Preprint / Version 1

Human Immune Response to COVID-19 Infection and Potential Role of Chloroquine Family of Drugs

A Review


  • Sunita Singh Reliance Industries Limited
  • Chandra Shekharaiah PS Reliance Industries Limited
  • Vishal Paul Reliance Industries Limited
  • Santosh Kodgire Reliance Industries Ltd, Jamnagar, India
  • Shivbachan Kushwaha Reliance Industries Ltd, Jamnagar, India
  • Debanjan Sanyal Reliance Industries Ltd, Jamnagar, India
  • Santanu Dasgupta Reliance Industries Ltd, Reliance Corporate Park, Ghansoli, India



Currently, world is witnessing a massive morbidity and mortality due to COVID-19 pandemic.  A novel strain of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). The virus enters inside the body and infect the cells through angiotensin-converting enzyme 2 (ACE2) receptor. The S1 protein of SARS-CoV-2 binds to the ACE2 receptor which results in endocytosis and transfer of virus into endosomes of body cells. Entry of SARS-CoV-2 results in activation of innate immune responses first followed by adaptive immune responses. The effective host immune responses are crucial to control and prevent viral infection. However, excessive production of proinflammatory cytokines and decrease in number of T-lymphocytes are the major reasons associated with severity of COVID-19. Therapies and drugs that can modulate the immune responses appropriately may play a crucial role to control and prevent the progression of disease. Chloroquine (CQ) and hydroxychloroquine (HCQ) have anti-inflammatory, immunomodulatory, antitumor, antimicrobial and antithrombotic effects. These drugs have already been registered in many countries to treat arthritis, lupus and malaria. The treatment responses of COVID-19 patients to these drugs have been found positive in some cases and clinical studies are underway for evaluating these drugs for the same. However, there are some serious side effects and health hazards associated. Many regulatory bodies are demanding more conclusive data on efficacy and safety from the clinical studies. Moreover, some regulatory bodies such as Food and Drug Administration (FDA) and European Medicines Agency (EMA) have recommended to use these drugs in emergency and chronic situation to treat critically ill COVID-19 patients under doctor’s supervision with all issued guidelines. The national task force (NTF) set up by Indian Council of Medical Research has recommended high risk individuals to take HCQ for prophylaxis. This review summarizes human immune response and various aspects of CQ and HCQ with special reference to COVID-19.


Chloroquine, COVID-19, Hydroxychloroquine, Immune response, SARS-CoV-2


Download data is not yet available.


De Groot, R.J.; Baker, S.C.; Baric R.S.; Brown, C.S.; Drosten, C.; Enjuanes, L. Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group. J Virol 2013, 87, 7790–7792.

Rothan, H.A.; Byrareddy, S.N. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. Journal of autoimmunity 2020, 102433.

Li, Q.; Guan, X.; Wu, P.; Wang, X.; Zhou, L.; Tong, Y.; et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med 2020.

Jin, Y.H.; Cai, L.; Cheng, Z.S.; Cheng, H.; Deng, T.; Fan, YP; et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res 2020, 7:4.

Xu, Z.; Shi, L.; Wang, Y.; Zhang, J.; Huang, L.; et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet Respiratory Medicine 2020.

Guan, W.J.; Ni Z.Y; Hu Y.; Liang W.H.; Ou, C.Q, et al. Clinical characteristics of coronavirus disease 2019 in China. The New England Journal of Medicine. 2020.

Mizumoto, K.; Kagaya, K.; Zarebski, A.; Chowel, l.G. Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Euro surveillance 2020, 25.

Ganyani, T.; Kremer. C.; Chen, D.; Torneri, A.; Faes, C.; Wallinga, J.; et al. Estimating the generation interval for COVID-19 based on symptom onset data. 2020. Available from:

Yang, X.; Yu, Y.; Xu, J.; Shu, H.; Xia, J.; Liu, H.; et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir Med 2020.

Hoffmann, M.; Kleine-Weber, H.; Krüger, N.; Müller, M.; Drosten, C.; Pöhlmann, S. The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells. Bio Rxiv. 2020.

Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395,497–506.

Zou, L.; Ruan, F.; Huang, M.; Liang, L.; Huang, H.; Hong, Z.; et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med. 2020.

Gorbalenya, A.E.; Baker, S.C.; Baric, R.S.; de Groot, R.J.; Drosten, C.; Gulyaeva, A.A.Severe acute respiratory syndrome-related coronavirus: the species and its viruses – a statement of the Coronavirus Study Group. bioRxiv 2020.

Lu, H.; Stratton, C.W.; Tang, Y.W. Outbreak of pneumonia of unknown etiology in Wuhan, China: the mystery and the miracle. J Med Virol 2020, 92, 401–402.

Lai, C.C.; Shih, T.P.; Ko, W.C.; Tang, H.J. Hsueh P.R. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges. Int. J. Antimicrob. Agents 2020, 55.

McCloskey, B.; Heymann, D.L. SARS to novel coronavirus: old lessons and new lessons. Epidemiol. Infect 2020, 22, e22

Wilder-Smith, A.; Chiew, C.J.; Lee, V.J. Can we contain the COVID-19 outbreak with the same measures as for SARS? Lancet Infect. Dis 2020, doi: 10.1016/S1473-3099(20)30129-8.

