Funder: National Key R&D Program of China (2018YFA0107500), Suzhou 2020 Emergency Innovation Funding on COVID-19 Infection, the National Natural Science Foundation of China (81530043, 81861138015, 31771641 and 81571612)Funder: Italian Ministry of Healt

Bucci, Enrico

Gan, Jianhe

Huang, Jianan

Huang, Xiaoping

Ippolito, Giuseppe

Melino, Gerry

Piacentini, Mauro

Shao, Changshun

Shi, Yufang

Wang, Ying

Apollo (Cambridge)

Cell Death & Differentiation (2020) 27:1451–1454https://doi.org/10.1038/s41418-020-0530-3EDITORIALCOVID-19 infection: the perspectives on immune responsesYufang Shi1,2 ● Ying Wang2 ● Changshun Shao 1 ● Jianan Huang1 ● Jianhe Gan1 ● Xiaoping Huang1 ●Enrico Bucci 3,4 ● Mauro Piacentini5 ● Giuseppe Ippolito5 ● Gerry Melino6,7Received: 1 March 2020 / Revised: 10 March 2020 / Accepted: 10 March 2020 / Published online: 23 March 2020© ADMC Associazione Differenziamento e Morte Cellulare 2020More than 100 years since the outbreak of the 1918 influ-enza pandemic, we now seem to face another pandemic.The outbreak of the new coronavirus (SARS-CoV-2)infection is spreading to every continent, forcing us to livewith this virus for perhaps a long time. Scientists andclinicians have learned much of coronavirus disease 2019,COVID-19, and its pathogenesis [1]: not all people exposedto SARS-CoV-2 are infected and not all infected patientsdevelop severe respiratory illness. Accordingly, SARS-CoV-2 infection can be roughly divided into three stages:stage I, an asymptomatic incubation period with or withoutdetectable virus; stage II, non-severe symptomatic periodwith the presence of virus; stage III, severe respiratorysymptomatic stage with high viral load [2]. From the pointof view of prevention, individuals at stage I, the stealthcarriers, are the least manageable because, at least on someoccasions, they spread the virus unknowingly: indeed, thefirst asymptomatic transmission has been reported in Ger-many [3]. The role of asymptomatic SARS-CoV-2 infectedindividuals in disseminating the infection remains to bedefined.Among over 1000 patients analyzed in Wuhan, exceptoccasionally in children and adolescence, it infects all theother age groups evenly. About 15% of the confirmed casesprogress to the severe phase, although there is a higher chancefor patients over 65 to progress into the severe phase [1]. Oneof the biggest unanswered questions is why some developsevere disease, whilst others do not. Clearly, the conventionalwisdom based on overall immunity of the infected patientscannot explain this broad spectrum in disease presentation.Two-phase immune responses induced byCOVID-19 infectionClinically, the immune responses induced by SARS-CoV-2infection are two phased. During the incubation and non-severe stages, a specific adaptive immune response isrequired to eliminate the virus and to preclude diseaseprogression to severe stages. Therefore, strategies to boostimmune responses (anti-sera or pegylated IFNα) at thisstage are certainly important. For the development of anendogenous protective immune response at the incubationand non-severe stages, the host should be in good generalhealth and an appropriate genetic background (e.g. HLA)that elicits specific antiviral immunity. Genetic differencesare well-known to contribute to individual variations in theimmune response to pathogens. However, when a protectiveimmune response is impaired, virus will propagate andmassive destruction of the affected tissues will occur,especially in organs that have high ACE2 expression, suchas intestine and kidney. The damaged cells induce innateinflammation in the lungs that is largely mediated by pro-inflammatory macrophages and granulocytes. Lunginflammation is the main cause of life-threatening respira-tory disorders at the severe stage [4]. Therefore, goodgeneral health may not be advantageous for patients whohave advanced to the severe stage: once severe lung damage* Yufang Shiyfshi@suda.edu.cn1 The First Affiliated Hospital of Soochow University, State KeyLaboratory of Radiation Medicine and Protection, Institutes forTranslational Medicine, Soochow University Medical College,Suzhou, China2 Shanghai Institute of Nutrition and Health, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 YueyangRoad, Shanghai 200031, China3 