Biologia Futura

https://doi.org/10.1007/s42977-023-00153-8

ORIGINAL PAPER

How much (evil) intelligence can be encoded by 30 kb?

Ernő Duda1

Received: 20 July 2022 / Accepted: 13 January 2023

© Akadémiai Kiadó Zrt. 2023

Abstract
Genomes of most RNA viruses are rarely larger than the size of an average human gene (10–15 kb) and still code for a number
of biologically active polypeptides that modify the immune system and metabolism of the host organism in an amazingly
complex way. Prolonged coevolution developed tricks by which viruses can dodge many protective mechanisms of the host
and lead to the formation of molecular mimicry patterns. Some viruses inhibit the interferon response, interfere with the
membrane destroying effects of the activated complement cascade. They can replicate in cellular compartments formed by
inner membranes of the cell hiding their characteristic features from diverse pattern recognition receptors. In many cases—
and in this respect, the new coronavirus is a champion—they can exploit our own defensive mechanisms to cause serious
harm, severe symptoms and frequently deadly disease.

Keywords SARS-CoV-2 · RNA viruses · Molecular mimicry · NETosis · Pyroptosis · Interferon

RNA viruses
Taxonomically viruses are grouped at different hierarchi-
cal levels of order, family, subfamily, genus and species on
the basis of shared morphological and genetic properties.
Approximately 70% of all known viruses belong to RNA
viruses. They vary remarkably in genome structure. The
genome may be one piece of RNA or several separate seg-
ments; the RNA may be double-stranded or single-stranded.
The single-stranded genome may be either sense (plus) or
antisense (minus) strand. The first can directly function as
mRNA for protein translation. There are 14 families of RNA
viruses that cause disease in human. In general, they have a
relatively small coding capacity of 2–31 kb.
Coronaviruses are a large group of positive ssRNA
enveloped viruses of animals and humans. The first human
coronaviruses were identified in the mid-1960s; there are
four known human coronaviruses causing mild respiratory
infections (common cold) (Kapikian 1975). A new corona-
virus emerged in Southern China in 2002 that was believed
to originate in small mammals (Drosten et al. 2003). In
* Ernő Duda
duda@brc.hu
1
Department of Medical Biology, Albert Szent‑Györgyi
Medical School, University of Szeged, 6720 Szeged,
Hungary
humans, symptoms included fever, chills, and body aches
and frequently progressed to pneumonia and respiratory dis-
tress. SARS (Severe Acute Respiratory Syndrome) virus, as
it was named, spread to more than two dozen countries with
a mortality rate of about 10 per cent. Fortunately, human to
human spread of the virus was very low (reproduction num-
ber below 2) and the global outbreak was contained in 2003.
The next outbreak of a similar virus, MERS (Middle East
Respiratory Syndrome) virus, was first reported in Saudi
Arabia in 2012 (Zumla et al. 2015). MERS virus originated
in dromedary camels and spread to more than 25 countries.
MERS cases continue to occur, primarily in the Arabian
Peninsula. Mortality is very high, close to 40%, but human
to human infection has been exceedingly low.
At the end of 2019 emerged the novel coronavirus
(SARS-CoV-2) that also causes respiratory distress. The
unique CT scan of the lung of severe pneumonia patients
was recognized by Chinese doctors and the sequencing of
the biological sample identified the presence of a new virus
(Huang et al. 2020). CoVID-19 was declared a pandemic
by the World Health Organization in 2020. The genome of
SARS-CoV-2 shares 79% identity with SARS-CoV and 50%
with MERS-CoV. It codes for 4 structural proteins (S, E,
M, N), 16 non-structural proteins (nsp1–nsp16) and eight
auxiliary proteins (ORF3a, ORF3b, ORF6, ORF7a, ORF7b,
ORF8, ORF9b, ORF14) responsible for viral replication and
pathogenesis (Kim et al. 2020) (1).