Vincent, MJ; Bergeron, E.; Benjannet, S.; et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005, 2(69), 1-10. doi:10.1186/1743-422X-2-69

Savarino, A.; Boelaert, JR.; Cassone, A.; Majori, G.; Cauda, R. Effects of chloroquine on viral infections: an old drug against today’s diseases? Lancet Infect Dis 2003, 3(11), 722-727.

Gao, J.; Tian, Z.; Yang, X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 2020, 14, 72 -73

Colson, P.; Rolain, J.M.; Lagier, J.C.; Brouqui, P.; Raoult, D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents 2020, 105932

Zhou, D.; Dai, S.M.; Tong, Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J Antimicrob Chemother. 2020.

Su, S.G.; Wong, W.; Shi, et al. Epidemiology, Genetic recombination, and pathogenesis of coronaviruses. Trends Microbiol 2016, 24, 490-502.

Chan, J.F.; To, K.K.; Tse, H.; Jin, D.Y.; Yuen, K.Y. Interspecies transmission and emergence of novel viruses: lessons from bats and birds. Trends Microbiol 2013, 21, 544-55.

Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; et al. A Novel Coronavirus from Patients with Pneumonia in China 2019. The New England journal of medicine. 2020.

Schoeman, D.; Fielding, B.C. Coronavirus envelope protein: current knowledge. Virol J 2019, 16; 69.

Gupta, M.K.; Vemula, S.; Donde, R.; Gouda, G.; Behera, L.; Vadde, R. In silico approaches to detect inhibitors of the human severe acute respiratory syndrome coronavirus envelope protein ion channel. Journal of Biomolecular Structure and Dynamics 2020,

Belouzard, S.; Chu, V.C.; Whittaker, G.R. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc. Natl. Acad. Sci. U.S.A. 106 2009, 5871, e5876,

Van Hemert, M.J.; Van Den Worm, S. H. E.; Knoops, K.; Mommaas, A. M.; Gorbalenya, A.E.; Snijder, E.J. SARS-coronavirus replication/transcription complexes are membrane-protected and need a host factor for activity in vitro. PLoS Pathogens 2008, 4(5), e1000054,

Song, H. C.; Seo, M.Y.; Stadler, K.; Yoo, B.J.; Choo, Q.L.; Coates, S.R.; Uematsu, Y.; Harada, T.; Greer, C. E.; Polo, J. M.; Pileri, P.; Eickmann, M.; Rappuoli, R.; Abrignani, S.; Houghton, M.; Han, J. H. Synthesis and characterization of a native, oligomeric form of recombinant severe acute respiratory syndrome coronavirus spike glycoprotein. Journal of Virology 2004, 78(19), 10328–10335, 2004.

Masters, P.S. The molecular biology of coronaviruses. Advances in Virus Research, 2006, 65(06),193–292.

Wrapp, D.; Wang, N.; Corbett, K.S.; Goldsmith, J.A.; Hsieh, C.L.; Abiona, O.; et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science (New York, NY) 2020.

Huang, Q.; Herrmann, A. Fast assessment of human receptor binding capability of 2019 novel coronavirus (2019-nCoV). Preprint. Posted online February 04, 2020. bioRxiv 930537.

Coutard, B.; Valle, C.; de Lamballerie, X.; Canard, B.; Seidah, N.G.; Decroly, E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res 2020, 176, 104742,

Jacques, F.; Coralie, D.S.; Henri, C.; Nouara Y. Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection, International Journal of Antimicrobial Agents 2020, doi:

Mason, R.J. Pathogenesis of COVID-19 from a cell biology perspective. Eur Respir J 2020, 55, 2000607 [].

Wan Y.; Shang J.; Graham, R.; et al. Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS. J Virol 2020, 94, e00127-20.

Tang, N.L.; Chan, P.K.; Wong, C.K.; et al. Early enhanced expression of interferon-inducible protein-10 (CXCL-10) and other chemokines predicts adverse outcome in severe acute respiratory syndrome. Clin Chem 2005, 51, 2333–2340.

Hancock, A.S.; Stairikerm, C.J.; Boesteanu, A.C.; et al. Transcriptome analysis of infected and bystander type 2 alveolar epithelial cells during influenza A virus infection reveals in vivo Wnt pathway downregulation. J Virol 2018, 92, e01325-18.

Mossel, E.C.; Wang, J.; Jeffers, S.; et al. SARS-CoV replicates in primary human alveolar type II cell cultures but not in type I-like cells. Virology 2008, 372, 127–135.

Janeway, C.A.; Travers, P.; Walport, M.; Shlomchik, M. J. Immunobiology (5th ed.). New York and London: Garland Science. 2001, ISBN 0-8153-4101-6.

Parkin, J.; Cohen, B. An overview of the immune system. Lancet 2001, 357, 1777-89.

Stranford, Sharon A.; Jones, Patricia P.; Owen, J.A. (Eighth ed.). New York. Kuby immunology 1992, ISBN 978-1-4641-8978-4. OCLC 1002672752.

Huston, D.P. The biology of the immune system. JAMA 1997, 278, 1804–1814. [PubMed: 9396641]

Bretscher, P.; and Cohn, M. A theory of nonself discrimination. Science (Wash.D. C.) 1970, 169, 1042.

Delves, P.J.; Roitt, D.; The Immune System – First of two parts. N Engl J Med 2000, 343, 37-50.

