factor (TNF)-a, bacterial products and viral infection (Moreira et al., 2007). IL-6 gene, located at 7p15.3, is responsible for monitoring transcriptional activity during inflammatory responses (Chen et al., 2019).
Interleukin-12B is a proinflammatory cytokine that stimulate the production of interferon-γ (IFN- γ), favors the differentiation of T helper 1 (TH1) cells and forms a relation between the innate and adaptive immunity. IL-6 expression is higher in JEV infection and other viral diseases whereas IL-12 elevated in many viral and inflammatory diseases (Singh et al., 2017; Winter et al., 2004; Zwiers et al., 2004). Previously IL-6 and IL-12 gene polymorphism found to be associated in many viral diseases. Thus, the present study was hypothesized to examine the possible association of IL-6 and IL-12 gene polymorphism with JE disease.
Section snippets
Study population
Japanese encephalitis patients among Acute Encephalitis Syndrome were included in this study from Department of Medicine and Department of Pediatrics, King George Medical University, Lucknow, India. During onset of symptoms, patient's history (headache, vomiting, seizures, altered sensorium baseline Glasgow coma scale (GCS) score) was determined with the help of a questionnaire, and outcomes of patients were recorded after 6 months. This study was reviewed and approved by research cell
Results
A total number of 793 patients (children and adults) with acute encephalitis syndrome were screened for JE, among them, 125 were found JE positive.
Discussion
Japanese encephalitis virus is inducing acute infection and inflammation of the brain, causes activation of immune response. Cytokines and chemokines are essential to produce a potent immune response and contributing to host defense in a variety of viral diseases. (Hall et al., 2000; Tiroumourougane et al., 2002; Tiwari et al., 2012). Interleukins are a group of cytokines that regulate the immune and inflammatory responses. In previous studies high IL-6 was also found to relate with the
Conclusion
Overall this case control study state that IL-6 (174 G/C) gene polymorphism has not associated with the progression of JE susceptibility and clinical severity, but found to be associated with the headache and disease outcome whereas C/C genotype of IL-12B gene polymorphism was significantly associated with JE susceptibility and clinical symptoms like headache, alter mental status, behavioral abnormalities and neck stiffness. A/C and C/C was significantly associated with disease outcomes.
Acknowledgement
The authors acknowledge support from the National Polio Surveillance Program, Delhi, India (2017/746396-0), for this work. The authors would also like to Dr. Pooja Gaur and Mr. Hemant Varma for providing technical as well as writing assistance during the work.
References (20)
- et al.
Association of ICAM-1 (K469E) and MCP-1-2518 A> G polymorphism with risk of Japanese encephalitis in North Indian population
Cytokine
(2018) - et al.
The association between interleukin-6 gene-174G/C single nucleotide polymorphism and sepsis: an updated meta-analysis with trial sequential analysis
BMC Med. Genet.
(2019) - et al.
Suppression of immune response and protective immunity to a Japanese encephalitis virus DNA vaccine by coadministration of an IL-12-expressing plasmid
J. Immunol.
(2001) Cytokines as endogenous pyrogens
J. Infect. Dis.
(1999)- et al.
Genetic polymorphism of IL-12 p40 gene in immune-mediated disease
Genes Immun.
(2000) - et al.
Genetic polymorphism of CCL2-2510 and susceptibility to enterovirus 71 encephalitis in a Chinese population
Arch. Virol.
(2014) Biomarkers in Japanese encephalitis: a review
Biomed. Res. Int.
(2013)- et al.
Regulation of inflammation in Japanese encephalitis
J. Neuroinflammation
(2017) - et al.
Interleukin-6 expression and gene polymorphism are associated with severity of periodontal disease in a sample of Brazilian individuals
Clin. Exp. Immunol.
(2007) - et al.
Circulating cytokines as mediators of fever
Clin. Infect. Dis.
(2000)
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