Enrico Maggi°, MD, Bruno Giuseppe Azzarone°, MD, Giorgio Walter
Canonica*, MD, Lorenzo
Moretta°, MD.
° Department of Immunology, Bambino Gesù Children’s Hospital, IRCCS,
Rome, Italy.
* Asthma & Allergy Clinic, Humanitas University & Research Hospital,
IRCCS, Milan, Italy.
Key Words: COVID-19, Endotypes, Innate and adaptive Immunity,
Pathogenesis, SARS-CoV-2
Prof. Lorenzo Moretta, Bambino Gesù Children’s Hospital, IRCCS, Rome,
Italy
Disclosure of potential conflict of interest: The authors declare that
they have no conflicts of
interest.
Acknowledgements This work was supported by grants from
the Ministero della Salute (grant no.
RC-2020 OPBG to L.M. and E.M.) and from Associazione Italiana per la
Ricerca sul Cancro
(project no. 5x1000 2018 Id 21147 and project no. IG 2017 Id 19920 to
L.M.).
Abstract The coronavirus disease 2019 (COVID-19) pandemic started over one year
ago and produced almost 3.5 million deaths worldwide. We have been
recently overwhelmed by a wide literature on how the immune system
recognizes Severe Acute Respiratory Syndrome Coronavirus 2 and
contributes to COVID-19 pathogenesis. Although originally considered a
respiratory viral disease, COVID-19 is recognized as a far more complex,
multi-organ-, immuno-mediated-, and mostly heterogeneous disorder.
Though efficient innate and adaptive immunity may control infection,
when the patient fails to mount an adequate immune response, a high
innate-induced inflammation can lead to different clinical outcomes
through heterogeneous compensatory mechanisms. The variability of viral
load and persistence, the genetic alterations of virus-driven
receptors/signaling pathways and the plasticity of innate and adaptive
responses may all account for the extreme heterogeneity of pathogenesis
and clinical patterns. As recently done for some inflammatory disorders
as asthma, rhinosinusitis with polyposis and atopic dermatitis, herein
we suggest to define different endo-types and the related phenotypes
along COVID-19. Patients should be stratified for evolving symptoms and
tightly monitored for surrogate biomarkers of innate and adaptive
immunity. This would allow to preventively identify each endo-type (and
its related phenotype) and to treat patients precisely with agents
targeting pathogenic mechanisms.
.Introduction The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) started in late 2019 in
Wuhan (China) and caused already almost 3.5 million deaths. In a paper
published last year, we underscored the unknowns about virus receptors
and signaling, host immune response, disease pathogenesis and
therapeutic tools able to control virus entry, replication and spread
and harmful effects [1]. After over
one year of pandemic, we have been overwhelmed by an enormous number of
reports on SARS-CoV-2 infection and COVID-19 pathogenesis. Although
originally defined as a respiratory viral infection, COVID-19 is now
clearly recognized as a far more complex, multistep, multi-organ,
immuno-mediated and mostly heterogeneous disease.
The angiotensin-converting enzyme-2 (ACE2) is the SARS-CoV2 receptor and
in ACE2-bearing cells (as monocytes/macrophages and epithelial cells),
the virus triggers pattern recognition receptors as Toll-like receptors
(TLRs) and cytosolic sensors. Their signaling essentially follows three
pathways leading to the type I/III Interferon (IFN) secretion, the
expression of costimulatory molecules for T-cell activation, and
production of pro-inflammatory cytokines and chemokines
[1]. This contributes to activation of
innate immune responses, virus-specific cytotoxic CD8+ T cells and T
follicular helper (Tfh) cells cooperating with B cells to mount a
protective humoral response. Both innate and adaptive immunity can
control the viral infection and determine clinical recovery: however,
when an infected patient fails to produce the adequate immune responses,
an ongoing innate-induced inflammation can lead to cytokine storm,
interstitial pneumonia, diffuse organ involvement and failure.