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SARS‑CoV‑2
The first step in the replication of this coronavirus is a bio-
logical heresy. In all living creatures, synthesis of proteins,
the translation is based on amino acid-coding triplets.
Frameshifts, irregular jumps of ribosomes are forbidden
as they would lead to senseless polypeptide sequences
or truncated proteins due to early stop codons. Pro-
grammed ribosomal frameshifting, though not unknown,
is extremely rare in any organism (Ketteler 2012).
The ORF1ab gene at the 5’ terminal of the genomic
RNA of SARS-2 constitutes approximately 65–70% of the
genome codes for all the enzymes and factors that are nec-
essary for the replication of the viral genome and the syn-
thesis of all the subgenomic mRNAs of the structural pro-
teins (and accessory proteins) of the virus. Translation of
this RNA sequence results in two polyproteins, pp1a and
pp1ab (Kim et al. 2020) (1). There is nothing special about
the first one. It has two domains with proteolytic activities;
they cleave the pp1a polyprotein into 11 fragments with
biological activity. This is not unusual with small RNA
viruses. All mRNAs of eukaryotes are monocistronic: one
mRNA and one polypeptide chain. No start codon after the
stop. Probably the incapability of eukaryotic ribosomes to
read polycistronic mRNS was a protective feature against
mRNAs of intracellular prokaryotic pathogens and viruses.
This could have been the driving force that lead to the
evolution of polycistronic (poly) proteins with intrinsic
proteolytic activities in RNA viruses.
During the translation of the ORF1ab gene, one out
of four or five ribosomes makes an “illegal” step: a
frameshift, and proceeds reading the rest of the gene. The
result is an even larger polyprotein, pp1ab, that—after
proper processing—yields 5 more (altogether 16) biologi-
cally active proteins. These include the RNA-dependent
RNA polymerase, the helicase and a terminal nuclease,
that is responsible for proof reading (Kim et al. 2020).
Without these occasional frameshifts, the virus would
not be able to produce new RNA molecules and progeny.
Such a meticulous regulation—one essential mistake in
4–5 tries—must be the result of the special, flexible 3D
structure of the genomic RNA molecule.
The phenomenon of “programmed r ibosomal
frameshifting” observed in the case of SARS-2 is gener-
ally associated with viruses and retrotransposons (Ketteler
2012). Retroviruses, like HIV1, require efficient−1
frameshifting for the synthesis of the individual gag and
pol gene products (Brierley and Ramos 2006). A 1–15
nucleotide “slippery sequence” and stem-loop secondary
RNA structure (e.g. a pseudoknot) are usually needed for
frameshifting (Namy et al. 2006). It is believed that the
pseudoknot or stem-loop structure makes the ribosome
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Biologia Futura
“pausing” and eventually lead to frameshifting (Namy
et al. 2006).
Expression of extra polypeptides occurring in relevant
ratios is highly advantageous for RNA viruses with small
genomes because it can increase their coding capacity. In
some viruses, like in SARS-2, frameshifting increases the
proportion 5’ encoded proteins compared to 3’ encoded
ones. Quick recycling of ribosomes speeds up viral repli-
cation. Influenza A virus, non-segmented negative strand
viruses measles, mumps and Sendai and Ebola, a Filovi-
rus also utilize programmed transcriptional frameshifting
to synthesize additional products (Atkins et al. 2016). As
an interesting utilization of frameshifting, Ebola uses the
extra product to modulate the immune system. Deletion of
the slippage site of the Zaire ebolavirus radically increased
cytopathogenicity suggesting that slippage products play
