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Lymphocytic choriomeningitis virus injures the developing brain: effects and mechanisms

Pediatric Research volume 95, pages 551–557 (2024)Cite this article

Abstract

Lymphocytic choriomeningitis virus (LCMV) is a prevalent pathogen, whose natural host and reservoir is the wild mouse. Humans can be infected when they contact the secretions of mice. Most infections of postnatal humans result in mild illness. However, the consequences can be severe when the infection occurs during pregnancy, as the virus crosses the placenta to infect the fetus. LCMV infection of the human fetus can lead to severe neuropathologic effects, including microencephaly, hydrocephalus, focal destructive lesions, and cerebellar hypoplasia. Outcomes among children with congenital LCMV are variable, but most are permanently and severely disabled. The neonatal rat inoculated with LCMV models human prenatal infection. The rat model has demonstrated that effects of LCMV depend on host age at the time of infection. Some effects, including encephalomalacia and neuronal migration disturbances, are immune-mediated and depend on the actions of T-lymphocytes. Other effects, including cerebellar hypoplasia, are virus-mediated and do not depend on T-lymphocytes. Cerebellar neuronal migration disturbances are caused by immune-mediated corruption of Bergmann glia structure. The rat pup inoculated with LCMV is a superb animal model for human congenital infection. All neuropathologic effects observed in human congenital LCMV infection can be recapitulated in the rat model.

Impact

  • Lymphocytic choriomeningitis virus (LCMV) is a prevalent human pathogen that can cause serious neurologic birth defects when the infection occurs during pregnancy.

  • The effects of the virus on the developing brain depend strongly on the age of the host at the time of infection.

  • Some of the pathologic effects of LCMV are immune-mediated and are driven by T-lymphocytes, while other pathologic effects are due to the virus itself.

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Fig. 1: The neonatal rat model of congenital LCMV infection.
Fig. 2: Following intracranial injection on postnatal day 4, LCMV infects neurons in four brain regions.
Fig. 3: The time course of LCMV tissue concentration and sequential migration in the developing rat brain.
Fig. 4: Infectability of the brain depends strongly on host age at the time of inoculation.
Fig. 5: LCMV corrupts the configuration of Bergmann glia and induces a neuronal migration disturbance in the cerebellum.

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References

  1. Vilibic-Cavlek, T. et al. Lymphocytic choriomeningitis-emerging trends of a neglected virus: a narrative review. Trop. Med. Infect. Dis. 6, 88 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Olivieri, N. R., Othman, L., Flannery, D. D. & Gordon, S. M. Transmission, seroprevalence, and maternal-fetal impact of lymphocytic choriomeningitis virus. Pediatr. Res. https://doi.org/10.1038/s41390-023-02859-w (2023).

    Article  PubMed  Google Scholar 

  3. Castellar, A. et al. First evidence of lymphocytic choriomeningitis virus (arenavirus) infection in Mus musculus rodents captured in the urban area of the municipality of Sincelejo, Sucre, Colombia. Biomedica 37, 75–85 (2017).

    PubMed  Google Scholar 

  4. Childs, J. E., Glass, G. E., Korch, G. W., Ksiazek, T. G. & Leduc, J. W. Lymphocytic choriomeningitis virus infection and house mouse (mus musculus) distribution in urban Baltimore. Am. J. Trop. Med. Hyg. 47, 27–34 (1992).

    Article  CAS  PubMed  Google Scholar 

  5. Talley, P., Holzbauer, S., Smith, K. & Pomputius, W. Notes from the field: lymphocytic choriomeningitis virus meningoencephalitis from a household rodent infestation – Minnesota, 2015. Morb. Mortal. Wkly Rep. 65, 248–249 (2016).

    Article  Google Scholar 

  6. Ambrosio, A. M., Feuillade, M. R., Gamboa, G. S. & Maiztegui, J. I. Prevalence of lymphocytic choriomeningitis virus infection in a human population of Argentina. Am. J. Trop. Med. Hyg. 50, 381–386 (1994).

    Article  CAS  PubMed  Google Scholar 

  7. Stephensen, C. B. et al. Prevalence of serum antibodies against lymphocytic choriomeningitis virus in selected populations from two U.S. cities. J. Med. Virol. 38, 27–31 (1992).

    Article  CAS  PubMed  Google Scholar 

  8. Bonthius, D. J. Lymphocytic choriomeningitis virus: a prenatal and postnatal threat. Adv. Pediatr. 56, 75–86 (2009).

    Article  PubMed  Google Scholar 

  9. Bonthius, D. J. & Karacay, B. Meningitis and encephalitis in children: an update. Neurol. Clin. 20, 1013–1038 (2002).

    Article  PubMed  Google Scholar 

  10. Armstrong, C. & Lillie, R. D. Experimental lymphocytic choriomeningitis of monkeys and mice produced by a virus encountered in studies of the 1933 St. Louis encephalitis epidemic. Public Health Rep. 49, 1019–1022 (1934).

    Article  Google Scholar 

  11. Folk, S. et al. Lymphocytic choriomeningitis with severe manifestations, Missouri, USA. Emerg. Infect. Dis. 17, 1973–1974 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Fischer, S. A. et al. Transmission of lymphocytic choriomeningitis virus by organ transplantation. N. Engl. J. Med. 354, 2235–2249 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Centers for Disease Control and Prevention. Lymphocytic choriomeningitis virus transmitted through solid organ transplantation—Massachusetts, 2008. Morb. Mortal. Wkly Rep. 57, 799–801 (2008).

    Google Scholar 

  14. Bonthius, D. J. Lymphocytic choriomeningitis virus: an underrecognized cause of neurologic disease in the fetus, child and adult. Semin. Pediatr. Neurol. 19, 89–95 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Komrower, G. M., Williams, B. L. & Stones, P. B. Lymphocytic choriomeningitis in the newborn. Probable transplacental infection. Lancet 1, 697–698 (1955).

