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An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection
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Inborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis

Jie Chen1,2, Huie Jing3, Andrea Martin-Nalda4,5,6

  • 1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.

The Journal of Experimental Medicine
|November 2, 2021
PubMed

Insights

Toll-like receptor 3 (TLR3) and Interferon-induced helicase 1 (IFIH1) variants impair the immune response to enteroviruses (EV). These genetic defects hinder type I interferon production, increasing susceptibility to severe EV infections.

Area of Science:

  • Immunology
  • Virology
  • Genetics

Background:

  • Enterovirus (EV) infections can rarely cause severe central nervous system disease.
  • Genetic defects in immune pathways can predispose individuals to life-threatening viral infections.

Purpose of the Study:

  • To investigate the role of Toll-like receptor 3 (TLR3) and Interferon-induced helicase 1 (IFIH1) in enterovirus rhombencephalitis.
  • To characterize the impact of specific TLR3 and IFIH1 variants on cellular immunity and viral replication.

Main Methods:

  • Studied two unrelated children with enterovirus rhombencephalitis.
  • Genotyped patients for TLR3 and IFIH1 variants.
  • Assessed fibroblast response to poly(I:C) stimulation and EV infection.
  • Evaluated the effect of interferon-alpha2b (IFN-α2b) treatment.
  • Performed rescue experiments by expressing wild-type (WT) TLR3 or MDA5.

Main Results:

  • Patients carried loss-of-function or hypomorphic TLR3 and IFIH1 variants.
  • Fibroblasts from patients showed impaired responses to poly(I:C) and reduced baseline/virus-induced type I interferon production.
  • Enterovirus replication was enhanced in TLR3- and MDA5-deficient fibroblasts.
  • Exogenous IFN-α2b provided partial protection, with MDA5-deficient cells showing fuller rescue post-infection.
  • Fibroblast phenotypes were rescued by WT TLR3 or MDA5 expression.

Conclusions:

  • Human TLR3 and MDA5 are crucial for intrinsic immunity against enteroviruses.
  • These pathways control baseline and virus-induced type I interferon production, respectively.
  • Genetic deficiencies in TLR3 or IFIH1 compromise defense against severe enterovirus infections.

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