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Systems Biology Modeling of the Complement System Under Immune Susceptible Pathogens.

Nehemiah T Zewde1, Rohaine V Hsu1, Dimitrios Morikis1

  • 1Department of Bioengineering, University of California, Riverside, Riverside, CA, United States.

Frontiers in Physics
|February 11, 2022
PubMed
Summary

This study models the complement system

Keywords:
Neisseria meningitidiscomplement systemcomputational systems biologypredictive modelingpredictive network biologyprotein network

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Area of Science:

  • Immunology and Systems Biology
  • Mathematical Modeling of Biological Systems
  • Infectious Disease Dynamics

Background:

  • The complement system is crucial for innate immunity against pathogens but can be dysregulated in infections.
  • Pathogen resistance to therapies necessitates understanding host-pathogen interactions at the immune frontline.
  • Complement system dynamics with pathogens like *Neisseria meningitidis* remain incompletely understood.

Purpose of the Study:

  • To develop a comprehensive mathematical model of the human complement system.
  • To investigate the dynamic interactions between complement components and pathogens in different body sites.
  • To identify potential biomarkers for meningococcal disease based on complement activity.

Main Methods:

  • Developed a large-scale mathematical model (670 ODEs, 328 parameters) simulating alternative, classical, and lectin complement pathways.
  • Incorporated mannose-binding lectin, collectins, ficolins, factor H-related proteins, IgM, and pentraxins.
  • Modeled interactions with a general pathogen and *Neisseria meningitidis* in nasopharynx and bloodstream, analyzing complement component and Membrane Attack Complex (MAC) surface coverage.

Main Results:

  • Pathogens in the bloodstream were heavily coated with complement proteins, but MAC coverage remained minimal (<1.0%).
  • In the nasopharynx, MACs occupied a significant portion (1.5-10%) of the *N. meningitidis* surface, indicating much higher local concentrations.
  • Complement overactivation correlated with nasopharyngeal homeostasis, while balance disrupted it.

Conclusions:

  • Complement system dynamics differ significantly between bloodstream and nasopharyngeal environments.
  • Nasopharyngeal complement overactivation may be essential for maintaining homeostasis against pathogens like *N. meningitidis*.
  • Rising nasal levels of complement regulators could serve as early biomarkers for meningococcal disease.