a role in reducing early cytotoxicity (Alazard-Dany et al.
2006).
The IFN response
Virus infection triggers production of Type I IFNs in mam-
malian cells. Type I interferons are the largest IFN family
in humans, including IFN-α, IFN-β, IFN-ε, IFN-κ and IFN-
ω. (Pestka et al. 2004). Type I IFNs are part of a complex
cross-regulatory network that coordinates both innate and
adaptive immune responses against viruses. Induction of
IFNs is elicited by pattern recognition receptors (PPRs),
like Toll-like receptors (TLR) and RNA helicases retinoic
acid-inducible gene I (RIG-I)-like receptors (RLR). Activa-
tion of both TLR and RLR pathways leads to the secretion
of type I IFNs which mobilizes the immune system. Most
cell types harbour IFN receptors and IFN-stimulated genes
provide some protection against virus infection.
SARS-CoV-2 is champion in dodging PRRs (Viswana-
than et al. 2020) by modifying the 5’ end of the viral RNA,
replicating in host membrane created hideouts (Mohan and
Wollert 2021) and suppressing both IFN production and IFN
responses.
SARS-2 encodes a number of polypeptides that interfere
with IFN production and/or the subsequent activation of the
immune system. Open reading frame (ORF)6 and ORF9b,
non-structural proteins nsp1, nsp3, nsp6, nsp13 and nsp15
participate in blocking the signalling pathway leading to
IFN production (Kim et al. 2020). Membrane protein M,
ORF3b and ORF8 may also participate in this action. IFN-
stimulated genes are activated as a result of another signal-
ling pathway and the virus tries to block it too (by ORF6,
ORF7a and 7b, ORF 9 and nsp1, nsp6, nsp13). Spike (S),
nucleocapsid (N) nsp7 and nsp12 could also be involved in
this inhibition (Kim et al. 2020). The activity of these pro-
teins can contain mobilization of the immune response and
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development of the antiviral response, allowing uncontrolled
replication of the virus in host organisms for several days.
It is known that the IFN induction is much higher in
children and both inductivity and response to the presence
of IFN get less and less robust in elderly. It explains why
vulnerability of individuals to severe disease so extensively
increases with age (Molony et al. 2017; Li et al. 2015).
IKK kinases and IKK-related kinases TBK1 and IKKɛ
are crucial players in regulatory signalling pathways of host
antiviral defences. IKKε kinase is the target of the Dengue
virus NS2B/3 protease to inhibit IFN induction. (Anglero-
Rodriguez et al. 2014). IFN-antagonist function of Ebola
virus protein VP35 is based on blocking the signalling path-
way leading to activation of interferon-regulatory factor-3,
by preventing interactions between the IKKε and TBK1 and
their partners (Prins et al. 2009). Non-structural protein NS1
of influenza A virus blocks RIG-I downstream signalling
(Mibayashi et al. 2007). In a similar way, measles and other
paramyxovirus V proteins disrupt signalling of MDA5, a
RIG-like receptor by binding to it (Andrejeva et al. 2004).
Respiratory syncytial virus (RSV) NS1 protein also inter-
feres with RIG-I signalling by binding to mitochondrial anti-
viral proteins, MAVS, adaptor proteins of RLRs (Boyapalle
et al. 2012). MAVs are also the target of Coxsackie virus B.
The viral proteolytic enzyme 3C cleaves MAVS and another
adaptor protein, TRIF, inhibiting IFN response and apopto-
sis (Mukherjee et al. 2011). TRIF (TIR-domain-containing
adapter-inducing interferon-β) is an adaptor protein for
TLR3, a sensor of viral dsRNA in the endosome.
Virus and complement
The complement system augments the ability of phagocytic
cells to kill pathogens and clear damaged cells and syner-
gizes with antibodies to attack “non-self” membranes. Com-
