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director.niv@icmr.gov.in

Encephalitis Viruses

HomeResearch GroupsEncephalitis Viruses
HomeResearch GroupsEncephalitis Viruses
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Encephalitis viruses

Central nervous system (CNS) infections are emerging as an important public health problem worldwide. The causes of CNS infections are diverse and include viral and non-viral aetiologies as well as autoimmune processes. Globally viruses are the most common and important causes of acute encephalitis resulting in substantial morbidity, mortality, permanent neurologic sequelae in humans and economic loss. The cause of CNS infections varies with season and geographical location, and predominantly affects paediatric and elderly population. As the clinical symptoms associated with CNS infections are overlapping independent of the cause, World Health Organization coined the term “acute encephalitis syndrome” (AES), which simply means acute onset of fever with convulsions or altered consciousness or both. Aetiological diagnosis of AES cases still represents a diagnostic challenge, as 40-60% of AES cases are unexplained worldwide. Historically Japanese encephalitis is known to be a leading cause of AES endemic to all over the country. Furthermore, National Institute of Virology, Pune identified association of like West Nile virus (WNV), Chandipura virus (CHPV), Human enterovirus (EV), etc. with massive outbreaks and increasingly identified neuronal involvement of Dengue virus, Chikungunya virus, Nipah virus and Rickettsial (Orentia tsutsugamushi) infections. Apart from increasing identification of Human Herpesvirus 1 (HSV-1), association of Varicella Zoster virus (VZV) and Rabies virus (RV) in sporadic cases, infection with Epstein–Barr virus (EBV) and Cytomegalovirus (CMV) is increasingly detectedin immunocompromised individuals. Dedicated efforts by the Encephalitis Group resulted in development of a new research institute by Indian Council of Medical research in the form of Regional Medical Research Centre at Gorakhpur. Dedicated research on a decade old AES endemic to parts of UP annually affecting 2000 – 3000 paediatric cases resulted in identification of the cause, treatment and case management protocols and reduced disease burden.

The group is actively involved in routine investigation of AES outbreaks and supporting the public health system through offering diagnosis to referred human cases, entomological and serological surveys carried by different state health agencies. To meet the emerging challenges in diagnosis of AES, tremendous efforts are being made by the Encephalitis Group to develop newer virus specific and sensitive molecular and sero-diagnostic assays. The existing sero-diagnostic assays are being refined through development and use of viral recombinant immune-dominant proteins and monoclonal antibodies to increase their specificities. Considering the increasing association of less known and newly emerging viruses with AES in India, the Encephalitis Group has strengthened capacity by establishing ‘Virus Discovery Platform” through use of Next Generation Sequencing tools. Molecular evolution studies performed on JEV, WNV, CHPV and HSV-1 resulted in identification of newer genetic variants and newer arboviruses like Bagaza virus (BAGV). Genetic analysis of these viruses resulted in classification of Indian WNV endemic strains into distinct genetic lineage 5 and identification of frequent introduction of neuropathogenic lineage 1 WNV strains in India. Studies on JEV first time documented introduction of genotype I JEV strain to India from China and circulation of genetically divergent CHPV strain in endemic region of India.The group was instrumental in evaluation of the protective efficacy of live attenuated JE vaccine SA-14-14-2 in Indian population. Vaccine development research by the group resulted in development of first indigenously developed JE vaccine candidate marketed as JENVAC in India. Furthermore, efforts are being made to develop recombinant vaccine candidates against JEV and WNV through knocking down the virulence determinants using newly constructed infectious cDNA clones. The group is also dedicating efforts to evaluate licenced antiviral drugs to repurpose them for therapy against CHPV, JEV and WNV infections. In addition to the applied research, the group is performing basic research on host-virus interactions leading to identification of viral factors governing the virulence and antigenic variations; studying pathways of virus entry and mechanism of cellular damage to evaluate their potential as antiviral targets.

India bears the highest burden of global dog-mediated human rabies deaths estimated to be approximating 21,000 deaths a year (35% of global human deaths annually). Achieving the global 2030 target set for zero human rabies deaths due to canine rabies requires coordinated and systematic efforts in the form of detection and vaccination. To contribute towards the global vision to reach the Zero by 2030 target to eliminate dog-mediated rabies, the Encephalitis Group has established a dedicated rabies research and diagnosis laboratory and dedicated to the nation. The state of art laboratory is equipped with modern infrastructure necessary for rabies surveillance, diagnosis and research.