Today the main unanswered question is why the viral immune evasion
predominates on the host immunity leading to hyper activation of
macrophages and neutrophils with cytokine storm only in a proportion of
patients. Even though many hypotheses have been proposed, the causes
inducing variable responses of the immune system along such a multistep
disease are only partially known [2, 3]. We will discuss such
pathogenic hypotheses, underscoring the role of defective or excessive
immune responses and the high degree of heterogeneity of the clinical
patterns.Immuno-pathogenesis of COVID-19Some hypotheses attempting to unify immuno-pathogenesis of COVID19 have
been proposed recently. They will be summarized, taking into account
that the described mechanisms are not mutually exclusive.Altered coordination between innate and adaptive
Immunity. When innate response lasts too long due to viral
immune-evasion or impaired innate cell function, SARS-CoV-2 further
replicates and compromises the adaptive immune responses [3]. The
virus may develop mechanisms which impair components of type I/III IFN
signaling pathway in infected cells as plasmacytoid dendritic cells
(pDCs). The low levels of type I IFN detected in COVID-19 patients,
suggest a potential defect in viral defense, which is negatively
associated to disease severity [4]. Even though SARS-CoV-2 is highly
sensitive to IFN, however, it interferes with downstream signaling at
several levels, or inhibits IFN-stimulated gene products [5].
Remarkably, ACE2 expression on epithelial cells is upregulated by type I
IFN itself, thus the virus can even exploit the most effective
anti-viral molecule, when present [6]. In addition, pDCs (the main
source of type I IFN) decrease in COVID-19 due to recruitment into
tissues and apoptosis and their number is negatively related to disease
severity [7]. Low numbers of pDCs can be responsible for the reduced
presentation of viral epitopes to T cells and for defective activation
of natural killer (NK) cells [8]. NK cells may be impaired early due
to: i. the over production of cytokines (mainly IL-6) by infected APC
[9], ii. the excess of cytokines inducing metabolic changes and
signs of exhaustion [10], iii. the spike subunit 1 (S1)-driven HLA-E
expression on lung epithelium which binds S1 peptides and is recognized
by the inhibitory receptor NKG2A [11], iv. the KLRC2 gene (encoding
the activating receptor NKG2C) deletion or HLA-E*0101/0103 variants
(poorly recognized by NKG2C) with consequent reduction of the NKG2C+
“memory” NK cells [10]; v. the impaired release from the bone
marrow of “inflammatory precursors” which rapidly differentiate into
mature NK progenies [12].
The factors delaying adaptive immunity are mostly due to early impaired
innate responses. Endogenous corticosteroids and IL-10 might condition
the timing of adaptive cellular response. IL-10 is elevated in COVID-19,
mainly in critical/non-survivors, and mimics systemic sepsis [3,
13]. Factors compromising the adaptive response can be amplified by
the age, since elderly patients show few naive T cells and a limited TCR
repertoire, leading to delayed specific T cell responses which, in turn,
cause the impaired B cells activation and production of neutralizing
antibodies (Abs) [14]. It is likely that the innate immunity, in an
attempt to compensate the defective T cells, mounts excessive responses
leading to lung immunopathology and damages of other organs. Notably,
the virus can directly (via TLR2) or indirectly (via FcRγ-induced
trigger by virus/anti-virus Abs immune complexes) activate the NLRP3
inflammasome (NI), perpetrating the production of inflammatory mediators
which favor severe outcomes [13-15]. This agrees with reports in
which innate cytokine/chemokine signatures of immunopathology [7]
have been associated with end-stage COVID-19 disease [16]. The lack
of temporal coordination between innate and adaptive responses allows
the persistence of a high viral load, which can trigger a second wave of
inflammation, occurring during the third week from infection, which is
crucial for the worst clinical outcomes [8].Pre-existing immunity to the virus in unexposed individuals.SARS-CoV-2-specific T cells have been detected in about 50% of
unexposed individuals, suggesting T cell cross-reactivity between
SARS-CoV-2 and common cold coronaviruses (CCC), which affect
>75% of general young population [17]. High level of
pre-existing memory CD4+ and CD8+ T cells could allow to favor a faster
and stronger adaptive immune response upon exposure to SARS-CoV-2,
limiting disease severity. Such a secondary-like response could
associate with increased memory Tfh cells which cooperate with B cells
and favor a more rapid humoral response [3]. This might look like
what happens in recovered patients at six months from primary infection
where a robust SARS-CoV-2-specific T cell response is maintained and
prevents reinfection [18].