plement is activated by the presence of most RNA viruses,
usually resulting in virus neutralization. Evolution of RNA
viruses resulted in superb strategies to restrict complement.
One solution is modulation of host genes: upregulation of
complement regulatory proteins or downregulation of acti-
vation components (C3, C4) to keep complement at bay
(Mazumdar et al. 2012; Li et al. 2016). Virus-associated pro-
tease activity makes Nipah virus, a paramyxovirus resistant
to neutralization by antibody-dependent classical pathway.
The presence of the F and G glycoproteins was sufficient to
reduce surface deposition of C3b and protect the virus from
being neutralized by complement (Johnson et al. 2011). In a
similar way, Chikungunya virus, a Togavirus, was also found
to resist complement-mediated neutralization inhibiting
deposition of C3b and C4b on the virus (Nag et al. 2020).
Dangerous Flaviviruses, like Dengue, West Nile and Yellow
fever viruses, incorporate soluble regulators of complement
activation (Avirutnan et al. 2011). Enveloped RNA viruses
can also hijack membrane-associated regulators of comple-
ment activation. Retroviruses HIV-1, HTLV, or hepatitis C
(HCV), a Flavivirus recruit membrane-associated regulators
(CD46, CD55, CD59), HCV also downregulates synthesis
of C2, C4 and C9 (Marschang et al. 1995; Johnson et al.
2009; Amet et al. 2012). Measles virus (Edmonton strain)
uses CD46 as a receptor (Dorig et al. 1993); interaction of
M1 protein of influenza virus (A/WSN/33) with C1q results
in blockade of IgG binding and activation of the classical
pathway (Zhang et al. 2009).
SARS viruses do not use any of these tricks. Spike protein
of SARS-CoV (N-linked glycosylation at N330) activates
the lectin pathway through binding to mannose-binding lec-
tin (Ip et al. 2005). When immune complexes with virus
specific antibodies are formed, the classical pathway is also
activated. Deposition of C3 and C4 on the SARS-CoV-2
virion may lead to their neutralization, but N protein of
SARS-CoV2 was found to activate MBL-associated serine
protease (MASP)-2, leading to the aberrant complement
activation and deposition of MASP-2 and C4 in the lung
tissue of severely affected COVID-19 patients (Gao et al.
2022). The spike protein of the virus has high affinity to hep-
aran sulphate, competing with C3b-regulatory factor H. This
may sustain activation of the alternative pathway removing
the inhibitory effects of factor H on C3 (Lo et al. 2022).
Virus-induced activation of the complement can fre-
quently exacerbate the symptoms of the disease and contrib-
ute to overall morbidity (Kumar et al. 2020). C5a receptor 1
expression is upregulated in SARS-CoV-2-primed endothe-
lial cells, making them highly vulnerable to pathological
C5a activation and insertion of the membrane attack com-
plex (MAC) (Afzali et al. 2022). In summary, SARS-2 can-
not escape complement-mediated neutralization, but—like
suicide bombers—significantly aggravate symptoms of the
infection by overactivation of the complement.
Molecular mimicry
The coevolution of hosts and pathogens frequently leads to
development of peptide sharing (molecular mimicry). Spon-
taneous mutations might create molecular patterns (epitopes)
on parasites that resemble ones on different organs of the
host. Host immune system recognizes these as “self”, toler-
ating them therefore molecular mimicry is advantageous for
the pathogen. Long coevolution results in the accumulation
of more and more host-like epitopes on parasites.
SARS-CoV-2 encodes very high number of peptides
sequences that are identical or very similar to human pro-
teins (Adiguzel 2021). This fact suggests that in 2019,
Wuhan was probably not the first encounter between this
virus and human-like creatures (SE Asian apes and monkeys
13

