OPINION published: 23 October 2020 doi: 10.3389/fcimb.2020.559209 Numbers Game and Immune Geography as Determinants of Coronavirus Pathogenicity Gennady Bocharov 1,2,3*, Valentina Casella 4 , Jordi Argilaguet 5 , Dmitry Grebennikov 1,2,3 , Roberto Güerri-Fernandez 6 , Burkhard Ludewig 7 and Andreas Meyerhans 4,8* 1 Marchuk Institute of Numerical Mathematics, Russian Academy of Sciences, Moscow, Russia, 2 Moscow Center for Fundamental and Applied Mathematics at Marchuk Institute of Numerical Mathematics, Russian Academy of Sciences (INM RAS), Moscow, Russia, 3 Institute for Personalized Medicine, Sechenov First Moscow State Medical University, Moscow, Russia, 4 Infection Biology Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain, 5 Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Centre de Recerca en Sanitat Animal (CReSA, IRTA-UAB), Campus de la Universitat Autònoma de Barcelona, Bellaterra, Spain, 6 Infectious Diseases Unit, Hospital del Mar-IMIM, Universitat Autònoma de Barcelona, Barcelona, Spain, 7 Institute for Immunobiology, Kantonsspital St.Gallen, St. Gallen, Switzerland, 8 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain Keywords: COVID-19, SARS - CoV-2, IFN-I, innate immunity, viral dynamics, pathogenesis Once again, the new SARS-CoV-2 reminds us about the potential of infectious pathogens to fiercely Edited by: Heather Shannon Smallwood, spread worldwide and puts our well-being in danger. With respect to its pathogenicity, one may be University of Tennessee Health reminded of two simple principles that underlie our constant fight with viruses of our surrounding, Sciences Center, United States the “numbers game” and “immune geography” (Zinkernagel et al., 1985). These conceptual terms Reviewed by: refer to the kinetics of virus growth and immune reactions, and the spatial organization of immune Artur Summerfield, responses in relation to viral entry sites and tissue tropism which determines cytokine gradients and Institute of Virology and immune cell homing patterns across tissues, respectively. Jointly, both concepts provide a rationale Immunology (IVI), Switzerland for a dynamic view on the balance between virus expansion and development of antiviral immune *Correspondence: responses that will ultimately help to understand virus pathogenicity and how to gain immune Andreas Meyerhans control (Figure 1A). andreas.meyerhans@upf.edu Coronaviruses are a family of enveloped plus-strand RNA viruses that infect mammals and Gennady Bocharov birds. In humans, there are four endemic, usually mildly pathogenic viruses 229E, OC43, NL63 and g.bocharov@inm.ras.ru HKU1, and the newly emerged viruses SARS-CoV, MERS-CoV, and SARS-CoV-2 that cause lethal infections in around 10, 30, and 1% of cases, respectively (Gaunt et al., 2010; Raoult et al., 2020). Specialty section: All these viruses can be transmitted by aerosols and infect the upper respiratory tract and the lung. This article was submitted to Virus and Host, However, since human infections only allow for very limited experimental manipulations, much a section of the journal of our fundamental knowledge of virus infections are derived from animal studies. To understand Frontiers in Cellular and Infection the containment of the initial virus spread, which subsequently determines virus pathogenicity, Microbiology the murine coronavirus (M-CoV, also known as mouse hepatitis virus, MHV) model system is Received: 25 May 2020 most instructive. M-CoV is a rapidly replicating, highly cytopathic virus that leads to severe Accepted: 11 September 2020 inflammation in several organs and can disseminate via the bloodstream. In particular, the liver, Published: 23 October 2020 a peripheral organ and the spleen, a secondary lymphoid organ, are the major target organs of this Citation: virus, and hematopoietic cell-derived type I interferon (IFN) primarily controls viral replication Bocharov G, Casella V, Argilaguet J, and virus-induced liver disease. Three clinical outcomes are observable that depend on the balance Grebennikov D, Güerri-Fernandez R, of infection spreading and the innate immune response (Figure 1B). With an optimal innate Ludewig B and Meyerhans A (2020) response, the infection is well controlled and generates only mild symptoms, whereas, a delayed and Numbers Game and Immune weak innate response results in severe infection spread and fatal outcome. Between these extremes, Geography as Determinants of Coronavirus Pathogenicity. tissue damage of various severity is observed but the host ultimately survives. Front. Cell. Infect. Microbiol. How can this qualitative description of virus-induced pathogenicity be transformed into a more 10:559209. quantitative characterization of host protection and its limits? A systems biology-based analysis doi: 