Multi-scale Modeling of the Immune Response to Aspergillus Fumigatus

Henrique de Assis L Ribeiro, Adam C Knapp, Luis L Fonseca, Luis Sordo Vieira, Matthew Weeler, Reinhard Laubenbacher

This project aims to simulate the immune response to Aspergillus fumigatus and the role of iron. Aspergillus fumigatus is a common mold that causes pneumonia in immunocompromised people. When the infection is established, the death rate can be higher than 50%; moreover, multidrug resistance is also common. Iron is an essential nutrient for fungus; however, in-vivo, its serum concentration is tightly controlled by inflammatory signals such as the interleukin IL-6. In this project, we want to explore the mechanisms of iron regulation as targets for aspergillosis treatment. For this, we constructed a multi-scale agent-based model of this disease that integrates immunological aspects, such as the monocyte and neutrophils response to the fungus, and nutritional (I.e., iron) aspects. That last one includes the host regulation of iron by IL-6 and the fungus iron acquisition via the siderophore triacetylfusarinine C (TAFC). We are developing this model with knowledge extracted from the literature. Likewise, the parameter values are estimated a-priori from literature data. Finally, to validate this model, we use both literature and our own generated data.

Multi-scale Modeling of the Immune Response to Aspergillus fumigatus


Laubenbacher R, Niarakis A, Helikar T, An G, Shapiro B, Malik-Sheriff RS, Sego TJ, Knapp A, Macklin P, Glazier JA. Building digital twins of the human immune system: toward a roadmap. npj Digit. Med. 2022 May 20;5,64. doi: 10.1038/s41746-022-00610-z.

Sordo Vieira L, Laubenbacher R. Computational models in systems biology: standards, dissemination, and best practices. Curr Opin Biotechnol. 2022 Jun;75:102702. doi: 10.1016/j.copbio.2022.102702. Epub ahead of print.

Knapp AC, Sordo Vieira L, Laubenbacher R, Chifman J. SteadyCellPhenotype: A web-based tool for the modeling of biological networks with ternary logic. Bioinformatics. 2022 Feb 18. doi: 10.1093/bioinformatics/btac097. Epub ahead of print.

Masison, J., J. Beezley, Y. Mei, H. a. L. Ribeiro, A. C. Knapp, L. Sordo Vieira, B. Adhikari, et al. “A Modular Computational Framework for Medical Digital Twins.” Proceedings of the National Academy of Sciences 118, no. 20 (May 18, 2021).

Cagnina, R. Elaine, Kathryn R. Michels, Alexandra M. Bettina, Marie D. Burdick, Yogesh Scindia, Zhimin Zhang, Thomas J. Braciale, and Borna Mehrad. “Neutrophil-Derived TNF Drives Fungal Acute Lung Injury in Chronic Granulomatous Disease.” The Journal of Infectious Diseases, April 5, 2021.

Wooten, David J., Jorge Gómez Tejeda Zañudo, David Murrugarra, Austin M. Perry, Anna Dongari-Bagtzoglou, Reinhard Laubenbacher, Clarissa J. Nobile, and Réka Albert. “Mathematical Modeling of the Candida Albicans Yeast to Hyphal Transition Reveals Novel Control Strategies.” Preprint. Systems Biology, January 20, 2021.

L. Sordo Vieira, R. Laubenbacher, and D. Murrugarra, Control of Intracellular Molecular Networks Using Algebraic Methods, Bull. Math. Biol., 82(2), 2019.

Aguilar, Boris, Pan Fang, Reinhard Laubenbacher, and David Murrugarra. 2020. “A Near-Optimal Control Method for Stochastic Boolean Networks”. Letters in Biomathematics 7 (1), 67–80.

E. Paul, G. Pogudin, W. Qin and R. Laubenbacher, The dynamics of canalizing Boolean networks, Complexity,, 2020.

Michels KR, Solomon AL, Scindia Y, Vaulont S, Burdick MD, Laubenbacher R, Mehrad B. Aspergillus utilizes heme as an iron source during invasive pneumonia. Submitted to mBio (revising manuscript to resubmit).

Solomon A, Michels K, Laubenbacher R, Scindia Y, Mehrad B. The role of heme uptake and hemopexin in invasive pulmonary aspergillosis. American Thoracic Society Virtual Conference, 2020.

Qu G, Solomon A, Yang N, Lin C, Scindia Y, Mehrad B. Alveolar macrophages protect against acute lung injury. American Thoracic Society Virtual Conference, 2020. 


R01 AI135128: Multiscale Modeling of the Battle Over Iron in Invasive Lung Infection