The pre-existing memory T cells induced by CCC previous infections
might, however, be harmful, through an antibody-mediated disease
enhancement mechanism [19]. High pre-existing T cell response may be
detrimental if associated to a parallel dysfunction of naive- and
induced-T regulatory (Treg) cells [20]. Since Treg cells limit
antiviral responses and tissue immunopathology [21], their reduction
may favor a vigorous amplification of any (specific or non-specific) T
cell response including autoreactive T cells triggering autoimmunity.
The direct interaction of CD147 (mainly expressed on Treg cells) and
Spike 1 (S1) protein of SARS-CoV-2, which mediates infection of host
cells, has been suggested to be responsible for Treg cell dysfunction
observed in severe COVID-19 [8, 15, 21]. Indeed, CD147, also called
Basigin (an inducer of matrix metalloproteases), is highly expressed by
the early activated memory Foxp3+ Treg cells displaying the strongest
suppressive activity [22].Super-antigen hypothesis. The similarity between severe
COVID-19 and sepsis suggests that SARS-CoV-2 could contain
super-antigenic sequences. Super-antigens (SAtgs) may enroll a large
(even if variable) proportion of polyclonal T cells, which become
chronically activated till exhaustion. Some HLA haplotypes are more
permissive in binding SAtgs and account for the heterogeneity of immune
responses and clinical outcomes [23]. Several SARS-CoV-2 SAtgs have
been discovered: i. a polybasic sequence of S protein with a high
homology to the SARS-Cov1 18-mer S protein peptide with SAtgs activity,
ii. the homology of the previous sequence with SEB: notably, an anti-SEB
monoclonal Ab inhibits SARS-CoV-2 infection by blocking the access of
TMPRSS2 to the cleavage site [23], iii. the homology of the SAtg
motif with a neurotoxin-like sequences binding TCR [24]. The
analysis of TCR repertoire from patients with severe disease indicates a
TCR skewing with extensive junctional diversity, enrichment of Vβ genes
and increased J diversity, all consistent with SAtgs-induced activation
[25]. Since SAtgs bind the non-polymorphic sequences of TCR and MHC
class II, these molecules may activate T and B cells in non-specific way
and contribute to the dysfunction of humoral and cellular responses
[23].Unmasking latent auto-inflammatory/autoimmune mechanisms.Viruses are considered the major trigger of autoimmune diseases in
susceptible individuals. The hyper activation of the immune response
against SARS-CoV2 may result, in some cases, in unpredictable symptoms
of autoimmune/auto-inflammatory disorders (AAD), as observed in other
infections. Even though they may often represent transient
post-infectious epiphenomena, some COVID-19-related manifestations
fulfill the diagnostic criteria of specific AAD. Several symptoms,
related to autoimmune hematological diseases, autoimmune neuropathies,
autoimmune coagulopathies and Kawasaki Disease-like vasculitis have been
documented during COVID-19 [26, 27]. Histological patterns, as
alveolar damage and fibro-myxoid proliferation observed in lung of
COVID-19, are identical to those of Systemic Lupus Erythematosus (SLE),
Dermatomyositis (DM), and Progressive Systemic Sclerosis [28].