10.3389/fcimb.2020.559209 combining experimental data of murine coronavirus infection and mathematical modeling has Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 1 October 2020 | Volume 10 | Article 559209 Bocharov et al. Determinants of Coronavirus Pathogenicity FIGURE 1 | Kinetic view on CoV pathogenesis. (A) The numbers game between virus growth and immune response determines virus infection outcomes. (B) Early innate immune responses determine viral pathogenesis. (C) Degree of robustness of protection against a faster replicating M-CoV strain in relation to its preferential site of replication, i.e., a peripheral organ (liver) vs. a lymphoid organ (spleen). Virus is represented as a solid line while broken lines characterize the immune response. Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 2 October 2020 | Volume 10 | Article 559209 Bocharov et al. Determinants of Coronavirus Pathogenicity shown that the robustness of innate immune response-mediated later during the infection course (Prompetchara et al., 2020). protection from severe disease is rather limited (summarized With respect to SARS-CoV-2 infections, recent data suggest that in Figure 1C) when putative CoV variants exhibiting enhanced an impaired systemic type I IFN response correlates with the tropism and replication in peripheral organ cells like hepatocytes severity of COVID-19 (Arunachalam et al., 2020). Furthermore, rather than lymphoid tissue cells were considered (Bocharov since aging affects multiple layers of the immune control of et al., 2010, 2018). For example, a 20% increase of the exponential viruses including an altered innate response and correlates to growth rate of M-CoV A59 strain (estimated to be 0.78 infectious COVID-19 severity (Akbar and Gilroy, 2020)(https://ebrary.net/ particles/ml/h) leads to a severe infection as manifested by a 30820/health/pdcs), further longitudinal studies in humans of substantial rise of liver enzyme values in serum (i.e., alanine this complex relationship are warranted. transferase (ALT) level rise to 1,000 IU/L) within 2 days. Clearly, the degree of fragility, i.e., the sensitivity of On the contrary, a substantial rise of up to 30-fold of the CoV-induced infection severity to viral infection dose and growth virus replication rate in macrophages of the spleen (estimated rate increases in humans, and the limits of protection provided to be about 37 infectious particles/cell/h for M-CoV A59 in by the type I IFN system that acts at the front line of the virus- C57BL/6 mice) is efficiently disarmed by plasmacytoid dendritic host interaction deserve further quantitative analyses. The higher cell-produced type I IFN, thus providing robust protection type I IFN sensitivity of SARS-CoV-2 compared to SARS-CoV against severe disease (Bocharov et al., 2010). In general terms, indicates that a type I IFN treatment of a virus-exposed individual differences of innate immune responses in lymphoid tissues would be an efficient early therapeutic modality that could such as the spleen or lymph nodes in which local levels of prevent subsequent severe disease. This view is now supported type I IFN increase sharply when viruses replicate, provide a by latest clinical data that show favorable clinical responses and swift host protection, whereas virus replication in non-lymphoid reduced mortality after early type I IFN administration (Wang tissue like liver or lung generate slower type I IFN increases et al., 2020). Furthermore, given the large reservoir of CoVs in reaching lower levels and thus being less efficient in restriction of bats (Menachery et al., 2015), testing their properties with respect viral replication. to growth rates, IFN-sensitivity and IFN-suppressive capacity How do the above numbers relate to the rate of infection might help to be prepared for the next pandemic to come. It is spreading in the case of SARS-CoVs? The available experimental only a question of time. data on the virus growth kinetics in Vero E6 cells in vitro provide estimates of the exponential growth rates of SARS-CoV-1 to be AUTHOR CONTRIBUTIONS about 0.74 RNA/ml/h (Keyaerts et al., 2005) and 0.84 infectious particles/ml/h. Recent data for SARS-CoV-2 provide a similar VC, JA, DG, RG-F, BL, GB, and AM jointly discussed CoV growth rate (Lokugamage et al., 2020). The remarkable similarity pathogenesis. GB and AM drafted the manuscript. VC, JA, DG, of the values and the preferential tropism of the SARS-CoV RG-F, BL, GB, and AM revised the manuscript. All authors viruses to cells of the upper respiratory tract and lungs would contributed to the article and approved the submitted version. suggest that the robustness of protection against SARS-CoV spreading in this peripheral organ by the innate IFN response FUNDING is limited. Thus, it is