Systems Biology Modeling of the Complement System Under Immune Susceptible Pathogens

Abstract

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) Neisseria meningitidis 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 <<1.0% of the pathogen surface. Conversely, the MAC production in nasopharynx occupies about 1.5-10% of the total N. meningitidis 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.

Keywords: Neisseria meningitidis; complement system; computational systems biology; predictive modeling; predictive network biology; protein network.

FIGURE 1 |

Summary of the complement system biochemical network. Activation and propagation of the alternative pathway are shown in blue, the classical pathway is shown in yellow, and the lectin pathway in conjunction with different segments of humoral immunity is shown in magenta. The interconnection between all pathways is shown in green. The continued propagation terminates in the formation of either fC5b-9 (soluble MAC) or surface-bound MAC. LP is used as an umbrella term that equates to pattern recognition molecules, such as MBL trimers and tetramers, collectin liver 1 (CL-L1), collectin kidney 1 (CL-K1), heteromeric CL-L1/K1 known as CL-LK, ficolin-1 (M-ficolin), ficolin-2 (L-ficolin), and ficolin-3 (H-ficolin), MBL-associated serine proteases (MASPs)-1, MASP-2, MASP-3, MBL-associated proteins (MAp19 and MAp44). Complement proteins that make up the regulatory checkpoints such FH, FHL-1, and Vn are shown in red. Activated C1 (C1*) will use C1s* to cleave C4 into C4a and nascent C4b (nC4b). Similar to nC3b, nC4b can also covalently attach to nearby cells and initiate complement.

FIGURE 2 |

Percent of surface occupation (type 1 pathogens) under the different modes of complement activation of (i) FP in blue (ii) CP in green, (iii) LP in magenta, and (iv) FHR1-5 in yellow, and complement system with pentraxins (CSP). (A) FP occupied <1.0% of the pathogen surface, whereas all other modes of complement activation rapidly saturate the pathogen surface. The inset shows membrane attack complex (MAC) production is the highest under FP, but all four modes occupied <<1.0% of the pathogen surface. (B) Pathogen surface is rapidly saturated by CSP components as shown in blue. The inset shows MAC production is similar to (A) inset where MACs occupied <<1.0% of the pathogen surface.

FIGURE 3 |

Nasal complement profiles on N. meningitidis that occupy the pathogen surface under three conditions: (i) FP and FHR-3 recruitment in blue; (ii) FP and C4BP, Vn, FH, and FHL-1 recruitment in green; and (iii) FP and FHR-3, C4BP, Vn, FH, and FHL-1 recruitment in red. (A) Conditions (ii) and (iii) rapidly occupy the surface of N. meningitidis and account for 81.1 and 83.1% of its surface, respectively. Condition (i) occupies a lower percent of the bacterial surface (52.8%). (B) Conversely, condition (i) produces the highest membrane attack complex (MAC) level, occupying 6.1% N. meningitidis surface, whereas, conditions (ii) and (iii) led to lower MAC production that occupied 2.3 and 2.1% of the bacterial surface, respectively.

FIGURE 4 |

Bloodstream time profiles on N. meningitidis under three conditions: (i) FP and FHR-3 recruitment in blue; (ii) FP and C4BP, Vn, FH, and FHL-1 recruitment in green; and (iii) FP and FHR-3, C4BP, Vn, FH, and FHL-1 recruitment in red. All three conditions rapidly occupy the bacterial surface. However, condition (i) occupied a lower amount of 84.5% of the bacterial surface. Time profile of condition (ii) is under the profile of condition (iii). Moreover, membrane attack complex (MAC) profiles in the inset show condition (i) produced the highest amount, whereas under conditions (ii) and (iii) MAC levels are lower and overlapping.

FIGURE 5 |

Nasal complement profiles on N. meningitidis under complement enhancement, varying recruitment capabilities, and absence of FHR-3. (A) Complement proteins are increased to 20.0% of their serum values. Compared to the membrane attack complex (MAC) deposition under N. meningitidis that recruits C4BP, Vn, FH, and FHL-1 (red, 2.3% occupation), the terminal module enhancement of proteins C5 (green, 3.3% occupation), C6 (blue, 3.6% occupation), and C9 (yellow, 4.0% occupation) led to higher MAC levels. However, enhancing the concentrations of C7 (cyan) and C8 (black) had minor effects. Time profile for N. meningitidis that recruits C4BP, Vn, FH, and FHL-1 (red) was increased to show the source of comparison. (B) Compared to the MAC deposition under N. meningitidis that recruits C4BP, Vn, FH, and FHL-1 (red), removing the ability of N. meningitidis to recruit Vn (yellow) had the largest effect with MAC level increasing by 2-fold. This was followed by an increase in the MAC deposition through the removal of FH and FHL-1 (green) recruitment capabilities. Lastly, removing the ability of N. meningitidis to recruit C4BP (blue) also increased the MAC deposition, but this had the smallest effect in comparison to Vn, FH, and FHL-1.

FIGURE 6 |

Nasal complement profiles on N. meningitidis with varying regulatory levels and absence of FHR-3. Concentrations of C1-INH, C4BP, Vn, Cn, FH, and FHL-1 are varied between 2.0 and 0.0002% of their respective serum levels. The highest membrane attack complex (MAC) levels with the surface occupation of about 10.0% are produced when the concentration of the complement regulators is reduced to either 0.002% (green) or 0.0002% (yellow) of their serum levels. This is followed by 0.02% (blue) of serum levels where MACs occupied 6.4% of the bacterial surface. Lastly, the MAC production under 0.2% (red) of serum occupies 1.3% of the bacterial surface, and subsequently increasing the complement regulators to 2.0% of their serum levels led to MAC pores occupying 0.008% of the bacterial surface.

FIGURE 7 |

Model predictions for the susceptibility of developing meningococcal disease. States associated with a dysfunctional complement system due to an overactivation may have protective effects in the nasal cavity against invasive pathogens.