Complement activation and function in highly pathogenic
coronaviruses
The complement system senses invading pathogens as well as environmental
or self-derived antigens by pattern recognition molecules of the
canonical classical and lectin pathways (CP and LP). This function is
critical to our sustained health and survival. It results in a cascade
of proteolytic events leading to the cleavage of C3 into the
anaphylatoxin (AT) C3a and the opsonin C3b by pathway-specific canonical
C3 convertases. Consecutively, such C3 convertases build the framework
for C5 convertases that cleave C5 into the AT C5a and C5b. In addition
to classical and lectin pathway activation, the thioester in C3 can be
directly activated by any nucleophilic attack leading to the activation
of the so-called alternative pathway (AP), driving strong cleavage of C3
and C5. Eventually, C5b forms the nucleus for non-proteolytic terminal
pathway activation leading to the formation of the soluble (s)C5b-9
complex in the circulation of the poring-forming membrane attack complex
(MAC) on cell surfaces which can drive cell lysis (Figure 1).
Similar to SARS-CoV, the genome of SARS-CoV-2 encodes for several
structural and non-structural proteins including the spike (S) protein
which is critical for cell entry through engagement of
angiotensin-converting enzyme 2 (ACE2) and the employment of the
cellular serine protease TMPRSS2 for S protein priming (Hoffmann et al.,
2020). The S protein of SARS-CoV is sensed by Mannan-binding lectin
(MBL) suggesting that complement activation in SARS-CoV infection is
driven by activation of the LP of complement (Ip et al., 2005; Zhou et
al., 2010). In addition to S protein sensing by MBL, nucleocapsid (N)
protein interaction with MASP-2, the key protease of the LP activation
has been described for SARS-CoV, MERS-CoV and SARS-CoV-2 that strongly
affects LP activation (Figure 1) (Gao et al 2020 medRxiv preprint doi:
doi.org/10.1101/2020.03.29.20041962). In addition to MBL/MASP-2-driven
activation of the LP, complement might be activated by the classical
pathway (CP) through virus-neutralizing IgG antibodies (Figure 1). In
COVID-19 patients, seroconversion occurred similar or slightly earlier
than in SARS-CoV patients. Around 50% of COVID-19 patient showed
seroconversion on day 7 after development of symptoms (Wolfel et al.,
2020). Of note, in SARS-CoV-infected patients, the appearance of
anti-viral IgG coincides with onset of ARDS in 80% of patients (Peiris
et al., 2003).
The small cleavage fragments of C3 and C5, the ATs C3a and C5a are
important effector molecules that attract, activate and regulate innate
and adaptive immune cells (Laumonnier, Karsten & Kohl, 2017). C5a
exerts powerful proinflammatory properties through activation of such
proinflammatory cells. For example, C5a induces the expression of IL-1β
and IL-8 in mononuclear cells and enhances the release of IL-6 and TNF-α
(Schindler, Gelfand & Dinarello, 1990). ARDS is mediated by the
recruitment and activation of inflammatory cells such as neutrophils,
eosinophils, monocytes and T lymphocytes (Meliopoulos et al., 2014).
Similar to SARS-CoV-2, MERS-CoV or SARS-CoV as well as other respiratory
virus such as the Influenza virus can be associated with a similar rapid
progression to ARDS. MERS-CoV drives the production of inflammatory and
chemotactic cytokines as well as chemokines such as CXCL-10, CCL2, IL-8,
IL-12 and IFN-γ, which can cause severe lung damage (Jiang et al., 2019;
Jiang et al., 2018). High levels of C5a have been also found in
bronchoalveolar lavage fluid (BAL) of individuals affected by
viral-mediated acute lung injury (ALI) but not in BAL from recovered
patients with ARDS (Wang, Xiao, Guo, Li & Shen, 2015). Further, the
histopathological changes in the lung from patients infected with
influenza virus mimic those infected with SARS-CoV (Meliopoulos et al.,
2014). The influenza virus is highly pathogenic replicating in the lower
respiratory tract. It drives pulmonary complement activation leading to
high levels of C5a in BAL and serum (Ohta, Torii, Imai, Kimura, Okada &
Ito, 2011). In experimental, highly pathogenic avian influenza H5N1
infection, C5a contributes ALI in mice. Further, inhibition of C5a by a
C5a-specific mAb alleviated such lung injury in H5N1 virus infection in
this model (Sun et al., 2013). Similarly, anti-C5a mAb treatment
improved the outcome of H7N9 virus infection in African green monkeys;
in particular such treatment attenuated ALI and systemic inflammation,
i.e. the “cytokine storm”(Sun et al., 2015). Maybe even more
important, blockade of the C5a/C5aR1 axis reduced lung and spleen tissue
damage and reduced inflammatory responses in experimental MERS-CoV
infection. Also, it decreased viral replication in the lung. Recently,
it was further shown that C3-deficient mice infected with SARS-CoV
suffered from less respiratory dysfunction associated with less
recruitment of neutrophils and inflammatory monocytes in the lungs and
less cytokine and chemokine levels (Gralinski et al., 2018).
Taken together, the available data suggest that complement is activated
in highly pathogenic coronavirus infection and contributes to the
development of ALI that has been observed in experimental models and in
patients. In the following sections, we will discuss complement-mediated
microvascular injury in COVID-19 patients, complement genetics as a
potential clue to race differences in COVID-19 severity, options to
target complement in COVID-19 patients with atypical ARDS and TMA and
potential intersection of complement with other inflammatory pathways,
offering the opportunity for concurrent interventions.