Modelling original antigenic sin in dengue viral infection

Area of Science:

• Immunology
• Virology
• Mathematical Modeling

Background:

• Dengue virus infections can lead to severe disease, particularly upon secondary infection with a different serotype.
• The phenomenon of original antigenic sin suggests pre-existing T cell responses may exacerbate heterologous infections.
• Understanding T cell cross-reactivity is crucial for explaining dengue disease severity variations.

Purpose of the Study:

• To develop and analyze in-host mathematical models of T cell responses during primary and secondary dengue virus infections.
• To investigate the role of T cell cross-reactivity in dengue disease enhancement.
• To determine the contribution of specific versus non-specific T cell responses in different dengue disease outcomes.

Main Methods:

• Development of in-host mathematical models simulating T cell dynamics.
• Inclusion of T cell cross-reactivity parameters to model heterologous infections.
• Model fitting and analysis using published patient data from dengue infections.

Main Results:

• Overall infected cell killing is comparable between dengue fever and dengue hemorrhagic fever following heterologous infections.
• Severe dengue hemorrhagic fever cases are predominantly driven by non-specific T cell responses.
• Milder dengue fever cases show a greater contribution from high-avidity, strain-specific T cell responses.

Conclusions:

• The study supports the hypothesis that cross-reactive T cell responses are primarily associated with severe heterologous dengue virus infections.
• Distinct T cell response profiles characterize severe (dengue hemorrhagic fever) versus milder (dengue fever) secondary infections.
• Mathematical modeling provides insights into the immunological mechanisms underlying dengue pathogenesis.