conceivable that SARS-CoV infections are operating close to the edge of the protective capacity of the The authors were supported by grants from the Russian Science host’s type I IFN system. Consequently, changes in type I IFN- Foundation (project number 18-11-00171 to GB, DG, and AM), sensitivity of the viruses, their IFN-suppressive properties as the RFBR (project number 20-04-60157 to GB and DG), the well as changes in type I IFN-responsiveness of infected hosts Moscow Center for Fundamental and Applied Mathematics i.e., due to genetic polymorphisms, immunosuppressive drugs or (agreement with the Ministry of Education and Science of the aging might all have relevant clinical consequences. Indeed, it Russian Federation No. 075-15-2019-1624 to GB and DG), has already been speculated for SARS- and MERS-CoVs that a the Spanish Ministry of Science and Innovation (PID2019- delay in virus restriction by the early type I IFN response may 106323RB-I00/AEI/10.13039/501100011033 to AM and VC), and lead to exaggerated inflammatory, life-threatening conditions the María de Maeztu grant (CEX2018-000792-M). REFERENCES Bocharov, G., Züst, R., Cervantes-Barragan, L., Luzyanina, T., Chiglintsev, E., Chereshnev, V. A., et al. (2010). A systems immunology approach to Akbar, A. N., and Gilroy, D. W. (2020). Aging immunity may exacerbate COVID- plasmacytoid dendritic cell function in cytopathic virus infections. PLoS Pathog. 19. Science 369, 256–257. doi: 10.1126/science.abb0762 6:e1001017. doi: 10.1371/journal.ppat.1001017 Arunachalam, P. S., Wimmers, F., Mok, C. K. P., Perera, R. A. P. M., Scott, Gaunt, E. R., Hardie, A., Claas, E. C. J., Simmonds, P., and Templeton, K. E. (2010). M., Hagan, T., et al. (2020). Systems biological assessment of immunity to Epidemiology and clinical presentations of the four human coronaviruses 229E, mild versus severe COVID-19 infection in humans. Science 369, 1210–1220. HKU1, NL63, and OC43 detected over 3 years using a novel multiplex real-time doi: 10.1126/science.abc6261 PCR method. J. Clin. Microbiol. 48, 2940–2947. doi: 10.1128/JCM.00636-10 Bocharov, G., Volpert, V., Ludewig, B., and Meyerhans, A. (2018). Keyaerts, E., Vijgen, L., Maes, P., Neyts, J., and Van Ranst, M. (2005). Growth Mathematical Immunology of Virus Infections. Cham: Springer. kinetics of SARS-coronavirus in vero E6 cells. Biochem. Biophys. Res. Commun. doi: 10.1007/978-3-319-72317-4 329, 1147–1151. doi: 10.1016/j.bbrc.2005.02.085 Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 3 October 2020 | Volume 10 | Article 559209 Bocharov et al. Determinants of Coronavirus Pathogenicity Lokugamage, K. G., Hage, A., Schindewolf, C., Rajsbaum, R., and Menachery, V. favorable clinical responses in COVID-19 patients. Cell Host Microbe. 28, D. (2020). SARS-CoV-2 is sensitive to type I interferon pretreatment. bioRxiv 455–464.e2. doi: 10.1016/j.chom.2020.07.005 [Preprint]. doi: 10.1101/2020.03.07.982264 Zinkernagel, R. M., Hengartner, H., and Stitz, L. (1985). On the role of Menachery, V. D., Yount, B. L. Jr, Debbink, K., Agnihothram, S., Gralinski, viruses in the evolution of immune responses. Br. Med. Bull. 41, 92–97. L. E., Plante, J. A., et al. (2015). A SARS-like cluster of circulating bat doi: 10.1093/oxfordjournals.bmb.a072033 coronaviruses shows potential for human emergence. Nat. Med. 21, 1508–1513. doi: 10.1038/nm.3985 Conflict of Interest: The authors declare that the research was conducted in the Prompetchara, E., Ketloy, C., and Palaga, T. (2020). Immune responses in absence of any commercial or financial relationships that could be construed as a COVID-19 and potential vaccines: lessons learned from SARS and MERS potential conflict of interest. epidemic. Asian Pac. J. Allergy Immunol. 38, 1–9. doi: 10.12932/AP-200220- 0772 Copyright © 2020 Bocharov, Casella, Argilaguet, Grebennikov, Güerri-Fernandez, Raoult, D., Zumla, A., Locatelli, F., Ippolito, G., and Kroemer, G. (2020). Ludewig and Meyerhans. This is an open-access article distributed under the terms Coronavirus infections: Epidemiological, clinical and immunological of the Creative Commons Attribution License (CC BY). The use, distribution or features and hypotheses. Cell Stress 4, 66–75. doi: 10.15698/cst2020. reproduction in other forums is permitted, provided the original author(s) and the 04.216 copyright owner(s) are credited and that the original publication in this journal Wang, N., Zhan, Y., Zhu, L., Hou, Z., Liu, F., Song, P., et al. (2020). Retrospective is cited, in accordance with accepted academic practice. No use, distribution or multicenter cohort study shows early interferon therapy is associated with reproduction is permitted which does not comply with these terms. Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 4 October 2020 | Volume 10 | Article 559209