Fengyan, Yu.; Herui, Yao.; Pengcheng, Zhu.; Xiaoqin, Zhang.; Qiuhui, Pan.; Chang, Gong.; Yijun Huang.; Xiaoqu, Hu.; Fengxi, Su.; Judy, Lieberman.; Erwei, Song. Let-7 Regulates Self Renewal and Tumorigenicity of Breast Cancer Cells. Cell 2007, l 131, 1109–1123.

Kaminski, NE.; Faubert, K.B.L.; Holsapple, M.P. Toxic responses of the immune system. In: Casarett and Doull’s Toxicology. The Basic Science of Poisons. Edited by Klassen C.D. Seventh Edition, McGraw-Hill Medical Publishing Division, USA 2008; 485-556.

Elgert, K.D. Immunology: Understanding the Immune System. Blacksburg, VA: Virginia Tech Biology Department 1994, 1-418.

Tizard, I. Veterinary Immunology. Philadelphia, PA: W.B. Saunders Co. 1997, 5(1)-175.

Janeway, C.A.; Medzhitov, R. Innate immunity recognition. Annu Rev Immunol 2002, 20, 197-216.

Medzhitov, R.; Jane way, C. Jr. Innate immune recognition: Mechanisms and pathways. Immunol Rev 2000a, 173, 89-97.

Bals R. Epithelial antimicrobial peptides in host defense against infection. Respir Res 2000, 1, 141-150

Fellermann, K.; Stange, E.F. Defensins—Innate immunity at the epithelial frontier. Eur J Gastroenterol Hepatol 2001, 13, 771-776.

Stone, K.D.; Prussin, C.; Metcalfe, D.D. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 2010, 125 (Suppl 2), S73–80.

Cooper, M.A, Colonna, M.; Yokoyama, W.M. Hidden talents of natural killers: NK cells in innate and adaptive immunity. EMBO Rep 2009, 10, 1103–1110, [PubMed: 19730434].

Soudja, S. M. H.; Chandrabos, C.; Yakob, E.; Veenstra, M.; Palliser, D.; Lauvau, G. Memory-T-Cell-Derived Interferon-? Instructs Potent Innate Cell Activation for Protective Immunity". Immunity 2014, 40 (6), 974–988.

Hoffmann, J. A.; Kafatos, F.C.; Janeway, C. A.; Ezekowitz, R.A. Phylogenetic Perspectives in Innate Immunity. Sci 1999, 284,

Turvey, S.E.; Broide, D.H. Innate immunity. J Allergy Clin Immunol 2010, 125(Suppl 2), S24–32.

Colloquium on Clinical Immunology, 1982

Diefenbach, A.; Raulet, D.H. Innate immune recognition by stimulatory immunoreceptors. Curr Opin Immunol 2003, 15, 37-44.

Gallucci, S.; Matzinger, P. Danger signals: SOS to the immune system. Curr Opin Immunol 2001, 13, 114-119.

Gordon, S. Pattern recognition receptors: Doubling up for the innate immune response. Cell 2002,111, 927–930.

Beutler, L.E.; Clarkin, J.F.; Bongar, B. Guidelines for the systematic treatment of the depressed patient. New York: Oxford University Press 2000.

Fraser C.M.; Norris, S.J.; Weinstock, G.M.; White, O.; Sutton, G.G.; Dodson, R.; Gwinn, M.; Hickey, E.K.; Clayton, R.; Ketchum, K.A.; Complete genome sequence of Treponema pallidum, the syphilis spirochete. Science 1998, 281, 375-388.

Medzhitov, R.; Janeway, C.Jr. The Toll receptor family and microbial recognition. Trends Microbiol 2000b, 8, 452-456.

Shizuo, Akira; Kiyoshi, Takeda; Tsuneyasu, Kaisho. Toll-like Receptors: Critical Proteins Linking Innate and Acquired Immunity. Nat. Immuno 2001.

Vasselon, T.; Hanlon, W.A.; Wright, S.D.; Detmers, P.A. Toll-like receptor 2 (TLR2) mediates activation of stress-activated MAP kinase p38. J. Leukoc. Biol 2002.

Stahl, P.D.; Ezekowitz, R.A. The mannose receptor is a pattern recognition receptor involved in host defense. Curr Opin Immunol 1998, 10:50-55.

Barrington, R.; Zhang, M.; Fischer, M.; Carroll, M.C. The role of complement in inflammation and adaptive immunity. Immunol Rev 2001, 180, 5-15.

Borrow P. Mechanisms of viral clearance and persistence. J Viral Hepat 1997, 4, (Suppl 2), 16-24.

Grey, H.M.; Chestnut, R. Antigen processing and presentation to T cells. Immunology Today 1985, 6(3), 101-106.

Medzhitov, R.; Janeway, C.A.Jr. Innate immune induction of the adaptive immune response. Cold Spring Harb Symp Quant Biol 1999, 64, 429-435.

Murphy, K.M.; Travers, P.; Walport, M. Janeway’s immunobiology. 7th ed. New York: Garland Science 2007.

Alberts, B.; et al. The Adaptive Immune System. In Molecular Biology of the Cell. New York: Garland Science 2002. Accessed August 2, 2018.

Bonilla, F.A.; Oettgen, H.C. Adaptive immunity. J Allergy Clin Immunol 2010, 125(Suppl 2), S33–40.

Craft, J. The adaptive immune system. In: Goldman L, Schafer AI, eds. Goldman-Cecil Medicine. 25th ed. Philadelphia, PA: Elsevier Saunders, 2016, 46.

