key: cord-0759855-i66e5umh authors: Zhou, Z.; Zhao, Z.; Shi, S.; Wu, J.; Li, D.; Li, J.; Zhang, J.; Gui, K.; Zhang, Y.; Mei, H.; Hu, Y.; Ouyang, Q.; Li, F. title: Model-based cellular kinetic analysis of SARS-CoV-2 infection: different immune response modes and treatment strategies date: 2021-01-13 journal: nan DOI: 10.1101/2021.01.11.21249562 sha: 8a37f49849d72aa4c6a11f4024d91f3309914004 doc_id: 759855 cord_uid: i66e5umh Increasing number in global COVID-19 cases demands for mathematical model to analyze the interaction between the virus dynamics and the response of innate and adaptive immunity. Here, based on the assumption of a weak and delayed response of the innate and adaptive immunity in SARS-CoV-2 infection, we constructed a mathematical model to describe the dynamic processes of immune system. Integrating theoretical results with clinical COVID-19 patients' data, we classified the COVID-19 development processes into three typical modes of immune responses, correlated with the clinical classification of mild & moderate, severe and critical patients. We found that the immune efficacy (the ability of host to clear virus and kill infected cells) and the lymphocyte supply (the abundance and pool of naive T and B cell) play important roles in the dynamic process and determine the clinical outcome, especially for the severe and critical patients. Furthermore, we put forward possible treatment strategies for the three typical modes of immune response. We hope our results can help to understand the dynamical mechanism of the immune response against SARS-CoV-2 infection, and to be useful for the treatment strategies and vaccine design. usually cause bad clinical outcome and even death, although the overall intensity of the 48 cytokine storm in COVID-19 patients is milder than SARS patients (3). 49 More studies and evidences show that the SARS-CoV-2 virus, compared to SARS- and antibodies remain controversial (7-13). 61 Here, we investigated the immune response against SARS-CoV-2 infection by We simplified both innate and adaptive immune response processes within-host 94 caused by the SARS-CoV-2 infection, and constructed a virus-immune interaction 95 network with the viral infection module, innate immunity, cellular immunity, humoral 96 immunity, and immunosuppression modules (Fig. 1) . During the SARS-CoV-2 infection, perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 13, 2021. ; https://doi.org/10.1101/2021.01.11.21249562 doi: medRxiv preprint the unit of cytokines is pg/mL, and the unit of antibodies is μg/mL. In the viral infection module, we have the following equations to depict how the 138 SARS-CoV-2 virus infects the lung epithelial cells. , the population of virus will decrease; otherwise the population 161 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 13, 2021. ; https://doi.org/10.1101/2021.01.11.21249562 doi: medRxiv preprint of virus will increase. When the naïve CD8+T cells meet and interact with antigen-loaded APCs in the 163 lymph nodes, they are activated, proliferate and differentiate to CTL, then move to the 164 lung area to fight against the virus. We use a logistic term to describe the homeostasis of 165 naïve CD8+ T cell supply with capacity KCD8 and growth rate rCD8, kCTL represents the 166 activation rate to CTL from the naïve CD8+ T cell by APC interaction. Thus, we wrote 167 the dynamics of naïve CD8+T cell as: Steady state solution gives out . We define 170 the host supply ability of naïve CD8+T cell as indicates the ability of CD8+ T cell supply to produce more CTL. If perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 13, 2021. ; https://doi.org/10.1101/2021.01.11.21249562 doi: medRxiv preprint Demographically, the immune system's capability and response vary individually, 188 susceptible to age, fitness and gender differences (14, 15). In Fig. 2A , we adopted Fig. 2C and Fig. 2D . In comparison to mode 2, mode 3 is more likely to appear in older patients with 214 underlying diseases, including but not limited to hypertension and diabetes mellitus, 215 for their fragile immune systems. This view is also supported by recent study on the 216 association between adaptive immunity and age (18). In addition to these, in mode 3, 217 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 13, 2021. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 13, 2021. ; https://doi.org/10.1101/2021.01.11.21249562 doi: medRxiv preprint perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 13, 2021. ; https://doi.org/10.1101/2021.01.11.21249562 doi: medRxiv preprint temporarily stronger inflammatory response (higher IL-6 level) than the class 1, whose 268 IL-6 peak usually has a 3-day full width at half maximum (FWHM). The class 3 269 patients show a longer period of cytokine storm status with IL-6 peak and a 13-day Combing the theoretical results and clinic classification, for the in silico patients 290 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 13, 2021. ; https://doi.org/10.1101/2021.01.11.21249562 doi: medRxiv preprint with different immune response modes, we simulated their disease processes and 291 possible clinic outcomes, and try to put forward the available treatment strategies. The main treatment strategies of COVID-19 are to prevent the potential chronic load is zero, equals to 0 when virus is not cleared. 314 We first assessed the effect of the above drugs used singly on the in silico patients perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 13, 2021. ; https://doi.org/10.1101/2021.01.11.21249562 doi: medRxiv preprint whole course of disease for preventing superinfection (this situation is seen in our 322 simulation results). Usage of GC on mode 1 and 2 patients during middle stage 323 decreases patient's Q score and is not recommended. Middle and late stage Ig benefits 324 the most on mode 3 patients for their role in cooperating with host's immunity. 325 We next tested all combinations of treatment strategies with different kinds of drugs Bacterial co-infection is tested positive in more than 50% of the deceased patients 340 (2, 25), which we also found clinically. We simulated the course of disease with 341 bacterial co-infection arising from mode 2 and 3, and denoted them as mode 2*, mode In bacterial co-infection, antibiotics (AntBio) is also included into treatment plans. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 13, 2021. ; https://doi.org/10.1101/2021.01.11.21249562 doi: medRxiv preprint All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 13, 2021. ; https://doi.org/10.1101/2021.01.11.21249562 doi: medRxiv preprint in treating COVID-19 patients. The immune system is a complex defense system that protects us from the pathogens, perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 13, 2021. ; https://doi.org/10.1101/2021.01.11.21249562 doi: medRxiv preprint hand, it has checks and balance to prevent the over activation of immune system. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 13, 2021. ; https://doi.org/10.1101/2021.01.11.21249562 doi: medRxiv preprint Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics. 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