Sbarro Health Research Organization, Temple University,Philadelphia, PA 19122, USA4 Resis Srl, 10010 Samone, TO, Italy5 National Institute for Infectious Diseases ‘Lazzaro Spallanzani”IRCCS, 00149 Rome, Italy6 Department of Experimental Medicine, TOR, University of RomeTor Vergata, 00133 Rome, Italy7 Medical Research Council (MRC) Toxicology Unit, University ofCambridge, Cambridge CB2 1QP, UK1234567890();,:1234567890();,:occurs, efforts should be made to suppress inflammationand to manage the symptoms.Alarmingly, after discharge from hospital, some patientsremain/return viral positive and others even relapse. Thisindicates that a virus-eliminating immune response toSARS-CoV-2 may be difficult to induce at least in somepatients and vaccines may not work in these individuals.Those recovered from the non-severe stage should bemonitored for the virus together with T/B cell responses.These scenarios should be considered when determining thestrategies of vaccine development. In addition, there aremany types or subtypes of coronavirus. Thus, if vaccinesdirectly targeting SARS-CoV-2 prove to be difficult todevelop, the Edward Jenner approach should be considered.Cytokine storm and lung damageThe cytokine release syndrome (CRS) seems to affect patientswith severe conditions. Since lymphocytopenia is often seen insevere COVID-19 patients, the CRS caused by SARS-CoV-2virus has to be mediated by leukocytes other than T cells, as inpatients receiving CAR-T therapy; a high WBC-count iscommon, suggesting it, in association with lymphocytopenia,as a differential diagnostic criterion for COVID-19. In anycase, blocking IL-6 may be effective. Blocking IL-1 and TNFmay also benefit patients. Although various clinical sites inChina have announced the use of mesenchymal stromal/stemcells (MSCs) in severe cases with COVID-19 infection, solidresults have yet to be seen. One caveat is that MSCs need tobe activated by IFNγ to exert their anti-inflammatory effects,which may be absent in severely affected patients as T cellsare not well activated by SARS-CoV-2 infection. To enhanceeffectiveness, one could consider employing the “licensing-approach”: pretreat MSCs with IFNγ with/without TNF or IL-1 [5]. Such cytokine-licensed MSCs could be more effectivein the suppression of hyperactive immune response and pro-motion of tissue repair, as licensed-MSCs are effective in LPS-induced acute lung damage [6].Lung damage is a major hurdle to recovery in those severepatients. Through producing various growth factors, MSCsmay help repair of the damaged lung tissue. It is importantto mention that various studies have shown that in animalmodels with bleomycin-induced lung injury, vitamin B3(niacin or nicotinamide) is highly effective in preventinglung tissue damage [7]. It might be a wise approach tosupply this food supplement to the COVID-19 patients.HLA haplotypes and SARS-CoV-2 infectionThe major-histocompatibility-complex antigen loci (HLA)are the prototypical candidates for genetic susceptibility toinfectious diseases [8, 9]. Haplotype HLA-loci variabilityresults from selective pressure during co-evolution withpathogens. Immunologists have found that T-cell antigenreceptors, on CD4+ or CD8+ T cells recognize the con-formational structure of the antigen-binding-grove togetherwith the associated antigen peptides. Therefore, differentHLA haplotypes are associated with distinct disease sus-ceptibilities. The repertoire of the HLA molecules com-posing a haplotype determines the survival duringevolution. Accordingly, it seems advantageous to haveHLA molecules with increased binding specificities to theSARS-CoV-2 virus peptides on the cell surface of antigen-presenting cells. Indeed, the susceptibility to variousinfectious diseases such as tuberculosis, leprosy, HIV,hepatitis B, and influenza is associated with specific HLAhaplotypes. Particular murine MHC class II haplotypes areassociated with the susceptibility to influenza. In man, HLAclass I is also associated with H1N1 infections: HLA-A*11,HLA-B*35, and HLA-DRB1*10 confers susceptibility toinfluenza A(H1N1)pdm09 infection [10]. Therefore, it isimperative to study whether specific HLA loci are asso-ciated with the development of anti-SARS-CoV-2 immunityand, if so, to identify the alleles, either