and perhaps isolated indigenous people), but they underwent
several decades of unrecognized coevolution.
During the disease, accumulation of danger-associ-
ated molecular patterns (DAMPs) may trigger a shift
from immune tolerance to attack, leading to autoimmune
responses. After more than two years of pandemic, a number
of autoreactive antibodies have been characterized that may
play a role in different symptoms associated with the disease
and long covid, including thrombotic, respiratory, cardiac,
rheumatic and neurological complications (Damoiseaux
et al. 2022; Anaya et al. 2021; Cappello 2020; Lucchese
and Flöel 2020; Vasilevska et al. 2021; Angileri et al. 2020).
The best characterized ones are specific to phospholipids,
Annexin-A2, hsp proteins and PARP9/14. Annexin-A2 (cal-
pactin I, p36, lipocortin II) is a lipid raft-associated phos-
pholipid-binding protein. Among other roles, it stabilizes
plasma membrane of endothelial cells and functions as a
receptor for tissue plasminogen activator (tPA). Since tPA
converts plasminogen into plasmin, Annexin-A2 is involved
in control of fibrinolysis and coagulation. Anti-Annexin-A2
antibodies destabilize membrane of microvascular endothe-
lial cells and play a role in intravascular thrombosis, and
their level predicts mortality in COVID-19 patients (Zuniga
et al. 2021). Anti-phospholipid antibodies are known to
facilitate formation of blood clots, frequently causing prob-
lems in vital organs and severe pain in anoxic tissues. Since
these (and other) autoreactive immunoglobulins remain in
the circulation long after the acute disease, their harmful
effects are usually prolonged.
Viral molecular mimicry was first reported almost
40 years ago. A monoclonal antibody against the measles
virus phosphoprotein was found to cross-react with vimen-
tin, a human intermediate filament protein (Fujinami et al.
1983). Oldstone reported that 6 out of 41 monoclonal anti-
bodies raised against measles virus reacted with human
proteins and 6 out of 34 anti-Japanese encephalitis virus
monoclonals recognized human antigens (Oldstone 2014).
T cell-mediated autoimmunity was also shown to be
elicited by viral antigens. Five T cell clones specific to the
myelin basic protein (aa 85–99), a well characterized target
of multiple sclerosis, cross-reacted with—among others—
measles, influenza A and C, human T cell leukaemia virus,
parainfluenza type B and type 3, coxsackie A9 and human
coronavirus antigens (Wucherpfennig and Strominger 1995).
NETosis
Polymorphonuclear neutrophil granulocytes are the most
abundant type of circulating white blood cells in humans
and represent the first line of defence against invading patho-
gens; their functions include phagocytosis and generation of
reactive oxygen species (ROS). In addition, self-destructing
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neutrophils produce web-like structures (neutrophil extracel-
lular trap, NET) of decondensated chromatin, antimicrobial
peptides and granule enzymes with antimicrobial and antiviral
activity. This process is known as NETosis. NETosis is not a
general pathway of cell death; no other cell types are able to
generate these traps (Brinkmann et al. 2004; Yang et al. 2016).
NETosis can be initiated by receptors for immune com-
plexes, toll-like receptors (complement- and cytokine recep-
tors). The molecular trap effectively engulfs bacteria and
viruses. Its protective role against viruses was first reported in
the case of Chikungunya virus infection (Hiroki et al. 2020).
HIV has been shown to be trapped and inactivated by NETs,
like rhinovirus, poxvirus, Dengue virus, respiratory syncyt-
ial virus and influenza virus (Stacey et al. 2021). It was not
surprising that SARS-CoV-2 infection also triggered NETosis
(Gillot et al. 2021; Barnes et al. 2020).
The neutrophil traps efficiently eliminate infectious SARS-2
virions and have protective role. However, formation of the
traps has unwanted consequences. NETs have a tendency
to promote thrombosis by providing a scaffold for aggrega-
tion of platelets (Fuchs et al. 2010). The proteases, DNA and
histones present in the traps all exhibit procoagulant proper-
ties. Elastase can process the tissue factor pathway inhibitor
(Petersen et al. 1992). Nucleic acids increase the protease
activity of coagulation factors and facilitate thrombin genera-
tion (Swystun et al. 2011; Kannemeier et al. 2007). Histones
were reported to promote coagulation of plasma by elevat-
ing production of thrombin and inhibiting thrombomodulin-
dependent protein C activation (Ammollo et al. 2011). As long
as NETs are infrequent, they do not pose a serious danger.
However, in the case of SARS-2 infection, wide spread for-
mation of NETs contributes to organ damage and mortality
(Kim et al. 2020). Released histones exhibit direct toxicity to
epithelial and endothelial cells (Saffarzadeh et al. 2012) that
