The grand escape-how pathogens outsmart the human complement system

The g and escape – how pa hogens ou sma he human
complemen sys em
☆
A.A. Nowacka
a,1
, L. So do Viei a
b,1
, V. Pe
c,1
, B. Fage ¨
ang
d,e
, R. Wü zne
,*
,
M. Ohms
a,*
a
Ins i u e o Sys emic In lamma ion Resea ch, Uni e si y o Lübeck, Lübeck, Ge many
b
Di ision o Pulmona y, C i ical Ca e, and Sleep Medicine, Depa men o Medicine, Uni e si y o Flo ida, Gaines ille, FL, Uni ed S a es o Ame ica
c
Depa men o Neph ology, Ins i u e o Clinical and Expe imen al Medicine, P ague, Czech Republic
d
Depa men o Immunology, Uni e si y o Oslo, and Oslo Uni e si y Hospi al, Oslo, No way
e
Depa men o Clinical Immunology, Rigshospi ale , and Facul y o Heal h and Medical Sciences, Uni e si y o Copenhagen, Copenhagen, Denma k
Ins i u e o Hygiene & Medical Mic obiology, Medical Uni e si y o Innsb uck, Innsb uck, Aus ia
ARTICLE INFO
Edi o : Vi iana P. Fe ei a
Keywo ds:
Immune e asion
Complemen
Pa hogen
In ec ion
Bioma ke s
The apy
ABSTRACT
In ec ious diseases emain a signi ican cause o mo ali y and mo bidi y wo ldwide. Complemen is a c i ical
componen in he de ense agains pa hogens and despi e hei g ea di e ences, i uses, bac e ia, ungi, and
p o is s ha e all de eloped simila mechanisms o e asion om he human complemen sys em. Using examples
om ou mic obial g oups ( i uses, bac e ia, ungi and p o is s), his e iew expands on examples o hese
di e en mechanisms o e asion. The mechanisms a e g ouped as (A) a oidance o ecogni ion, (B) a oidance o
e adica ion, (C) a oidance o ac i a ion and unc ion, o (D) use o he complemen p o eins o en y in o he
hos , in acco dance wi h he classi ica ion ini ially p oposed in 1999. Fu he mo e, his e iew will expand on
no el desc ip ions o complemen e asion, o example in ol ing in acellula complemen . Taken oge com-
plemen e asion is an essen ial ool used by pa hogens no only in a de ensi e manne , p o ec ing he pa hogen
om he hos , bu can also employed in an agg essi e manne o aid he in asion o he hos . Unde s anding
hese mechanisms has al eady in luenced diagnos ic and he apeu ic ools, including accine de elopmen , and a
u he expansion o e asion molecules as bioma ke s, accines o a ge s o he apy appea s likely in he u u e.
1. In oduc ion
The complemen sys em is essen ial o many biological unc ions,
among he mos impo an is hos de ense agains pa hogens (Me le
e al., 2015a; Me le e al., 2015b). No only does complemen ha e he
abili y o kill bac e ia di ec ly by damaging hei cell memb anes (Xie
e al., 2020), bu i also enhances phagocy osis by opsoniza ion, in-
c eases immune cell ec ui men by chemo axis, and egula es he
g ea e immune s a e o he hos (Mo gan, 1999). The impo ance o he
complemen sys em can be demons a ed by he la ge numbe o e asion
s a egies ha pa hogens ha e de eloped du ing hei co-e olu ion wi h
humans.
The i s comp ehensi e e iew e iewing complemen e asion
mechanisms ac oss all ou majo kingdoms – i uses, bac e ia, ungi
and p o is s – was published in 1999 (Wü zne , 1999). Be o e hen, only
single g oups o mic oo ganisms o e en only single pa hogens had been
looked a . This e iew om 1999 in oduced he concep o dual ca e-
go isa ions. This ca ego isa ion classed hese mechanisms in o wo
pa s, whe e mos pa hogens aim o p ima ily a oid ecogni ion
( e iewed in sec ion A), bu upon ecogni ion can employ an a senal o
a oid des uc ion ( e iewed in sec ion B-D).
Howe e , since 1999 new subclasses and examples o mechanisms
ha e been p oposed, especially o he la e , whe e he in ade can
igno e any p o ec i e measu es, and ins ead employs i s a mamen-
a ium o in ade he hos ( e iewed in sec ion D2-D3). Fu he mo e, a
new subca ego y has only e y ecen ly become e iden . This ca ego y
in oduces in acellula complemen as a a ge o e asion ( e iewed in
sec ion B6).
☆
This a icle is pa o a Special issue en i led: ‘Complemen Sys em Du ing In ec ious Disease’ published in Immunobiology.