class I or II, thatdemonstrate induction of protective immunity. Once thedominant alleles are identified, simple detection kits can bedeveloped. Such information is critical for (1) strategicclinical management; (2) evaluation of the efficacy of vac-cination in different individuals in the general population;(3) assignment of clinical professional and managerialteams amid interactions with COVID-19 patients.Hyaluronan: a potential cause of fatalitiesThe innate immune response to tissue damage caused by thevirus could lead to acute respiratory distress syndrome(ARDS), in which respiratory failure is characterized by therapid onset of widespread inflammation in the lungs andsubsequent fatality [4]. The symptoms of ARDS patientsinclude short/rapid breathing, and cyanosis. Severe patientsadmitted to intensive care units often require mechanicalventilators and those unable to breath have to be connectedto extracorporeal membrane oxygenation (ECMO) to sup-port life [11]. CT images revealed that there are character-istic white patches called “ground glass”, containing fluid inthe lungs [2]. Recent autopsies have confirmed that thelungs are filled with clear liquid jelly, much resembling thelungs of wet drowning [4]. Although the nature of the clearjelly has yet to be determined, hyaluronan (HA) is asso-ciated with ARDS [12]; moreover, during SARS infection,the production and regulation of hyaluronan is defective.The levels of inflammatory cytokines (IL-1, TNF) are highin the lungs of COVID-19 patients and these cytokines are1452 Y. Shi et al.strong inducers of HA-synthase-2 (HAS2) in CD31+endothelium, EpCAM+ lung alveolar epithelial cells, andfibroblasts [13]. Importantly, HA has the ability to absorbwater up to 1000 times its molecular weight. Therefore,reducing the presence or inhibiting the production of HAholds a great promise in helping COVID-19 patientsbreathe. Doctors can simply provide patients medical gradehyaluronidase to reduce the accumulation of HA and thus toclear the jelly in the lung. In animal models, influenza-induced breathing difficulties can be relieved by intranasaladministration of hyaluronidase. Doctors can also use aclinically approved bile therapy drug, Hymecromone (4-Methylumbelliferone, 4-MU), an inhibitor of HAS2 [14].LPS-induced lung inflammation can be relieved by 4-MU.4-MU or its chemical derivatives exist widely in variousherbs used in traditional Chinese medicine, which mayexplain the observed effectiveness of combined herbalmedicine in some patients.Overall, this synopsis is based on some clinical commonsense. We propose some simple, but largely ignored,approaches to the treatment of COVID-19 patients (Fig. 1).We believe that the two-phase division is very important: thefirst immune defense-based protective phase and the secondinflammation-driven damaging phase. Doctors should try toboost immune responses during the first, while suppressing itin the second phase. Since Vitamin B3 is highly lung pro-tective, it should be used as soon as coughing begins. Whenbreathing difficulty becomes apparent, hyaluronidase can beused intratracheally and at the same time 4-MU can be givento inhibit HAS2. Of course, HLA typing will provide sus-ceptibility information for strategizing prevention, treatment,vaccination, and clinical approaches. We hope that some ofthe above ideas can be employed to help combat this deadlycontagious disease of increasing incidence around the world.Acknowledgements The work has been partially supported by grantsfrom the National Key R&D Program of China (2018YFA0107500),the Scientific Innovation Project of the Chinese Academy of Sciences(XDA16020403), Suzhou 2020 Emergency Innovation Funding onCOVID-19 Infection, the National Natural Science Foundation ofChina (81530043, 81861138015, 31771641 and 81571612),PANDORA-ID-NET (to GI), the European & Developing CountriesClinical Trials Partner-ship, supported under Horizon 2020 to GI),Italian Ministry of Health (RC, 1 to MP and GI).Fig. 1 Schematic representation of the progression of COVID-19infection and potential adjuvant interventions. After an incubationperiod, the invading COVID-19 virus causes non-severe symptomsand elicits protective immune responses. The successful elimination ofthe infection relies on the health