Scientists
Sr. No.Name of the staffDesignation
1Dr. Vijay P. Bondre         

Scientist F and Group Leader

2Dr. Ullas PTScientist C
2Dr. Chandhu BalachandranScientist B
Technical Staff
Sr. No.Name of the staffDesignation
1Mrs. Shubhangi A. Mahamuni        

Technical Officer-C

2Mrs. Vasudha SankararamanTechnical Officer-C
3Dr. Daya V. PavitrakarTechnical Officer-B
4Mr. Datta K. ButteSr. Technician-2
5Mr. Arava VenkataramanaiahTechnician-2
6Mr. Kunal SakhareTechnician-A
7Ms. Sonal MundhraResearch Fellow
8Ms. Deepali N. MaliResearch Fellow
Ongoing Projects

  • 1. Investigations of human clinical specimens collected during encephalitis outbreaks and diagnostic services to suspected Japanese encephalitis and Chandipura encephalitis patients from India.

  •  2. Development of molecular diagnostic assays for detection of viruses associated with human central nervous system infections in India.

  •  3. Role of Histidine residues of envelope protein in membrane fusion of Japanese encephalitis virus.

  • 4. Expression of Japanese encephalitis virus - genotype 1 envelope and non-structural proteins to explore in early diagnosis.

  • 5. Mechanism of apoptosis in the pathogenesis of West Nile virus infection.

  • 6. To determine the antiviral activity of viral RNA dependent RNA polymerase inhibitors against Chandipura virus infection.

  • 7. Development of an indirect ELISA assay for surveillance of Japanese encephalitis. Establishing Rabies diagnostics and research capabilities.

Significant Research Findings/Contributions

 

Achievements

I. Japanese encephalitis virus

  • VRC first time established existence of JE in India (1955-56).
  • Developed necessary infrastructure and technical expertise to undertake JE investigations.
  • Investigation of outbreaks occurred in various parts of India from 1954 onwards.
  • Established different species of mosquitoes as transmission vectors and studied the role of pigs and birds in JE natural cycle.
  • Development of monoclonal antibodies against JEV..
  • Development of IgM ELISA kit.
  • Development of molecular diagnostics assay.
  • JE live attenuated vaccine post marketing surveillance studies (SA14-14-2).
  • Technology transfer and strain handover for development of indigenous JE vaccine.
  • Study of the genetic makeup of JEV strains circulating for last 70 years.
  • Isolation, genetic characterization of JEV GI in India and its impact on vaccination.
  • Development of infectious cDNA clone of JEV GI strain.
  • Development of JE VLP using currently circulating GI strain and explored its potential in ELISA development.

II. Chandipura virus

  • The CHPV first time identified by the ICMR-NIV during the investigation of the Dengue outbreak in 1965 from, Chandipur village of Nagpur district of Maharashtra, India.
  • ICMR-NIV confirmed the sand flies belonging to the genus Phlebotomus and Sergentomyia acts as a transmission vector
  • Re-emergence of CHPV with outbreak potential in Andhra Pradesh (2003), followed by massive outbreaks in parts of Maharashtra (2004) and Gujarat in (2004) with case fatality of 55-70% in paediatric population. CHPV continued to be cause of outbreaks in endemic regions (Maharashtra, Gujarat and Telangana) during 2007, 2010, 2012, and 2014. Currently CHPV is responsible for sporadic AES cases annually occurring in the endemic region. Apart from the endemic region, CHPV cases also reported from Odisha (2009).
  • Clinically, the disease is resented with high grade fever of short duration, vomiting, generalized convulsions, altered Sensorium, and decerebrate posture, leading to Grade IV coma, acute encephalitis, and death within a few to 48 – 72 hours of hospitalization. In recovered cases, neurological or physiological sequelae is not documented.
  • Development of molecular and serological diagnostic assay.
  • Development of monoclonal antibodies against CHPV
  • Carried out phylogenetic analysis of circulation CHPV strain and identification of genetic variant (2015) with >11% divergence from the endemic strain circulating year 1965 onwards.
  • ICMR-NIV developed an inactivated tissue culture base vaccine as well as G-protein based recombinant vaccine against CHPV. The technology transfer of promising inactivated vaccine is awaited.
  • Antiviral studies against CHPV revealed suitability of different RNA dependent RNA polymerase inhibitors as potent antivirals against CHPV infection in experimental animals.