Den, Haan; Joke, M.M.; Arens, Ramon; Zelm, Menno; Van, C. The activation of the adaptive immune system: Cross-talk between antigen-presenting cells, T cells and B cells". Immunology Letters 2014, 162 (2), 103–112. Doi:10.1016/j.imlet.2014.10.011. PMID 25455596.

Knight, S.C.; Stagg, A.J. Antigen-presenting cell types. Curr Opin Immunol 1993, 5, 374-382.

Blum, J.S.; Ma, C.; Kovats, S. Antigen-presenting cells and the selection of immunodominant epitopes. Crit Rev Immunol 1997, 17, 411-417.

Blackwell, J, M.; Jamieson, S.E.; Burgner, D. HLA and infectious diseases. Clin Microbiol Rev 2009; 22:370–85.

Medzhitov, R.; Janeway, C. Jr. The Toll receptor family and microbial recognition. Trends Microbiol 2000b, 8, 452-456.

Burnet, F.M. The Clonal Selection Theory of Acquired Immunity. Cambridge: Cambridge University Press 1959.

Crotty, S.; Ahmed, R. Immunological memory in humans. Semin Immunol 2004, 16, 197-203.

Mbongue, Jacques; Nicholas, Dequina; Firek, Anthony; Langridge, William. The Role of Dendritic Cells in Tissue-Specific Autoimmunity". Journal of Immunology 2014, 04, 30.

Le Bon, A.; Tough, D.F. Links between innate and adaptive immunity via type I interferon. Curr Opin Immunol 2002, 14, 432-436.

Bedoui, S.; Gebhardt, T.; Gasteiger, G.; Kastenmuller, W. Parallels and differences between innate and adaptive lymphocytes. Nat Immunol 2016, 17, 490–494.

Unanue, E.R. Antigen-presenting function of the macrophage. Annual Review of Immunology 1984, 2, 395-428.

Borrow, P.; Shaw, G.M. Cytotoxic T-lymphocyte escape viral variants: How important are they in viral evasion of immune clearance in vivo? Immunol Rev 1998, 164:37-51.

Holtmeier, W.; Kabelitz, D. Gamma delta T cells link innate and adaptive immune responses. Chem Immunol Allergy 2005, 86, 151- 83.

Stutman, O. Intra thymic and extrathymic T cell maturation. Immunol Rev 1978, 42, 138-84.

Townsend, A.; Bodmer, H. Antigen recognition by class I-restricted T lymphocytes. Annual Review of Immunology 1989; 7, 601-624

Tangye, S.G.; Tarlinton, D.M. Memory B cells: effectors of long-lived immune responses. Eur J Immunol 2009, 39, 2065–2075. [PubMed: 19637202].

Jiang, H.; Chess, L. An integrated view of suppressor T cell subsets in immunoregulation. J Clin Invest 2004, 114(9), 1198-208.

Wing, K.; Sakaguchi, S. Regulatory T cells exert checks and balances on self-tolerance and autoimmunity. Nat Immunol 2010, 11, 7–13.

Bhagavan, N.V.; Chung-Eun, Ha. In Essentials of Medical Biochemistry 2011.

Germain, R.N. MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell 1994, 76, 287-99.

Sonderstrup, G.; McDevitt HO, D.R.; DQ, and you. MHC alleles and autoimmunity. J Clin Invest 2001, 107,795–796, [PubMed: 11285296].

Zinkernagel, R.M.; Doherty, P.C. MHC-restricted cytotoxic T cells: Studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness. Adv Immunol 1979, 27, 51-177.

Konig, R.; Fleury, S.; Germain, R.N. The structural basis of CD4-MHC class II interactions: Co-receptor contributions to T cell receptor antigen recognition and oligomerization-dependent signal transduction. Curr Top Microbiol Immunol 1996, 205, 19–46. [PubMed: 8575196].

Hunter, C.A.; Reiner, S.L. Cytokines and T cells in host defense. Curr Opin Immunol 2000, 12, 413-418.

Van Kaer, L. Accessory proteins that control the assembly of MHC molecules with peptides. Immunol Res 2001, 23, 205–214, [PubMed: 11444385].

Croft, M.; Carter, L.; Swain, S.L.; Dutton, R.W. Generation of polarized antigen-specific CD8 effector populations: reciprocal action of interleukin (IL)-4 and IL-12 in promoting type 2 versus type 1 cytokine profiles. J Exp Med, 1994, 180: 1715–1728.

Atkinson, E.A.; Bleackley, RC. Mechanisms of lysis by cytotoxic T cells. Crit Rev Immunol 1995, 15, 359-384.

Rudin, C.M.; Thompson, C.B. B-Cell Development and Maturation. Seminar in Oncology 1998, 25(4), 435-46.

McHeyzer-W.; M.G. B cells as effectors. Curr Opin Immunol 2003, 15(3), 354-61.

Gray, D. A role for antigen in the maintenance of immunological memory. Nat Rev Immunol 2002, 2:60-65.

Larsson, Lars-Inge. Immunocytochemistry: Theory and practice. Crc Press 1988, 1, ISBN 0-8493-6078-1.

Flanagan, R.J.; Jones A.L. Fab antibody fragments: some applications in clinical toxicology. Drug Saf 2004, 27 (14), 1115–1133. Doi: 10.2165/00002018-200427140-00004. PMID 15554746.