* Co esponding au ho s.
E-mail add esses: [email p o ec ed] (R. Wü zne ), [email p o ec ed] (M. Ohms).
1
Equal con ibu ion: These au ho s con ibu ed equally o his wo k.
Con en s lis s a ailable a ScienceDi ec
Immunobiology
jou nal homepage: www.else ie .com/loca e/imbio
h ps://doi.o g/10.1016/j.imbio.2025.153126
Recei ed 17 Ap il 2025; Recei ed in e ised o m 1 Augus 2025; Accep ed 4 Oc obe 2025
Immunobiology 230 (2025) 153126
A ailable online 24 Oc obe 2025
0171-2985/© 2025 The Au ho s. Published by Else ie GmbH. This is an open access a icle unde he CC BY license (
h p://c ea i ecommons.o g/licenses/by/4.0/ ).
This e iew will ocus on di e en mechanisms hough which pa h-
ogens can e ade complemen . We ha e employed wo app oaches o
ou e iew. One was o s udy he mos ecen e iews on his opic and
he ci ed o iginal e e ences he ein. The second app oach in ol ed
conduc ing a b oad li e a u e sea ch in PubMed and Google Schola
using he e ms “complemen AND e asion”, along wi h ela ed key-
wo ds o ensu e comp ehensi e co e age. We sys ema ically examined
bo h e iew a icles and o iginal esea ch pape s, no only o ga he
es ablished indings bu also o iden i y ecu ing hemes, o e looked
mechanisms, o eme ging concep s. When a pa icula aspec o e ed a
no el angle, illed a knowledge gap, o challenged exis ing unde -
s anding, we pu sued i in g ea e dep h o gain a mo e nuanced
pe spec i e on he opic.
2. Complemen in immune de ense agains he in ade
2.1. Ac i a ion o complemen
Desc ip ion o complemen ac i a ion and egula ion is ou o scope
o his e iew, and we e e he eade o comp ehensi e pape s pub-
lished elsewhe e (Me le e al., 2015a). In b ie , he complemen sys em
can be ac i a ed by h ee pa hways, he classical (CP), lec in (LP) and
al e na i e (AP) pa hway. Each pa hway has a dis inc ini ia ing
mechanism ha allows ecogni ion o a b oad spec um o s uc u es.
The CP is ini ia ed by he binding o o he C1q molecule o p e-
bound immunoglobulins (Ig), IgM, and IgG, o speci ic pa hogen-
associa ed molecula pa e ns (PAMPs). LP ac i a ion occu s h ough
he in e ac ion o mannose-binding lec in (MBL), icolin-1, -2 o -3, o
collec in-11 wi h ca bohyd a e moie ies displayed on he pa hogen
su ace. The ac i a ion o he CP and LP leads o he clea age o C2 in o
C2a and C2b, and C4 in o C4a and C4b, and he subsequen o ma ion o
he C3 con e ase C4b2a. The AP is ac i a ed by he spon aneous hy-
d olysis o a labile hioes e bond p esen in he C3 molecule, gene a ing
a biologically ac i e con o ma ion, C3(H
2
O). C3(H
2
O) hen associa es
wi h ac o B (FB) and ollowing an in e ac ion wi h ac o D (FD), o
o m he C3 con e ase C3(H
2
O)Bb.
All h ee complemen pa hways con e ge a he o ma ion o a C3
con e ase, which exis s in wo main o ms: he C3bBb and he C4b2a.
The con e ases clea es C3 in o C3a and C3b, which binds co alen ly o
su aces wi h exposed hyd oxyl g oups, such as mic obial su aces.
Binding o C3b o a su ace s abilizes he molecule and inc eases com-
plemen ac i a ion h ough he ampli ica ion loop.
C3b hen joins he enzyma ic complexes, o ming he C5 con e ases
(C3bBbC3b o C4b2aC3b). The C5 con e ase clea es he inac i e C5
molecule in o wo ac i e agmen s: he anaphyla oxin C5a and he
bioac i e agmen C5b, and he eby ini ia es he e minal pa hway. C5b
sequen ially binds o C6, C7, and C8, ollowed by se e al C9 molecules. This
assembles he memb ane a ack complex (MAC), also known as C5b-9 o
he e minal complemen complex (TCC). The C5b-8 complex is embedded
in o he a ge memb ane, a e which C9 molecules polyme ize o o m a
po e, leading o calcium in lux and lysis o he pa hogen (Me le e al.,
2015a). Fu he de ails on MAC egula ion a e discussed below.