    Article  Google Scholar 

  16. Barton, L. L. et al. Congenital lymphocytic choriomeningitis virus infection in twins. Pediatr. Infect. Dis. J. 12, 942–946 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. Larsen, P. D., Chartrand, S. A., Tomashek, K. M., Hauser, L. G. & Ksiazek, T. G. Hydrocephalus complicating lymphocytic choriomeningitis virus infection. Pediatr. Infect. Dis. J. 12, 528–531 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Ansari, N., Demmler-Harrison, G., Coats, D. K. & Paysse, E. A. Severe congenital chorioretinitis caused by congenital lymphocytic choriomeningitis virus infection. Am. J. Ophthalmol. Case Rep. 22, 101094 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Barton, L. L., Peters, C. J. & Ksiazek, T. G. Lymphocytic choriomeningitis virus: an unrecognized teratogenic pathogen. Emerg. Inf. Dis. 1, 152–153 (1995).

    Article  CAS  Google Scholar 

  20. Barton, L. L. & Mets, M. B. Congenital lymphocytic choriomeningitis virus infection: decade of rediscovery. Clin. Infect. Dis. 33, 370–374 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Wright, R. et al. Congenital lymphocytic choriomeningitis virus syndrome: a disease that mimics congenital toxoplasmosis or cytomegalovirus infection. Pediatrics 100, 1–6 (1997).

    Article  Google Scholar 

  22. Bonthius, D. J. et al. Congenital lymphocytic choriomeningitis virus infection: spectrum of disease. Ann. Neurol. 62, 347–355 (2007b).

    Article  PubMed  Google Scholar 

  23. Olivieri, N. R., Othman, L. & Gordon, S. M. Health disparities revealed in a case of congenital LCMV. Pediatr. Res https://doi.org/10.1038/s41390-023-02772-2 (2023).

    Article  PubMed  Google Scholar 

  24. Biggar, R., Woodall, J., Walter, P. & Haughie, G. Lymphocytic choriomeningitis outbreak associated with pet hamsters: fifty-seven cases from New York state. JAMA 232, 494 (1975).

    Article  CAS  PubMed  Google Scholar 

  25. Monjan A. A., Cole G. A. & Nathanson N. Pathogenesis of LCM disease in the rat. In: Lymphocytic choriomeningitis Virus and Other Arenaviruses (Lehmann F., ed) 195–206 (Springer-Verlag, New York, 1973).

  26. Bonthius, D. J. & Perlman, S. Congenital viral infections of the brain: lessons learned from lymphocytic choriomeningitis virus in the neonatal rat. PLoS Pathog. 3, 1541–1550 (2007).

    Article  CAS  Google Scholar 

  27. Bonthius, D. J., Mahoney, J. C., Buchmeier, M. J. & Taggard, D. A. Critical role for glial cells in the propagation and spread of lymphocytic choriomeningitis virus in the developing rat brain. J. Virol. 76, 6618–6635 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bonthius, D. J., Nichols, B., Harb, H., Mahoney, J. & Karacay, B. Lymphocytic choriomeningitis virus infection of the developing brain: critical role of host age. Ann. Neurol. 62, 356–374 (2007a).

    Article  PubMed  Google Scholar 

  29. Klein, H., Rabe, G. K., Karacay, B. & Bonthius, D. J. T-cells underlie some, but not all, of the cerebellar pathology in a neonatal rat model of congenital lymphocytic choriomeningitis virus infection. J. Neuropathol. Exp. Neurol. 75, 1031–1047 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Sun, T., Vasek, M. J. & Klein, R. S. Congenitally acquired persistent lymphocytic choriomeningitis viral infection reduces neuronal progenitor pools in the adult hippocampus and subventricular zone. PLoS One 9, e96442 (2014).

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  31. Albarino, C. G. et al. High diversity and ancient common ancestry of lymphocytic choriomeningitis virus. Emerg. Inf. Dis. 16, 1093–1110 (2010).

    Article  Google Scholar 

  32. Plume, J. M., Todd, D. & Bonthius, D. J. Viral strain determines disease symptoms, pathology, and immune response in neonatal rats with lymphocytic choriomeningitis virus infection. Viruses 11, 1–22 (2019).

    Article  Google Scholar 

  33. Bonthius, D. J. Diagnosed cases of congenital LCMV infection: tip of the iceberg. Ann. Neurol. 64, 356 (2008).

    Article  Google Scholar 

  34. Tevaearai, F., Moser, L. & Pomar, L. Prenatal diagnosis of congenital lymphocytic choriomeningitis virus infection: a case report. Viruses 14, 1–9 (2022).

    Article  Google Scholar 

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Acknowledgements

Supported by grants from the NIH (K08-NS02007, T32-HD041922, F31-NS051161), March of Dimes Birth Defects Foundation (MOD-1-FY01-217), Child Neurology Society Young Investigator Award, and the Atrium Health Research Foundation. The author thanks Jo Mahoney, Glenda Rabe, Hannah Klein, and Jeffrey Plume for their technical and intellectual contributions.

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  1. Atrium Health/Wake Forest University College of Medicine, Levine Children’s Hospital, 4160 Medical Center Plaza, 1001 Blythe Blvd, Charlotte, NC, 28204, USA

    Daniel J. Bonthius

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D.J.B. conceived the work reported here, wrote the manuscript, and produced the figures.

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Correspondence to Daniel J. Bonthius.

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Bonthius, D.J. Lymphocytic choriomeningitis virus injures the developing brain: effects and mechanisms. Pediatr Res 95, 551–557 (2024). https://doi.org/10.1038/s41390-023-02985-5

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