Finkelman, F.D.; Holmes, J.; Katona, I.M.; Urban, J.F.; Jr.; Beckman, M.P.; Schooley, K.A.;Coffman, R.L.; Mosmann, T.R.; Paul, W.E.; Lymphokine control of in vivo immunoglobulin isotype selection. Annu.Rev.Immunol 1990, 8, 303.

Pulendran, B.; Palucka, K.; Banchereau, J. Sensing pathogens and tuning immune responses. Science 2001, 293, 253-256.

Schroeder, H.W.; Cavacini, L. Structure and function of immunoglobulins. J Allergy Clin Immunol, 2010, 125 (Suppl 2), S41–52.

Abbas, A.K.; Lichtman, A.H.; Pillai, S. Cellular and Molecular Immunology, 6a ed, Editora Saunders 2007.

Vojdani, A.; Erde, J. Regulatory T cells, a potential immunoregulatory target for CAM researchers: Modulating tumor immunity, autoimmunity and alloreactive immunity (III). Evid Based Complement Alternat Med (eCAm) 2006, 3, 309-316.

Janeway, C.A.; and Jr. The Humoral Immune Response.” Immunobiology: The Immune System in Health and Disease. 5th edition. U.S. National Library of Medicine, 1970, Available here. Accessed 20 Sept. 2017.

Mills, C.D.; Kincaid K.; Alt, J.M.; Heilman, M.J.; Hill, A.M. M-1/M-2 Macrophages and the Th1/Th2 Paradigm. J. Immunol. 2000, 164, 6166–6173, doi: 10.4049/jimmunol.164.12.6166.

Smith, JA. Neutrophils, host defense, and inflammation: a double-edged sword. J Leukoc Biol, 1994, 56, 672–86.

Kita H. The eosinophils: a cytokine-producing cells? J Allergy Clin Immunol 1996, 97, 889–892.

Galli, S.J. Mast cells and basophils. Curr Opin Hematol, 2000, 7, 32-39.

Amin, K.; Ludviksdottir, D.C.; Janson, O.; Nettelbladt, E.; Bjornsson, G.M.; Roomans, G.; Boman, L.; Seveus, P. Venge Inflammation and structural changes in the airways of patients with atopic and nonatopic asthma. BHR group Am J Respir Crit Care Med, 2000, 162, 2295-2301.

Gershon, RK.; Kondo K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology 1970, 18, 723–37.

Saha, P.; Geissmann, F. Toward a functional characterization of blood monocytes. Immunol Cell Biol 2010; 89, 2–4.

Carrega, P.; Ferlazzo, G. Natural killer cell distribution and trafficking in human tissues. Front Immunol 2012, 3, 347. Doi: 10.3389/fimmu 2012, 00347.

Spits, H: Development of alpha beta T cells in the human thymus. Nat Rev Immunol 2002, 2: 760-772.

Hardy, R.R.; Hayakawa, K. B. Cell development pathways. Annu Rev Immunol 2001, 19, 595–621. 10.1146/annurev.immunol.19.1.595.

Jia, Liu.; Ruiyuan, Cao.; Mingyue, Xu.; Xi, Wang.; Huanyu, Zhang.; et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery 2020, 6, 16.

Xu, H.; et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int. J. Oral. Sci 2020, 12, 8.

Hamming, I.; et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J. Pathol 2004, 203, 631–637.

Zhou, P.; et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020, 579, 270–273.

Zhao, Y.; et al. Single- cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019- nCov. Preprint at bioRxiv 2020,

Walls, A. C.; et al. Structure, function, and antigenicity of the SARS- CoV-2 spike glycoprotein. Cell 2020.

Jacobs, R.F.; Tabor, D.R.; Burks, A.W.; Campbell, G.D. Elevated interleukin-1 release by human alveolar macrophages during the adult respiratory distress syndrome. Am. Rev. Respir. Dis 1989. 140, 1686–1692.

Pison, U.; Brand, M.; Joka, T.; Obertacke, U.; Bruch. J. Distribution and function of alveolar cells in multiply injured patients with trauma induced ARDS. Intensive Care Med, 1988, 14, 602–609.

Kuipers, M.T.; van der Poll, T.; Schultz, M.J.; Wieland C.W. Benchto- bedside review: Damage-associated molecular patterns in the onset of ventilator-induced lung injury. Crit. Care 2011, 15:235.

Diebold, S.S.; Kaisho, T.; Hemmi, H.; Akira, S.; Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single stranded RNA. Science 2004, 303, 1529–1531.

Imai, Y.; Kuba, K.; Neely, G.G.; Yaghubian-Malhami, R.; Perkmann, T.; van Loo, G.; Ermolaeva, M.; Veldhuizen, R.; Leung, Y.H.; Wang, H.; et al. 2008. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 2008,133, 235–249.

Medzhitov, R.; Preston-H.P.; Janeway, C.A.; J.r. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature, 1997, 388, 394-7.

Martinon, F.; Burns, K.; Tschopp, J.; The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell 2002, 10, 417–426.

Zhang, B.; et al. Clinical characteristics of 82 death cases with COVID-19. Preprint at medRxiv 2020, https://doi. org/10.1101/2020.02.26.20028191

Wen, W.; Su, W.; Tang, H.; Le, W.; Zhang, X.; Zheng, Y.; Liu, X.; Xie, L.; Li, J.; Ye, J.; et al. Immune Cell Profiling of COVID-19 Patients in the Recovery Stage by Single-Cell Sequencing. medRxiv 2020, 2020.03.23.20039362.

