{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T22:59:46Z","timestamp":1790895586395,"version":"4.1.0"},"reference-count":127,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T00:00:00Z","timestamp":1619654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Phys."],"abstract":"<jats:p>The complement system is assembled from a network of proteins that function to bring about the first line of defense of the body against invading pathogens. However, complement deficiencies or invasive pathogens can hijack complement to subsequently increase susceptibility of the body to infections. Moreover, invasive pathogens are increasingly becoming resistant to the currently available therapies. Hence, it is important to gain insights into the highly dynamic interaction between complement and invading microbes in the frontlines of immunity. Here, we developed a mathematical model of the complement system composed of 670 ordinary differential equations with 328 kinetic parameters, which describes all three complement pathways (alternative, classical, and lectin) and includes description of mannose-binding lectin, collectins, ficolins, factor H-related proteins, immunoglobulin M, and pentraxins. Additionally, we incorporate two pathogens: (type 1) complement susceptible pathogen and (type 2)<jats:italic>Neisseria meningitidis<\/jats:italic>located in either nasopharynx or bloodstream. In both cases, we generate time profiles of the pathogen surface occupied by complement components and the membrane attack complex (MAC). Our model shows both pathogen types in bloodstream are saturated by complement proteins, whereas MACs occupy &amp;lt;&amp;lt;1.0% of the pathogen surface. Conversely, the MAC production in nasopharynx occupies about 1.5\u201310% of the total<jats:italic>N. meningitidis<\/jats:italic>surface, thus making nasal MAC levels at least about eight orders of magnitude higher. Altogether, we predict complement-imbalance, favoring overactivation, is associated with nasopharynx homeostasis. Conversely, orientating toward complement-balance may cause disruption to the nasopharynx homeostasis. Thus, for sporadic meningococcal disease, our model predicts rising nasal levels of complement regulators as early infection biomarkers.<\/jats:p>","DOI":"10.3389\/fphy.2021.603704","type":"journal-article","created":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T12:13:36Z","timestamp":1619698416000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Systems Biology Modeling of the Complement System Under Immune Susceptible Pathogens"],"prefix":"10.3389","volume":"9","author":[{"given":"Nehemiah T.","family":"Zewde","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohaine V.","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Morikis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Palermo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1003057","DOI":"10.1371\/journal.ppat.1003057","article-title":"Viral and bacterial interactions in the upper respiratory tract","volume":"9","author":"Bosch","year":"2013","journal-title":"PLoS Pathog"},{"key":"B2","doi-asserted-by":"publisher","first-page":"28","DOI":"10.5152\/eajm.2010.09","article-title":"Acute inhalation injury","volume":"42","author":"Gorguner","year":"2010","journal-title":"Eurasian J Med"},{"key":"B3","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1146\/annurev-physiol-021115-105238","article-title":"The microbiome and the respiratory tract","volume":"78","author":"Dickson","year":"2016","journal-title":"Annu Rev Physiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/nri.2016.117","article-title":"Early local immune defenses in the respiratory tract","volume":"17","author":"Iwasaki","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1183\/09059180.05.00009501","article-title":"Lung defences: an overview","volume":"14","author":"Nicod","year":"2005","journal-title":"Eur Respir Rev"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1016\/j.jaci.2017.11.046","article-title":"The complement system in the airway epithelium: an overlooked host defense mechanism and therapeutic target?","volume":"141","author":"Kulkarni","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1165\/rcmb.2013-0485TR","article-title":"Complement system in lung disease","volume":"51","author":"Pandya","year":"2014","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1111\/imr.12500","article-title":"Complement component C3 - The \u201cSwiss Army Knife\u201d of innate immunity and host defense","volume":"274","author":"Ricklin","year":"2016","journal-title":"Immunol Rev"},{"key":"B9","first-page":"2500","article-title":"Spontaneous activation of the first component of human complement (C1) by an intramolecular autocatalytic mechanism","volume":"128","author":"Ziccardi","year":"1982","journal-title":"J Immunol Baltim Md 1950"},{"key":"B10","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.4049\/jimmunol.147.6.1884","article-title":"Spontaneous activation of serum C1 in vitro. 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