Anti-nuclear-, centromere-, PM-Scl, SS-B/La, Jo-1, and Scl-70 auto-Abs
have been described in a proportion of severe patients [29], while
inconsistent results have been reported on anti-phospholipid Abs
[29-31]. Circulating anti-PF4 auto-Abs are likely responsible for
the very rare post-vaccination thromboses with thrombocytopenia. The
anti-IFN- auto-Abs, which may contribute to further impairment of
anti-viral response, have been frequently detected in patients with
life-threatening COVID-19 [32]. The repertoire of auto-Abs examined
in MIS-C patients identified 189 peptide candidates for IgG- and 108 for
IgA autoantigens. In this library the peptides expressed in cells of the
immune system, La and Jo-1 autoantigens (present in SLE and autoimmune
Myopathies), and those of tissues involved in the MIS-C are particularly
abundant [33]. Furthermore, by using a high-throughput auto-Abs
discovery technique analyzing the specificities towards more than 2,500
extracellular and secreted proteins, it was recently reported that a
large panel of COVID-19 patients exhibited a dramatic increase of
auto-Abs compared to uninfected people. Importantly, the majority of
auto-Abs recognized immunomodulatory proteins including cytokines,
chemokines, complement (C’) components, and cell surface proteins, thus
contributing to perturb immune function and viral load control in a very
heterogeneous manner [34]. Such auto-Abs could also exacerbate
disease severity in a mouse model of SARS-CoV-2 infection and were
pathogenic, since their recognition of tissue antigens correlated with
specific clinical patterns and severity [34].
Apparently, in odds with the ability of SARS-CoV2 to elicit
autoimmunity, many reports indicate that patients, already affected by
AAD and clinically stabilized with immunosuppressive drugs, display,
when infected with SARS-CoV-2, similar morbidity rates of general
population [35]. It has been suggested that the treatment with such
drugs likely allows also to prevent the severity of infection,
indirectly confirming that COVID-19 and AAD share common pathogenic
pathways. Such explanation seems to be true also in asthmatic patients,
controlled with inhaled corticosteroids (ICS), who display similar
morbidity of infection of general population [36]. Indeed,
budesonide (an ICS), largely employed in asthma, if administered at the
initial phase of infection, has been recently shown to markedly reduce
viral load and persistence, duration and severity of symptoms and timing
of recovery in infected non-asthmatic patients [37]. Indeed, ICS are
able to impair ACE2 expression on respiratory mucosa through the
inhibition of type I IFN [38, 39]. If confirmed, this may be a real
important breakthrough in the treatment of COVID-19.
Besides Treg cells defect, several virus-related mechanisms impair
peripheral tolerance and each mechanism, by itself or in association
with others, may contribute to COVID-19 pathogenesis.Molecular mimicry. S1 protein shares sequence homology
with an extraordinary number of tissue proteins that, if altered,
mutated, deficient or improperly functioning by cross-reacting Abs, may
associate with a wide range of AAD [40]. An epitope mapping analysis
has identified linear immunogenic epitopes from DM patients matching
with the SARS-CoV-2 peptides. HLA-B*15:03 which associates to Sjogren
Syndrome, is able to present highly conserved SARS-CoV-2 peptides.
Lastly, SARS-CoV-2 shares sequences with three proteins of the brainstem
respiratory nucleus and with pulmonary surfactant, just offering a
further possible explanation to neurological and pulmonary damages
[41].Neutrophils extracellular traps and epitope
spreading. The Neutrophil extracellular traps (NETs) have
been observed in COVID-19 patients with elevated serum levels of
cell-free DNA, myeloperoxidase-DNA complexes, and citrullinated histone
H3 [16, 42]. NETs are a way to control microbial infections and this
unique cell death program is called “NETosis”. In this process,
citrullinated chromatin and bactericidal proteins are released and
produce a network structure, which immobilizes and kills invading
pathogens in the environment. NETs can be activated through
disease-related stimuli (as pathogens, Abs, etc.) and mediate tissue
damage. Excessive spread of self-antigens, as dsDNA, granule proteins,
and histones, associated with increased NETosis and/or defects of
mechanisms for their elimination leads to AAD and clotting activation
[42].Bystander Damage (BD). It starts when the virus-specific
CD8+ T cells are recruited into the infected tissues where they exert
cytotoxic activity. Dead cells activate macrophages to release reactive
oxygen species and nitric oxide resulting in bystander killing of
uninfected cells [43]. CD4+T cells may also contribute to the BD
through the release of pro-inflammatory cytokines [43]. Impaired
clearance of killed cells induces spreading of autoantigens with the
activation of bystander autoreactive T and B cells. BD is one of the
mechanisms responsible for ARDS, myocarditis, and neurological
involvement of COVID-19.Trained immunity and hyper-activation of T cells.When the virus persists, it may activate a dysregulated NI in infected
cells favoring an excessive immune reaction through the combination of
“trained innate immunity” effect and bystander T cells activation. The
former process leads to increased response of previously activated
innate cells, mostly myeloid and NK cells, to subsequent triggers,
defined as ‘innate immune memory’, responsible for the persistence of
inflammation in some disorders [44]. “Trained memory” NK cells
have been described as a rapid protective mechanism in secondary
infections, while their activation/proliferation upon SARS-CoV-2
(primary) infection would contribute to increase the late inflammation.