Tian, S.; et al. Pulmonary pathology of early phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer. J. Thorac. Oncol 2020.

Harker, J.A.; Lewis, G.M.; Mack, L.; Zuniga. E.I. Late interleukin-6 escalates T follicular helper cell responses and controls a chronic viral infection. Science 2011.334:825–829.

Chen, L.; Liu, H.G.; Liu, W.; Liu, J.; Liu, K.; Shang, J.; et al. Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi, 2020, 43, 203–8.

Grupp, S.A.; Kalos, M.; Barrett, D.; Aplenc, R.; Porter, D.L.; Rheingold, S.R.; Teachey, D.T.; Chew, A.; Hauck, B.; Wright, J.F. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med 2013. 368:1509–1518.

Mehta, P.; McAuley, D.F.; Brown, M.; Sanchez, E.; Tattersall, R.S.; Manson, J.J. Hlh Across Speciality Collaboration, U. K. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020, 395, 1033–1034.

Diao, B.; Wang, C.; Wang, R.; Feng, Y.; Tan, Z.; Wang, H.; Wang, C.; Liu, L.; Liu, Y.; Liu, Y.; et al. Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection. medRxiv 2020b.

Yao, X.; Ye, F.; Zhang, M.; Cui, C.; Huang, B.; Niu, P.; et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020.

Ahmed, R.; Salmi, A.; Butler, L.D.; Chiller, J.M.; Oldstone, M.B. Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J. Exp. Med 1984,160, 521–540.

Wong, R.S.; et al. Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis. BMJ 2003, 326, 1358–1362.

Cui, W.; et al. Expression of lymphocytes and lymphocyte subsets in patients with severe acute respiratory syndrome. Clin. Infect. Dis 2003, 37, 857–859.

Li, T.; et al. Significant changes of peripheral T lymphocyte subsets in patients with severe acute respiratory syndrome. J. Infect. Dis 2004, 189, 648–651.

Zheng, H. Y.; et al. Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients. Cell. Mol. Immunol 2020.

Thevarajan, I. et al. Breadth of concomitant immune responses prior to patient recovery: a case report of non- severe COVID-19. Nat. Med 2020.

Nie, Y.; et al. Neutralizing antibodies in patients with severe acute respiratory syndrome- associated coronavirus infection. J. Infect. Dis 2004, 190, 1119–1126.

Temperton, N. J.; et al. Longitudinally profiling neutralizing antibody response to SARS coronavirus with pseudotypes. Emerg. Infect. Dis 2005, 11, 411–416.

Haveri, A.; Smura, T.; Kuivanen, S.; Österlund, P.; Hepojoki, J.; Ikonen, N.; Pitkäpaasi, M.; Blomqvist, S.; Rönkkö, E.; Kantele, A.; et al. Serological and molecular findings during SARS-CoV-2 infection: the first case study in Finland, January to February. Eurosurveillance, 2020, 25, 2000266.

Lou, B.; Li, T.; Zheng, S.; Su, Y.; Li, Z.; Liu, W.; Yu, F.; Ge, S.; Zou, Q.; Yuan, Q.; et al. Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset. medRxiv 2020, 2020.03.23.20041707.

Okba, N.M.A.; Muller, M.A.; Li, W.; Wang, C.; Geurtsvan, K.C.H.; Corman, V.M.; Lamers, M.M.; Sikkema, R.S.; de Bruin, E.; Chandler, F.D.; et al. Severe Acute Respiratory Syndrome Coronavirus 2-Specific Antibody Responses in Coronavirus Disease 2019 Patients. Emerg. Infect. Dis 2020, 26.

Tan, W.; Lu, Y.; Zhang, J.; Wang, J.; Dan, Y.; Tan, Z.; He, X.; Qian, C.; Sun, Q.; Hu, Q.; et al. Viral Kinetics and Antibody Responses in Patients with COVID-19. medRxiv 2020b, 2020.03.24.20042382.

Wölfel, R.; Corman, V.M.; Guggemos, W.; Seilmaier, M.; Zange, S.; Müller, M.A.; Niemeyer, D.; Jones, T.C.; Vollmar, P.; Rothe, C.; et al. Virological assessment of hospitalized patients with COVID-2019. Nature 2020.

Wu, F.; Wang, A.; Liu, M.; Wang, Q.; Chen, J.; Xia, S.; Ling, Y.; Zhang, Y.; Xun, J.; Lu, L.; et al. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. medRxiv 2020b. 2020.03.30.20047365.

Zhao, J.; Yuan, Q.; Wang, H.; Liu, W.; Liao, X.; Su, Y.; Wang, X.; Yuan, J.; Li, T.; Li, J.; et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin. Infect. Dis. 2020a.

Amanat, F.; Nguyen, T.; Chromikova, V.; Strohmeier, S.; Stadlbauer, D.; Javier, A.; Jiang, K.; Asthagiri-Arunkumar, G.; Polanco, J.; Bermudez-Gonzalez, M.; et al. A serological assay to detect SARSCoV-2 seroconversion in humans. medRxiv 2020, 2020.03.17.20037713.

Ju, B.; Zhang, Q.; Ge, X.; Wang, R.; Yu, J.; Shan, S.; Zhou, B.; Song, S.; Tang, X.; Yu, J.; et al. Potent human neutralizing antibodies elicited by SARS-CoV-2 infection. bioRxiv 2020, 2020.03.21.990770.

