Samantha Hall (Sam) is a rising senior at Bryn Mawr College majoring in Mathematics. Sam is an Accelerated Masters student enrolled at the University of Pennsylvania pursuing an MSE in Systems Engineering. She is from Downingtown, a small suburban town outside of Philadelphia. This summer, Sam is part of Dr. Ravi Radhakrishnan’s lab, which is developing a multiscale computational model for targeting drug-filled nanoparticles to the inflamed lung regions to combat Acute Respiratory Distress Syndrome (ARDS), which manifests in a majority of COVID-19 patients with severe symptoms.
Towards a Multiscale Computational Model of the Human Complement System for Predicting Immune Response in COVID-19 Patients
Virion envelope flexibility and receptor spatial arrangement impacts immune modulation, recruitment, and internalization. Given the pandemic’s topical nature, it is advantageous to investigate the mechanics of virion elicited immune response, and how it manifests in patients under pulmonary duress. The majority of COVID-19 deaths occur in patients who have Acute Respiratory Distress Syndrome (ARDS), an acute, diffuse, inflammatory lung injury caused by a variety of insults, most commonly pneumonia, sepsis, trauma, and COVID-19. ARDS affects 200,000 patients each year in the US, has a 40% mortality rate, and occurs in 25% of hospitalized COVID-19-infected patients, yet there are currently no FDA-approved drugs for ARDS. Inflammatory conditions resulting from ARDS are caused by the interaction between the virus and immune cells, namely neutrophils and macrophages. These signaling interactions are primarily mediated via the complement pathway, a part of the immune system that enhances the ability of antibodies to clear pathogens, playing a role in inflammation, host defense, and signaling adaptive immunity. In this project, using methods of systems biology, we look towards signaling models of the complement system to compartmentally understand this complex system. COPASI is a computer software that creates and solves mathematical models, encoding differential equations of biological processes, and was a part of the methodology behind this research. A previously existing computational model involving the enhancement and suppression mechanisms that regulate complement activity provided a template model in Systems Biology Markup Language (SBML) format, a standard form of systems biology XML codes (Liu et al, 2011). Plots were produced of complement regulation with inhibitors under infection inflammation conditions in terms of mediator protein deposition, and of positive feedback amplification of neutrophil activation. Results focused on three aspects: validation of existing data, exploring the amplification modules of the complement pathway, and characterizing emergent properties such as bistable switches regulating the complement cascade. The broader question to be explored in next steps involves how this modeled mechanism would work on the viral surface. Because the complement cascade occurs on the surface of the virus during neutrophil interaction, we believe that the mechanics of the virus, whether it is crystalline or noncrystalline (COVID-19 is noncrystalline), in conjunction with the spatial arrangement of the cascade proteins determine this behavior. Future work involving spatial and stochastic models will involve looking at mechanical and spatio-temporal criterion in virion interaction.