No data are at present available regarding “memory” NKG2C+ NK cells in
response to viral peptides in recovered or vaccinated people.
The bystander activation of CD44+ T cells, including autoreactive T
cells, is favored by the excess of environment signals facilitated by
the early dysfunction of Treg cells. Bystander T cell activation
contributes to not effective virus clearance and stimulates long-lived
autoreactive B cells and auto-Abs. Autoreactive T cells prevalently
display a Th17 profile as such development is favored by cytokines
(IL-1β, IL-23) overproduced by NI-activated macrophages. Notably,
autoreactive Th17 cells have been associated to the majority of AAD.
Since Th17 cells are very plastic the environmental IL-12 and TNF-α
usually induce their shift to a more aggressive profile (cytotoxic
non-classical Th1 – ncTh1- cells) exerting further tissue injury in AAD
and, likely, in COVID-19 [45]. The overproduction of IFN-γ from
ncTh1 and NK cells (favored by the IL-18 excess) improves macrophage
activation, thus starting a vicious circle leading to a clinical pattern
known as macrophages activating syndrome (MAS) [46]. The
environmental conditions with the chronic stimulation can shift memory
Th17 cells to the production of IL-21 and TGF-β, but not IFN-γ, which in
severely affected COVID-19 patients, may contribute to suppress T
effector cells and, in parallel, favoring IgA2 production (absent in the
moderate COVID-19) and the egress of circulating plasmablasts [47]Prevalence of memory vs naïve T and B cells conditioning severe
outcomes. Age, male-gender, and pre-existing comorbidities are risk
factors for a high morbidity and mortality of SARS-CoV-2 infection. They
display a higher basal pro-inflammatory condition coupled with a
progressive inability of the immune system to mount protective responses
[48] This complex status called immune-senescence, often associated
to the age, is characterized by: i. reduction in the CD4+/CD8+ T cell
ratio, ii. impaired development of Tfh cells and, in turn, of memory B
cells and humoral response, iii. reduction of the TCR repertoire and
clonal expansion under the stimulation with novel antigens, iv.
decreased cytotoxicity of CD8+ T and NKT cells favoring not effective
response to new viruses, vi. improved trained immunity coupled with
pro-inflammatory cytokines [48]. Since the immuno-senescence is
associated with higher memory- and lower naive T cells, it has been
speculated that such unbalance may contribute to the more severity
observed in adult patients compared with children [49]. In adults
the improved trained immunity is associated with bystander T cell
activation, poor clonal T cell expansion and low viral clearance, while,
in children, the predominant naïve T cells develop a valid antiviral
response with efficient clonal T cell expansion, viral clearance, and
less tissue damage [48]. Besides naïve T cells, children exert
higher levels of pre-existing innate or cross-reactive IgM+ memory B
(mB) cells [50]. They produce natural antibodies and generate most
IgA+ and IgG+ switched mB cells, leading to protective Abs at mucosal
level during early infection [50]. Natural Abs do not undergo any
modification by the antigen, exert few somatic mutations and broad
reactivity, giving early protection in absence of previous encounter
with antigen. Neutralizing IgG mB cells in COVID-19 display none or very
few somatic mutations, thus suggesting that the innate mB cells
repertoire may contain some SARS-CoV-2 specificities [49]. The
excess of naïve T and mB cells in children might explain why most
pediatric cases display no or mild symptoms and recovery within few days
[51].