3. Complemen e ec o unc ions
Complemen is highly capable a p e en ing in ec ion by in ading
pa hogens and is a cen al componen o bo h he adap i e and inna e
immune esponses. Complemen e ec o unc ions include, bu a e no
limi ed o:
•Opsoniza ion o mic obes o imp o e phagocy osis
•Chemoa ac ion o immune cells o si es o in ec ion
•Fo ma ion o memb ane a ack complex (MAC) on mic obe
memb anes
•Ac i a ion o phagocy es o imp o e immune unc ions
•Connec ion o he inna e and adap i e immune sys em
3.1. Opsoniza ion
Complemen -media ed opsoniza ion is a key immune p ocess in
which ac i a ed agmen s o complemen p o eins – p ima ily C3b,
iC3b, and C4b – bind co alen ly o mic obial su aces, ypically glyco-
p o eins. This deposi ion e ec i ely " ags" mic obes o ecogni ion by
he immune sys em. These complemen agmen s ac as opsonins,
acili a ing he engagemen o complemen ecep o s (CR1, CR3, and
CR4) on phagocy ic cells such as mac ophages and neu ophils. This
in e ac ion p omo es phagocy osis and esul s in he clea ance o he
mic obe (Vandend iessche e al., 2021; Lamb is e al., 2008).
3.2. Chemoa ac ion
Chemoa ac ion is he mo emen o cells in he di ec ion o
inc easing concen a ions o a signaling molecule. This occu s in im-
muni y, in which immune cells a e a ac ed o an a ea o in lamma ion
h ough he binding o a ious signaling molecules, including comple-
men agmen s (Fe nandez e al., 1978). Complemen ac i a ion gen-
e a es he anaphyla oxins, C3a and C5a, which a e e y po en
chemoa ac an s. Anaphyla oxins bind o he ecep o s C3aR, C5aR1
and C5aR2 and can induce he mig a ion o leukocy es exp essing he
C3aR and C5aR1 ecep o s (Klos e al., 2009). Bo h C3a and C5a a e
chemo ac ic o g anulocy es (neu ophils, eosinophils and basophils),
monocy es/mac ophages and mas cells. In addi ion, C5a is also
chemo ac ic o dend i ic cells (DCs), ge minal cen e B cells and T cells
(Klos e al., 2009).
3.3. Mechanisms o MAC
The MAC is a c ucial componen o he immune sys em’s de ense
agains pa hogens, pa icula ly bac e ia. MAC o ma ion begins when
he complemen sys em is ac i a ed on he su aces o pa hogens,
esul ing in he clea age o complemen componen C3 and e en ually
C5. The C5b o ms a s able C5b-6 complex upon binding o C6, which
hen associa es wi h C7, he limi ing molecule o his assembly
(Wü zne , 2001), o c ea e a i mly a ached C5b7 complex on he
memb ane (Me le e al., 2015a). The subsequen ec ui men o C8
causes memb ane p o usions and o ms a binding si e o C9 (B annen
and Sode z, 2007). Once he i s C9 molecule in eg a es in o he C5b–8
complex, addi ional C9 molecules join, o ming a po e ha dis up s he
bac e ial cell memb ane and induces lysis (Ramm e al., 1982).
The MAC is adi ionally known o i s abili y o lyse g am-nega i e
bac e ia. G am-nega i e bac e ia a e pa icula ly ulne able o MAC
lysis due o he ou e memb ane and hei ela i ely hin pep idoglycan
laye . G am-posi i e bac e ia, on he o he hand, ha e long been
conside ed esis an o MAC-media ed lysis because o hei hick
pep idoglycan walls. Howe e , his iew is becoming inc easingly
challenged. Recen s udies ha e shown ha MAC componen s can
assemble on G am-posi i e bac e ia a ce ain si es, and ha he e ec-
i eness o his assembly a ies among bac e ial s ains (Be ends e al.,
2013). In ac , de iciencies in MAC componen s ha e been shown o be
associa ed wi h inc eased suscep ibili y o in ec ions, no only by G am-
nega i e bac e ia bu also by ce ain G am-posi i e bac e ia (Ska um
e al., 2011).
Some G am-posi i e species, such as S ep ococcus pyogenes, ha e
e ol ed mechanisms o e ade MAC o ma ion – o example, by p o-
ducing p o eins ha block essen ial s eps in he po e o ma ion (Akesson
e al., 1996). This demons a es ha he hick pep idoglycan ba ie
alone is no necessa ily su icien o p o ec ion agains MAC-induced
damage (Akesson e al., 1996). Fu he mo e, he classical no ion ha
he MAC simply o ms po es s e ching h ough bac e ial en elopes o
cause cell dea h is s ill deba ed; e idence sugges s ha he mechanism
may no in ol e comple e memb ane pene a ion in all cases (Maye ,
1972). Local assembly o he MAC a he bac e ial su ace is i al o
e ec i e bac e icidal ac i i y, wi h memb ane-bound C5 con e ases
A.A. Nowacka e al.