status and the HLA haplotype of theinfected individual. In this period, strategies to boost immune responsecan be applied. If the general health status and the HLA haplotype ofthe infected individual do not eliminate the virus, the patient thenenters the severe stage, when strong damaging inflammatory responseoccurs, especially in the lungs. At this stage, inhibition of hyaluronansynthase and elimination of hyaluronan can be prescribed. Cytokineactivated mesenchymal stem cells can be used to block inflammationand promote tissue reparation. Vitamin B3 can be given to patientsstarting to have lung CT image abnormalities.COVID-19 infection: the perspectives on immune responses 1453Compliance with ethical standardsConflict of interest The authors declare that they have no relevantconflict of interest.Publisher’s note Springer Nature remains neutral with regard tojurisdictional claims in published maps and institutional affiliations.References1. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. ClinicalCharacteristics of Coronavirus Disease 2019 in China. The NewEngland journal of medicine. 2020. https://doi.org/10.1056/NEJMoa2002032.2. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. ClinicalCharacteristics of 138 Hospitalized Patients With 2019 NovelCoronavirus-Infected Pneumonia in Wuhan, China. Jama.2020. https://doi.org/10.1001/jama.2020.1585.3. Rothe C, Schunk M, Sothmann P, Bretzel G, Froeschl G, WallrauchC, et al. Transmission of 2019-nCoV Infection from an Asympto-matic Contact in Germany. The New England journal of medicine.2020;382:970-1. https://doi.org/10.1056/NEJMc2001468.4. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al.Pathological findings of COVID-19 associated with acuterespiratory distress syndrome. The Lancet Respiratory medicine.2020. https://doi.org/10.1016/S2213-2600(20)30076-X.5. Wang Y, Chen X, Cao W, Shi Y. Plasticity of mesenchymal stemcells in immunomodulation: pathological and therapeutic impli-cations. Nat Immunol. 2014;15:1009–16. https://doi.org/10.1038/ni.3002.6. Wang G, Cao K, Liu K, Xue Y, Roberts AI, Li F, et al. Kynurenicacid, an IDO metabolite, controls TSG-6-mediated immunosup-pression of human mesenchymal stem cells. Cell death anddifferentiation. 2018;25:1209-23. https://doi.org/10.1038/s41418-017-0006-2.7. Nagai A, Matsumiya H, Hayashi M, Yasui S, Okamoto H, KonnoK. Effects of nicotinamide and niacin on bleomycin-inducedacute injury and subsequent fibrosis in hamster lungs. Experi-mental lung research. 1994;20:263-81. https://doi.org/10.3109/01902149409064387.8. Blackwell JM, Jamieson SE, Burgner D. HLA and infectiousdiseases. Clin Microbiol Rev. 2009;22:370–85. https://doi.org/10.1128/CMR.00048-08.9. Matzaraki V, Kumar V, Wijmenga C, Zhernakova A. The MHClocus and genetic susceptibility to autoimmune and infectiousdiseases. Genome Biol. 2017;18:76. https://doi.org/10.1186/s13059-017-1207-1.10. Dutta M, Dutta P, Medhi S, Borkakoty B, Biswas D. Poly-morphism of HLA class I and class II alleles in influenza A(H1N1)pdm09 virus infected population of Assam, NortheastIndia. J Med Virol. 2018;90:854–60. https://doi.org/10.1002/jmv.25018.11. MacLaren G, Fisher D, Brodie D. Preparing for the most criticallyIll patients with COVID-19: the potential role of extracorporealmembrane oxygenation. JAMA. 2020. https://doi.org/10.1001/jama.2020.2342.12. Hallgren R, Samuelsson T, Laurent TC, Modig J. Accumulationof hyaluronan (hyaluronic acid) in the lung in adult respiratorydistress syndrome. Am Rev Respir Dis. 1989;139:682–7. https://doi.org/10.1164/ajrccm/139.3.682.13. Bell TJ, B O, Morgan DJ, Salek-Ardakani S, Jagger C,Fujimori T, et al. Defective lung function following influenzavirus is due to prolonged, reversible hyaluronan synthesis. MatrixBiol. 2018;80:14–28.14. Collum SD, Chen NY, Hernandez AM, Hanmandlu A, SweeneyH, Mertens TCJ, et al. Inhibition of hyaluronan synthesis attenu-ates pulmonary hypertension associated with lung fibrosis. Britishjournal of pharmacology. 2017;174:3 284–301. https://doi.org/10.1111/bph.13947.1454 Y. Shi et al.

COVID-19 infection: the perspectives on immune responses.

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COVID-19 infection: the perspectives on immune responses.

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