Table 1 summarizes the topics of the previously examined pathogenic
mechanisms which are partially supported and that must to be further
thoroughly investigated.Multiple endotypes may explain the variability of COVID-19Despite the extraordinary amounts of reports, we are aware that many
unknowns on the immune response to the virus and COVID-19 pathogenesis
have to be clarified. Although the described pathogenic hypotheses
contribute to shed light on multiple aspects of COVID-19, actually none
of them is sufficient to fully explain the variability of the disease.
Indeed, the major problem of this infection is its heterogeneity. The
heterogeneity concerns the viral load (varying more than
105 times among different patients) which conditions
the degree and the efficacy of the immune response [3].
Heterogeneity has been observed on viral replication and persistence
(from some days to more than 3 months) or tissue distribution [3, 7,
14, 16]. The clinical course of infection exhibits heterogenic
features (poor or no symptoms, mild disease with recovery, severe and
critical illness with Acute Respiratory Distress Syndrome -ARDS-, multi
organ failure, death). Different biological features are prevalent in
patients with severe/critical disease: i. the reduction of class I and
II expression on infected APC with dysregulated response of NK and T
cells, ii. the NI activation in macrophages associated to high levels of
IL-1β, IL-18, IL-23; iii. poor specific T cells with a prevalence of
Th2/Th17 profiles; iv. high levels of Abs with activation of C’ and
clotting; v. pathogenic auto-Abs that affect immune responses and/or
damage tissues. Such a variability of endotypes translates into
different clinical outcomes of severe COVID-19 (Sepsis-like syndrome,
Cytokine Released Syndrome -CRS -, ARDS, MAS, Secondary Haemophagocytic
Lympho-histiocytosis -HLH -, Disseminated Intravascular Coagulation
-DIC-, Multi-organ failure), and the variable symptoms of so-called
“long COVID-19” of recovered patients. Heterogeneity of adverse events
to new COVID-19 vaccines (from frequent minimal- to rare severe
reactions, including anaphylaxis and thrombosis) have been documented.
Heterogeneous response to therapies addressed to pathogenic mechanisms
as those antagonizing TLR signaling (hydroxychloroquine), or cytokines
as TNFα, IL-1β, or IL-6 has been shown [9, 52]. This has been likely
the cause of failure of many clinical trials using these drugs in
patients not stratified for endotypes. Heterogeneity has been observed
also in the timing of onset and intensity of innate and adaptive immune
responses [53]. The size of Abs responses to SARS-CoV-2 ranges of
more than 1000 times, and the proportion of virus-specific T cells or NK
cells is highly variable [14, 15, 17]. Single-cell transcriptomic
analysis of virus-reactive CD4+ T cells provided evidence of
heterogeneity across individual patients with different disease
severity.
The current problem is, therefore, to establish the causes of this
heterogeneity. Some other viral infections, as, HBV, show variable
clinical outcomes (recovery, chronicity or fatality) owing to the
different balance between viral load and efficacy of antiviral immune
response [54]. Three variable components can contribute to the
different outcomes also in SARS-CoV2 infection: the viral load, the
preexisting genetic factors conditioning the early immune response and
the plasticity and/or redundancy of innate and adaptive responses to the
virus along the disease.
The variability and persistence of viral load along the disease is of
the utmost importance. The virus triggers a lot of co-receptors able to
start signals, which, in turn, activate a series of immunological
mechanisms: genetics, epigenetics, pre-existing immunity, polymorphisms
of signals/receptors of immune system, actually may contribute to the
heterogeneity of the final response. Figure 1 summarizes the receptors
and the antigenic activity of S1, the cells involved and their impact on
immune response.
In addition, the immune system is diverse in different people and one
individual rarely responds to an infection in similar way to another
person. Genetic variations as TLR7 in men [55], HLA haplotype
allowing valid adaptive immunity or recognizing cross-reactive
autoantigens or SAtgs of SARS-CoV2 sequence, molecules involved in
signaling of type I IFN [55], predisposition to mount auto-Abs, ease
to induce NI activation [33], all are important to explain the
heterogeneity of antiviral response [8]. Elderly and related
co-morbidities, showing a pro-inflammatory not completely controlled
condition, introduce further elements of variability. Some pre-existing
factors conditioning the heterogeneity of immune response to SARS-CoV2
infection are listed in Table 2.
