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Review
. 2021 Jul:31:49-60.
doi: 10.1016/j.jare.2020.12.013. Epub 2021 Jan 5.

Recovery scenario and immunity in COVID-19 disease: A new strategy to predict the potential of reinfection

Zahra Khoshkam  1 , Younes Aftabi  2   3 , Peter Stenvinkel  4 , B Paige Lawrence  5 , Mehran Habibi Rezaei  1 , Gaku Ichihara  6   7 , Sasan Fereidouni  3
Affiliations
Review

Recovery scenario and immunity in COVID-19 disease: A new strategy to predict the potential of reinfection

Zahra Khoshkam et al. J Adv Res. 2021 Jul.

Abstract

Background: The recent ongoing outbreak of coronavirus disease 2019 (COVID-19), still is an unsolved problem with a growing rate of infected cases and mortality worldwide. The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is targeting the angiotensin-converting enzyme 2 (ACE2) receptor and mostly causes a respiratory illness. Although acquired and resistance immunity is one of the most important aspects of alleviating the trend of the current pandemic; however, there is still a big gap of knowledge regarding the infection process, immunopathogenesis, recovery, and reinfection.

Aim of review: To answer the questions regarding "the potential and probability of reinfection in COVID-19 infected cases" or "the efficiency and duration of SARS-CoV-2 infection-induced immunity against reinfection" we critically evaluated the current reports on SARS-CoV-2 immunity and reinfection with special emphasis on comparative studies using animal models that generalize their finding about protection and reinfection. Also, the contribution of humoral immunity in the process of COVID-19 recovery and the role of ACE2 in virus infectivity and pathogenesis has been discussed. Furthermore, innate and cellular immunity and inflammatory responses in the disease and recovery conditions are reviewed and an overall outline of immunologic aspects of COVID-19 progression and recovery in three different stages are presented. Finally, we categorized the infected cases into four different groups based on the acquired immunity and the potential for reinfection.

Key scientific concepts of review: In this review paper, we proposed a new strategy to predict the potential of reinfection in each identified category. This classification may help to distribute resources more meticulously to determine: who needs to be serologically tested for SARS-CoV-2 neutralizing antibodies, what percentage of the population is immune to the virus, and who needs to be vaccinated.

Keywords: ACE2, Angiotensin-converting enzyme 2; ADE, Antibody-dependent enhancement; ARDS, Acute respiratory distress syndrome; Ang II, Angiotensin II; BAL, Bronchoalveolar lavage; COVID-19; COVID-19, Coronavirus disease 2019; Coronavirus; ERS, Early recovery stage; FcR, Fc receptor; ISGs, Interferon-stimulated genes; Immunity; LRS, Late recovery stage; N, Nucleocapsid; NAb, Neutralizing antibody; NK, Natural killer; PBMCs, Peripheral blood mononuclear cells; PSO, Post symptom onset; RBD, Receptor-binding domain; RT-PCR, Real-time reverse transcriptase–polymerase chain reaction; Recovery; Reinfection; SARS-CoV-2; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; sACE2, Soluble ACE2.

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Conflict of interest statement

The authors declare that they have no actual or potential conflict of interests.

Figures

None
Graphical abstract
Fig. 1
Fig. 1
Target cell infection by SARS-CoV-2 and contribution of ACE2. SARS-CoV-2 uses the ACE2 receptors in target cells, for its entry and infection. ACE2 is a catalytically active protective enzyme, which in normal conditions degrades angiotensin-II peptides. After the attachment of the virus, it enters into the cell and then its genome starts to replication and production of virus proteins, and ACE2 loses its catalytic activity. Upon virus binding to the membrane-anchored ACE2 receptor, ADAM-17 enzyme mediates ACE2 catalytic shedding and release of the sACE2. During this catalytic shedding, the release of some proinflammatory cytokines such as IL-1β and TNFα due to the activity of the TNFα-converting enzyme may also occur. The sACE2 maintains its ability for binding to viral spike protein, so its presence could intercept SARS-CoV-2 and prevents interaction with cell surface ACE2 receptors. Moreover, intracellular virus replication and accumulation of ACE2 substrate (Ang II) activates cell signaling cascades, which may lead to activation of innate immunity receptors by the production of INF-α/β and proinflammatory cytokines. Subsequently, the process of virus propagation and shedding of the infected cells may result in cell damage and apoptosis.
Fig. 2
Fig. 2
Progression of SARS-CoV-2 infection and inflammation. (A) Mild infection and innate immunity responses. SARS-CoV-2 entry and replication may cause primary inflammation through the release of pro-inflammatory cytokines produced by cellular damage and ADAM17-mediated shedding of sACE2, and activation of the interferon pathway. Mild infection possibly occurs before seroconversion and the production of neutralizing IgG. ADE response does not appear in this stage and subsequent events including ACE2 shedding and down-regulation, neutralizing activity of soluble ACE2, low level of inflammation, recruitment of cytotoxic immune cells, activation of innate immune responses, and activity of tissue-resident macrophages may lead to final viral clearance and recovery. (B) Severe infection and cytokine storm. Increased viral replication leads to the upregulation of inflammation and tissue damage, which recruits more immune cells to the infected area. This coincides with seroconversion and development of neutralizing antibodies, resulted in FcR-mediated ADE response upon generation of antibody-virus complexes. ADE response could cause a cytokine storm and may lead to severe lymphopenia via increased infiltration of lymphocytes and finally causes severe damage to immune cells and infected tissue.
Fig. 3
Fig. 3
The cycle of infection and recovery. Infection loop in mild symptomatic infected cases includes events of primary inflammation, cytokine release, and recruitment of immune cells leading to recovery. In severe symptomatic infected cases, the primary inflammation loop also with the occurrence of seroconversion and ADE response develops cytokine storm and secondary inflammatory responses. In this context, secondary inflammation could cause severe damage and subsequent immune dysfunction. These also lead to loss of ACE2 expressing cells and final ACE2 downregulation, which together with the elevation of neutralizing activity of antibodies and soluble ACE2 resulted in viral clearance and recovery.
Fig. 4
Fig. 4
COVID-19 disease progression. COVID-19 Infected patients are categorized into groups of severely symptomatic (A), mild symptomatic (B), and asymptomatic (C) based on the clinical manifestations associated with disease progression into different stages. The SARS-CoV-2 infection progresses in several stages including (I) asymptomatic incubation period, (II) moderately symptomatic period, (III) severe respiratory symptomatic stage progressing ARDS. Here disease progress in these categories depicted in graphical curves indicating viral load variations from infection to clearance. Also, the main cellular and molecular mechanisms are addressed for each group.
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