Lymphocytes have a role in protection, but not in pathogenesis, during La Crosse Virus infection in mice
Clayton W Winkler1, Lara M Myers1, Tyson A Woods1
1Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), 903 S. 4th St., Hamilton, MT, 59840, USA.
Insights
Lymphocytes do not cause La Crosse Virus (LACV) encephalitis in young mice but are crucial for protecting adult mice from severe neurological disease. Adaptive immunity is essential for preventing CNS invasion by LACV.
Area of Science:
- Neurovirology
- Immunology
- Pediatric Infectious Diseases
Background:
- La Crosse Virus (LACV) is a major cause of viral encephalitis in US children, exhibiting age-related susceptibility.
- Younger individuals (≤16 years) and weanling mice are susceptible to severe LACV disease, while adults are resistant.
- Leukocyte infiltration into the central nervous system (CNS) is observed during LACV infection, but the specific cell types and their roles are unclear.
Purpose of the Study:
- To investigate the types of lymphocytes infiltrating the CNS during LACV infection.
- To determine the role of these lymphocytes in LACV pathogenesis in susceptible weanling mice.
- To explore the protective function of lymphocytes against LACV-induced neurological disease in resistant adult mice.
Main Methods:
- Flow cytometry was used to analyze lymphocyte populations in the CNS of LACV-infected mice.
- Lymphocyte contributions to pathogenesis were assessed in weanling mice using knockout models and antibody-mediated depletion.
- The role of lymphocytes in preventing neurological disease was studied in adult mice.
Main Results:
- In susceptible weanling mice, infiltrating lymphocytes (NK, CD4 T, CD8 T cells) did not affect disease severity upon depletion.
- In resistant adult mice, depletion of CD4 T cells, CD8 T cells, or B cells exacerbated neurological disease and increased viral brain loads.
- These findings suggest lymphocytes play a protective role in adult mice against LACV.
Conclusions:
- Lymphocytes do not significantly impact neurological disease in young mice infected with LACV.
- Adaptive immune responses, involving T and B cells, are critical for protecting adult mice from LACV-induced neurological disease.
- Innate immunity alone is insufficient for protection against LACV in adults; adaptive immunity is necessary to prevent CNS invasion.
Background:
La Crosse Virus (LACV) is a primary cause of pediatric viral encephalitis in the USA and can result in severe clinical outcomes. Almost all cases of LACV encephalitis occur in children 16 years or younger, indicating an age-related susceptibility. This susceptibility is recapitulated in a mouse model where weanling (3 weeks old or younger) mice are susceptible to LACV-induced disease, and adults (greater than 6 weeks) are resistant. Disease in mice and humans is associated with infiltrating leukocytes to the CNS. However, what cell types are infiltrating into the brain during virus infection and how these cells influence pathogenesis remain unknown.
Methods:
In the current study, we analyzed lymphocytes recruited to the CNS during LACV-infection in clinical mice, using flow cytometry. We analyzed the contribution of these lymphocytes to LACV pathogenesis in weanling mice using knockout mice or antibody depletion. Additionally, we studied at the potential role of these lymphocytes in preventing LACV neurological disease in resistant adult mice.
Results:
In susceptible weanling mice, disease was associated with infiltrating lymphocytes in the CNS, including NK cells, CD4 T cells, and CD8 T cells. Surprisingly, depletion of these cells did not impact neurological disease, suggesting these cells do not contribute to virus-mediated damage. In contrast, in disease-resistant adult animals, depletion of both CD4 T cells and CD8 T cells or depletion of B cells increased neurological disease, with higher levels of virus in the brain.
Conclusions:
Our current results indicate that lymphocytes do not influence neurological disease in young mice, but they have a critical role protecting adult animals from LACV pathogenesis. Although LACV is an acute virus infection, these studies indicate that the innate immune response in adults is not sufficient for protection and that components of the adaptive immune response are necessary to prevent virus from invading the CNS.
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