Whatever the duration and the pathways used by the immune system to
counteract the virus and potentiate or regulate the inflammatory
process, the peculiar timing of this multistep disease suggests a
parallel underlying scenario of multistep pathogenic mechanisms. Even
though variable, it is likely that different phases of infection and
timing-related clinical outcomes (phenotypes), can be the expression of
a progressive failure of some immunological processes (detrimental
endotypes) with sometimes the reset (harnessing the redundancy and
plasticity of immune response) of a novel setting. This latter, however,
can recover in each clinical phase through the re-expansion of crucial
anti-viral immune components (as Abs, NK- and CD8+ T cells) modulated by
appropriate number of Treg cells or other regulatory mechanisms
(protective endotypes). If unstable, the novel setting can be
short-circuited by mechanisms of the virus and immune system itself,
that can induce newly uncontrolled hyper activation of innate and
adaptive immunity leading to a next worse phase, which, later on, may
lead to recovery or worsening. The virus, acting on several cellular
targets, activates and/or inhibits multiple mechanisms of the immune
system which tends to compensate, more or less validly, the produced
alterations and damages. Protective endotypes are those that facilitate
functional recovery (as IFN-γ-producing NK and memory T cells, clonally
expanded CD8+T cells, high levels of Tfh, plasmablasts and neutralizing
Abs, IgG and IgA1 prevalence, etc), while detrimental ones are unable to
cope with damage and favor clinical worsening (as NI overactivation,
hypersecretion of inflammatory cytokines/chemokines by macrophages and
neutrophils, expansion of polyclonal activated T cells, prevalence of
Th17 cells producing IL-21/TGF-β, early inhibition of memory Treg cells,
NK impairment, IFN defect, ‘C consumption, loss of circulating
plasmablasts, IgA2 prevalence, etc.). An attempt to explain this
concept, including different phenotypes and the corresponding protective
or detrimental endotypes, is reported in Figure 2. The multiple
phenotypes that characterize the critical phase of the disease may
recognize different evolving endo-types, which likely can overlap or
intersect in a variable way in each patient. An attempt to depict the
major evolving endo-types which, through several immune mechanisms, may
lead to more than one clinical pattern in severely affected COVID-19 is
reported in Table 3.Conclusion In our opinion, in order to better explain the heterogeneity of the
immune response in SARS-CoV-2 infection at molecular level, we need to
establish precise endotypes and the corresponding phenotypes of
COVID-19, similar to what has been made for asthma and other chronic
inflammatory diseases (Rhinosinusitis with nasal polyps, Atopic
dermatitis, Food allergy and eosinophilic esophagitis), through which
the personalized therapy, targeting different pathogenic mechanisms, is
successful today [56-60]. Recently, some sepsis endo-types and
clinical and biochemical phenotypes of ARDS have been reported in
COVID-19 [61-63]. Attempts to preventively identify endo-types
during symptom onset or at the hospital admission of patients at high
risks for a further clinical deterioration have been proposed [64,
65]. Therefore, it is important to stratify infected patients for
evolving symptoms and recovery along infection and, in parallel, to
monitor them tightly by detecting surrogate biomarkers of cells of
innate and adaptive immunity (as cytokines/chemokines signatures and
serum levels, proportion of circulating cells and function, neutralizing
Abs, etc.) in association with essential parameters of inflammation,
coagulation, organs’ function, etc. [66]. It will allow to establish
a detailed guideline able to preventively identify immunological
(frequent and unfrequent) alterations correlated to changes of symptoms
and, according to precision medicine dictates, to exploit this tool for
the most suitable diagnostic and therapeutic strategy in each patient.
Besides investigating the fine pathogenic mechanisms during SARS-CoV-2
infection, this strategy can also provide an outline of how we may
approach emerging infections/pandemic in the future.References