III. West Nile virus

  • Evidence of WNV circulation in India first reported in 1952 by ICMR-NIV.
  • Sero-surveillance activities conducted by NIV confirmed the circulation of WNV from Tamil Nadu, Karnataka, Andhra Pradesh, Maharashtra, Gujarat, Madhya Pradesh, Orissa and Rajasthan. Serologically confirmed cases of WNV infections were reported from Vellore and Kolar districts during 1977, 1978 and 1981.
  • Development of monoclonal antibodies against WNV.
  • Development of Molecular and serological diagnostic assays.
  • Development of infectious cDNA clone of WNV.
  • First time WNV detected to be cause of massive AES outbreak in India (Kerala, 2011) involving >300 cases. WNV isolation from human cases characterized it as a neuro-pathogenic lineage 1 strain introduced from Russia.
  • Genetic analysis of WNV strains isolated in India during last 65 years suggest independent evolution of less neuro-pathogenic lineage 1 strains in parts of southern India.
  • Investigations of sporadic cases from Northeast India (2008), first time established its circulation out of the southern India.
  • Full genome sequence based analysis of WNV strains isolated from sporadic human cases and a frugivorous bat liver tissue confirmed frequent introduction of highly pathogenic lineage 1 strains in India.

IV. Rabies virus

  • Rabies is a vaccine-preventable disease currently endemic to >150 countries and territories. India bears the highest burden of global dog-mediated annual human rabies.
  • With a global target of “Zero human deaths due to dog-mediated rabies by 2030”, worldwide, it is necessary to strengthen surveillance and diagnostic capacity of country.
  • Inaugurated of Rabies research and diagnostic facility by the Secretary, Department of Health Research, (Ministry of Health & Family Welfare), Government of India and Director General, Indian Council of Medical Research (ICMR) on September 28, 2021 and dedicated to the nation to cater the need of public health for diagnosis of human and animal rabies.
  • Laboratory currently offering the molecular and serological diagnosis of Rabies infection from referred clinical samples.

V. Herpes Simplex – 1 virus

  • Genetic characterization of Human Herpesvirus Type 1: First full-length genome sequence (151 kb) of HSV-1 strain from Asian countries isolated from an encephalitis case from India.
  • Development of molecular diagnostic assay for diagnosis of HSV-1, HSV-2 and other important members of Herpesviridae that causes human encephalitis.

VI. Acute Encephalitis Syndrome in Uttar Pradesh: Contributions to the Public Health Success Story

  • Uttar Pradesh state annually recorded major AES outbreaks affecting about 2000-3000 paediatric cases with 25-30% case fatality in the endemic region. Apart from 10-12% of annual JE cases, aetiology associated with 90% cases was unknown affecting the case management.
  • In year 2008, ICMR-NIV through the Encephalitis Group established Gorakhpur Field Unit (current ICMR-Regional Medical Research Centre) to investigate the yearly outbreaks.
  • Diagnostic capabilities established for >35 known AES associated infectious etiologist, systematic development of standard operating procedures for specimen collection, laboratory investigations and reporting through AES Cell established in Baba Raghav Das Medical College, resulted in diagnosis of >90% cases by the end of 2017 season.
  • Intensive efforts by ICMR through strengthening of laboratory diagnostic capabilities, implementation of intensive surveillance system and JE immunization campaigns resulted in successful control of AES outbreaks and mortality to 5.8% by the end of 2018.
  • The decade's long war with JE/AES in the region is now on decline as evidenced by decline in AES cases by 70% and mortality by 90% in year 2019.
  • The decade's long war with JE/AES in the region is now on decline as evidenced by decline in AES cases by 70% and mortality by 90% in year 2019.
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