Entry receptor bias in evolutionarily distant HSV-1 clinical strains drives divergent ocular and nervous system pathologies

Lulia Koujah, Mowafak Allaham, Chandrashekhar D. Patil, Joshua M. Ames, Rahul K. Suryawanshi, Tejabhiram Yadavalli, Alex Agelidis, Christine Mun, Bayasgalan Surenkhuu, Sandeep Jain, Deepak Shukla

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Purpose: Herpes simplex virus-1 (HSV-1) infection leads to varying pathologies including the development of ocular lesions, stromal keratitis and encephalitis. While the role for host immunity in disease progression is well understood, the contribution of genetic variances in generating preferential viral entry receptor usage and resulting immunopathogenesis in humans are not known. Methods: Ocular cultures were obtained from patients presenting distinct pathologies of herpes simplex keratitis (HSK). Next-generation sequencing and subsequent analysis characterized genetic variances among the strains and estimated evolutionary divergence. Murine model of ocular infection was used to assess phenotypic contributions of strain variances on damage to the ocular surface and propagation of innate immunity. Flow cytometry of eye tissue identified differential recruitment of immune cell populations, cytokine array probed for programming of local immune response in the draining lymph node and histology was used to assess inflammation of the trigeminal ganglion (TG). Ex-vivo corneal cultures and in-vitro studies elucidated the role of genetic variances in altering host-pathogen interactions, leading to divergent host responses. Results: Phylogenetic analysis of the clinical isolates suggests evolutionary divergence among currently circulating HSV-1 strains. Mutations causing alterations in functional host interactions were identified, particularly in viral entry glycoproteins which generated a receptor bias to herpesvirus entry mediator, an immune modulator involved in immunopathogenic diseases like HSK, leading to exacerbated ocular surface pathologies and heightened viral burden in the TG and brainstem. Conclusions: Our data suggests receptor bias resulting from genetic variances in clinical strains may dictate disease severity and treatment outcome.

Original languageEnglish
Pages (from-to)238-249
Number of pages12
JournalOcular Surface
StatePublished - 1 Jul 2021
Externally publishedYes


  • HSV-1
  • Herpes keratitis
  • Immunopathogenesis
  • Ocular infection

ASJC Scopus subject areas

  • Ophthalmology


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