To, K.K.W.; Tsang, O.T.Y.; Leung, W.S.; Tam, A.R.; Wu, T.C.; Lung, D.C.; Yip, C.C. Y.; Cai, J.P.; Chan, J.M.C.; Chik, T.S.H.; et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect. Dis 2020.

Browning, D.J. Hydroxychloroquine and chloroquine retinopathy. Springer 2014. [ISBN:9781493905973].

Jia, Liu.; Ruiyuan, Cao.; Mingyue, Xu.; Xi, Wang.; Huanyu, Zhang.; et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery 2020, 6:16.

Devaux, CA.; Rolain, J.M.; Colson, P.; Raoult, D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents 2020 11:105938.

Circu, M.; et al. Modulating lysosomal function through lysosome membrane permeabilization or autophagy suppression restores sensitivity to cisplatin in refractory non- small-cell lung cancer cells. PLoS One 2017, 12, e0184922.

Mauthe, M.; et al. Chloroquine inhibits autophagic flux by decreasing autophagosome- lysosome fusion. Autophagy, 2018, 14, 1435–1455.

Frustaci, A.; et al. Inhibition of cardiomyocyte lysosomal activity in hydroxychloroquine cardiomyopathy. Int. J. Cardiol 2012, 157, 117–119.

Sundelin, S.P.; Terman, A. Different effects of chloroquine and hydroxychloroquine on lysosomal function in cultured retinal pigment epithelial cells. APMIS 2002,110, 481–489.

Ballabio, A.; Bonifacino J.S. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat. Rev. Mol. Cell Biol 2019, 21, 101–118.

Lotteau, V.; et al. Intracellular transport of class II MHC molecules directed by invariant chain. Nature 1990, 348, 600–605.

Ghislat, G.; Lawrence, T. Autophagy in dendritic cells. Cell Mol. Immunol, 2018, 15, 944–952.

Munz, C. Autophagy beyond intracellular MHC class II antigen presentation. Trends Immunol. 2016, 37, 755–763.

Ireland, J.M.; Unanue, E.R. Autophagy in antigen- presenting cells results in presentation of citrullinated peptides to CD4 T cells. J. Exp. Med 2011, 208, 2625–2632.

Ohkuma, S.; Poole, B. Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proc. Natl Acad. Sci. USA 1978, 75, 3327–3331.

Rebecca, V.W.; et al. PPT1 promotes tumor growth and is the molecular target of chloroquine derivatives in cancer. Cancer Discov 2019, 9, 220–229.

Ma, C.; et al. Identifying key genes in rheumatoid arthritis by weighted gene co- expression network analysis. Int. J. Rheum. Dis 2017, 20, 971–979.

Ewald, S.E.; et al. The ectodomain of Toll- like receptor 9 is cleaved to generate a functional receptor. Nature 2008, 456, 658–662.

Kuznik, A.; et al. Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J. Immunol 2011, 186, 4794–4804.

Hacker, H.; et al. CpG- DNA-specific activation of antigen- presenting cells requires stress kinase activity and is preceded by non- specific endocytosis and endosomal maturation. EMBO J 1998, 17, 6230–6240.

Lau, C.M.; et al. RNA- associated autoantigens activate B cells by combined B cell antigen receptor/Toll- like receptor 7 engagement. J. Exp. Med 2005, 202, 1171–1177.

Vollmer, J.; et al. Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll- like receptors 7 and 8. J. Exp. Med 2005, 202, 1575–1585.

An, J.; et al. Antimalarial drugs as immune modulators: new mechanisms for old drugs. Annu. Rev. Med 2017, 68, 317–330.

Zhang, X.; et al. The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch- like conformational changes in the activation loop. Cell Rep 2014, 6, 421–430.

Zhang, X.; et al. Cyclic GMP- AMP containing mixed phosphodiester linkages is an endogenous high- affinity ligand for STING. Mol. Cell 2013, 51, 226–235.

Shu, C.; Li, X.; Li, P. The mechanism of double- stranded DNA sensing through the cGAS- STING pathway. Cytokine Growth Factor Rev 2014, 25, 641–648.

An, J.; et al. Cutting edge: antimalarial drugs inhibit IFN- ? production through blockade of cyclic GMP- AMP synthase- DNA interaction. J. Immunol 2015, 194, 4089–4093.

Van den Borne, B.E.; et al. Chloroquine and hydroxychloroquine equally affect tumor necrosis factor- alpha, interleukin 6, and interferon- gamma production by peripheral blood mononuclear cells. J. Rheumatol 1997, 24, 55–60.

Wallace, D.J.; et al. The effect of hydroxychloroquine therapy on serum levels of immunoregulatory molecules in patients with systemic lupus erythematosus. J. Rheumatol 1994, 21, 375–376.

Wallace, D.J.; et al. The relevance of antimalarial therapy with regard to thrombosis, hypercholesterolemia and cytokines in SLE. Lupus 1993, 2, S13–S15.

Hjorton, K.; et al. Cytokine production by activated plasmacytoid dendritic cells and natural killer cells is suppressed by an IRAK4 inhibitor. Arthritis Res. Ther 2018, 20, 238.

Willis, R.; et al. Effect of hydroxychloroquine treatment on pro- inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multi ethnic US cohort. Lupus 21, 2012, 830–835.

Klinefelter, H. F.; Achurra, A. Effect of gold salts and antimalarials on the rheumatoid factor in rheumatoid arthritis. Scand. J. Rheumatol 1973, 2, 177–182.