can lead to serious complication in the lung microvasculature.
There are other problems with NETs that also contribute
to the negative consequences. Neutrophils secrete comple-
ment factor P, deposit it on NETs and induce the formation
of terminal complement complexes (C5b–9) (Yuen et al.
2016). This activation of complement participates not only
in endothelial cell toxicity but also play a role in the erratic
inflammatory response. Finally, NETosis shifts the immune
response to the Th17 direction and proinflammatory activity
of T helper 17 cells contributes to the exaggerated inflam-
mation characteristic of severe covid infections (Lambert
et al. 2019).
Pyroptosis
Early detection of infecting viruses is imperative for host
defence. Depending on the way how viruses replicate the
response of the innate immune system can follow two
Biologia Futura
strategies: detection of viral RNA in the cytoplasm by
RIG-like receptors (RLRs) can elicit type I IFN production
efficiently inhibiting viral replication, or—if IFN response
is inhibited or inefficient—cytopathic viruses trigger lytic
cell death, allowing K + efflux-induced NLRP3 (cryopy-
rin) inflammasome activation resulting in pyroptosis, mass
release of IL1β, IL18 and other inflammatory cytokines
(Costa et al. 2019). Unlike apoptosis that is immunologically
“silent”, thanks to the released TGFβ and IL10, pyroptosis
is highly proinflammatory.
Detection of cytopathogenic RNA viruses (like influenza
A, vesicular stomatitis virus, encephalomyocarditis virus, or
coronaviruses) by RLRs or Nod-like receptors (NLR) trig-
gers oligomerization of NLRP3 leading to recruitment of
caspases. Activated caspases (caspase-1/4/5 or 11) cleave
the N-terminal of gasdermin D (GSDMD) that can specifi-
cally bind to specific phospholipids (phosphorylated phos-
phatidylinositol on eukaryotic membranes or cardiolipin of
the mitochondrial membrane). Membrane-bound N frag-
ments of GSDMD rapidly undergo oligomerization form-
ing 16-mer pores leading to rapid lysis of the cells (Broz and
Dixit 2016). In a unique way, Zika virus initiates simultane-
ous pyroptosis and apoptosis of the infected macrophages
(Ch Wen et al. 2022).
Macrophages do not express ACE-2 and are not infected
by SARS-2. However, they carry FcγIIIRa (CD16) that binds
immunocomplexes of the virus. It was observed that sera of
non-vaccinated, infected people induce pyroptosis of mac-
rophages and monocytes, while sera of vaccinated people
do not. As it turned out, the difference was glycosylation.
Immunoglobulins contain a highly conserved N-linked gly-
can within the non-variable (Fc) domains which is indispen-
sable for IgG function. This glycan shows variable composi-
tion in humans. Decreased IgG fucosylation seems to be a
general response to enveloped viruses (HIV, Dengue virus,
etc.) (Wang et al. 2017; Ackerman et al. 2013), but generally
not against other antigens. Afucosylated IgG variants have
increased activity through FcγRIIIa receptors (Wang et al.
2017). Decreased IgG fucosylation was reported in severe
cases of COVID-19 as well (Larsen et al. 2021).
High concentrations of afucosylated IgG antibodies
against the spike protein of SARS-2 were detected in criti-
cally ill patients, but not in vaccinated people or patients
with mild symptoms (Larsen et al. 2021). Presence of these
immunoglobulins mediates stronger FcγRIIIa responses and
enhanced antibody-dependent cellular cytotoxicity. At the
same time, it amplifies the developing cytokine storm and
causes acute phase responses and immune-mediated pathol-
ogies. The synthesis of afucosylated antibodies might be
linked to special B cells. Extrafollicular B cell activation was
observed in critically ill patients with substantial antibody-
secreting cell expansion. It resulted in early production of
high concentrations of spike protein-specific neutralizing
antibodies followed by severe disease, high level inflamma-
tion, multiorgan failure and frequently even death (Woodruff
et al. 2020).
Immunization with subunit vaccines or—in case of
covid—mRNA vaccines elicits production of fully glyco-
sylated, high specificity Ig molecules synthesized by B cells
after affinity maturation. In vaccinated people reinfection
cannot induce synthesis of afucosylated antibodies. There-
fore, vaccination is not only a powerful tool to prevent pri-
mary infections, but also very useful to decrease the serious
symptoms of breakthrough infections.
Small RNA viruses developed sophisticated mechanisms
to evade different protective instrument of the host immune
system. Sometimes they use our own weapons to exacer-
bate the symptoms of the caused disease. The more we learn
about the evolutionary tricks of these viruses the better we
can treat viral diseases and decrease mortality and morbidity
caused by these pathogenic agents.
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