Dixon, J.S.; et al. Biochemical indices of response to hydroxychloroquine and sodium aurothiomalate in rheumatoid arthritis. Ann. Rheum 1981, 40, 480–488.

Wu, S. F.; et al. Hydroxychloroquine inhibits CD154 expression in CD4(+) T lymphocytes of systemic lupus erythematosus through NFAT, but not STAT5, signalling. Arthritis Res. Ther 2017,19, 183.

Qushmaq, N. A.; Al- Emadi, S.A. Review on effectiveness of primary prophylaxis in aPLs with and without risk factors for thrombosis: efficacy and safety. ISRN Rheumatol 2014, 348726.

Nuri, E.; et al. Long- term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol. Res 2017, 65, 17–24.

Dadoun, S.; et al. Mortality in rheumatoid arthritis over the last fifty years: systematic review and meta- analysis. Joint Bone Spine. 2013, 80, 29–33.

Van den Hoek, J.; et al. Mortality in patients with rheumatoid arthritis: a 15-year prospective cohort study. Rheumatol. Int 2017, 37, 487–493.

Avina- Zubieta, J. A.; et al. Risk of myocardial infarction and stroke in newly diagnosed systemic lupus erythematosus: a general population-based study. Arthritis Care Res 2017, 69, 849–856.

Tselios, K.; Gladman, D.D.; Su, J.; Ace, O.; Urowitz, M.B. Evolution of risk factors for atherosclerotic cardiovascular events in systemic lupus erythematosus: a long-term prospective study. J. Rheumatol 2017, 44,1841–1849.

Padol, I. T.; Hunt, R.H. Association of myocardial infarctions with COX-2 inhibition may be related to immunomodulation towards a Th1 response resulting in atheromatous plaque instability: an evidence- based interpretation. Rheumatology 2010, 49, 837–843.

Hage, M.P.; Al- Badri, M.R.; Azar, S.T. A favourable effect of hydroxychloroquine on glucose and lipid metabolism beyond its anti- inflammatory role. Ther. Adv. Endocrinol. Metab. 2014, 5, 77–85.

Cansu, D.U.; Korkmaz, C. Hypoglycaemia induced by hydroxychloroquine in a non- diabetic patient treated for RA. Rheumatology 2008, 47, 378–379.

Fasano, S.; et al. Long term hydroxychloroquine therapy and low- dose aspirin may have an additive effectiveness in the primary prevention of cardiovascular events in patients with systemic lupus erythematosus. J. Rheumatol 2017,44, 1032–1038.

Towers, C.G.; Thorburn, A. Therapeutic targeting of autophagy. E.Bio.Medicine 2016, 14, 15–23.

Rand, J.H.; et al. Hydroxychloroquine directly reduces the binding of antiphospholipid antibody- ?2-glycoprotein I complexes to phospholipid bilayers. Blood 2008,112, 1687–1695.

Jancinova, V.; Nosal, R.; Petrikova, M. On the inhibitory effect of chloroquine on blood platelet aggregation. Thromb. Res 1994,74, 495–504.

Bertrand, E.; et al. Anti-aggregation action of chloroquine. Med. Trop 1990, 50, 143–146.

Nosal, R.; Jancinova, V.; Petrikova, M. Chloroquine inhibits stimulated platelets at the arachidonic acid pathway. Thromb. Res 1995, 77, 531–542.

Biot, C.; Daher, W.; Chavain, N.; Fandeur, T.; Khalife, J.; Dive, D.; et al. Design and synthesis of hydroxy ferroquine derivatives with antimalarial and antiviral activities. J Med Chem 2006, 49, 2845–9.

Laaksonen, A.L.; Koskiahde, V.; Juva, K. Dosage of antimalarial drugs for children with juvenile rheumatoid arthritis and systemic lupus erythematosus. A clinical study with determination of serum concentrations of chloroquine and hydroxychloroquine. Scand. J. rheumatol 1974, 3, 103–108.

Philippe, Gautret, Jean C.; Lagier, Philippe, P.; Van, T.H.; Line, M.; et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open label non-randomized clinical trial. Journal of Antimicrobial agents 2020.

Awadhesh, K.S.; Akriti, S.; Altamash, S.; Ritu, S.; Anoop M. Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 2020, 14:241-246.

Rolain, J.M.; Colson, P.; Raoult, D. Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century. Int J Antimicrob Agents 2007, 30 (4), 297–308.

Mingo, R.M.; et al. Ebola virus and severe acute respiratory syndrome coronavirus display late cell entry kinetics: evidence that transport to NPC1+ endo lysosomes is a rate-defining step. J. Virol. 2015,89, 2931–2943.

Schrezenmeier, E.; Dorner, T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 2020, 16:155–66.

Al-Bari, M.A. Chloroquine analogues in drug discovery: New directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. J. Antimicrob. Chemother. 2015, 70, 1608–1621.

US Food and Drug Administration (FDA). Emergency use authorization: Therapeutics. Maryland: FDA, 2020 (accessed 6 April 2020).

Treatment of COVID-19: Hydroxychloroquine and Chloroquine. Reports from the Congressional Research Service 2020.

European Medicines Agency, 2020. EMA/170590/2020.

Indian council of medical research. Department of health research Ministry of health and family welfare government of India. D.O.No.VIR/4/2020/ECD-1.

Therapeutic Goods Administration. New restrictions on prescribing hydroxychloroquine for COVID-19. Canberra: Australian Government Department of Health, 2020.