Immunobiology 230 (2025) 153126
2
playing a c i ical ole in gene a ing MAC po es ha can pene a e he
bac e ial memb anes (Doo duijn e al., 2019). Memb ane-bound C5
con e ases a e c ucial o o ming bac e icidal MAC po es because hey
clea e C5 di ec ly on he bac e ial su ace, enabling he uns able C5b
agmen o apidly bind o C6 and C7. This immedia e, localized as-
sembly main ains C5b’s ac i e s a e and suppo s e ec i e MAC inse -
ion. P eassembled C5b6 o med in solu ion lacks his coo dina ion and
quickly becomes non- unc ional (Hees e beek e al., 2019).
Recen indings emphasize ha o e ec i e bac e ial killing, MAC
mus damage bo h he ou e memb ane and inne memb ane o g am-
nega i e bac e ia, highligh ing he in ica e na u e o bac e ial de-
enses agains immune a acks (Doo duijn e al., 2019). O e all, he
assembly and unc ion o MAC po es a e essen ial o obus immune
esponses agains a wide ange o bac e ia.
3.4. Ac i a ion o phagocy es
The anaphyla oxins bind o a b oad spec um o immune and non-
immune cells. They ac i a e mas cells and basophils o elease his a-
mine and hey igge an oxida i e bu s in mac ophages, neu ophils,
and eosinophils. Mo eo e , hey egula e asodila ion, inc ease he
pe meabili y o small blood essels, and induce smoo h muscle con-
ac ions (Yasuda e al., 2023). Ac i a ed neu ophils play a c ucial ole
in he inna e immune esponse, pa icula ly h ough hei in e ac ion
wi h complemen ac o s. Among he complemen clea age p oduc s,
C5a and C5a des-A g signi ican ly enhance neu ophil unc ions, while
C3a and C4a show minimal e ec s. These ac i e agmen s s imula e
changes in memb ane po en ial, in acellula pH, glucose up ake, and
cellula size, leading o inc eased phagocy osis and eac i e oxygen
species (ROS) gene a ion (Vandend iessche e al., 2021; Mo is e al.,
2011; Messe e e al., 2018). C5a also modula es he exp ession o
c i ical neu ophil ac i a ion ma ke s and ecep o s, including C5aR1,
CD62L, CD10, and CD11b (Wohlgemu h e al., 2022). The C5a esponse
is cha ac e ized by apid kine ics, wi h dis inc phases obse ed o
depola iza ion and alkaliza ion, as well as delayed up egula ion o
ma ke s like CD11b and CD16 (Wohlgemu h e al., 2022).
Concen a ion-dependen s udies o C5a le els indica es i s binding o
speci ic ecep o s, wi h e ec i e concen a ions in he nanomola ange,
aligning wi h in lamma ion- ela ed le els (Wohlgemu h e al., 2022).
Impo an ly, he ac i a ion o neu ophils by C5a does no p omo e
pla ele -neu ophil complex o ma ion, sugges ing a di e en mecha-
nism o complemen -media ed ac i a ion (Wohlgemu h e al., 2022).
3.5. Linkage o he adap i e immune sys em
The complemen sys em has impo an oles in T cell biology,
including he egula ion o me abolism, egula ion o ac i a ion
h esholds, ecep o exp ession, and di e en ia ion. Fo example,
simul aneous signaling h ough pa e n ecogni ion ecep o s and an
anaphyla oxin ecep o on an igen p esen ing cells, a o s a ype 1 T
helpe esponse (Th1). The in acellula complemen sys em (complo-
some) a ec s cell physiology h ough di ec c oss- alk wi h o he
in acellula inna e senso sys ems – so called in lammasomes
(T ian a ilou e al., 2016; A bo e and Kempe , 2016). This egula es, o
example, human Th1 esponses by d i ing he signaling pa hways and
me abolic ep og amming necessa y o induce e ec o esponses
(Pa lo e al., 2008; S ainic e al., 2008; Lalli e al., 2008; Heege e al.,
2005; Song, 2012; Liu e al., 2005; Kole e al., 2015; Hess and Kempe ,
2016). Fu he mo e, complemen con ols he induc ion and con ac ion
o T cell esponses (Dunkelbe ge and Song, 2010; Cla ke and Tenne ,
2014; Kole e al., 2013). Complemen ’s egula o y e ec s can he e o e
be media ed di ec ly (by modula ing he T cell i sel ) and/o indi ec ly
(by a ec ing he unc ion o an igen p esen ing cells) (Wes e al., 2018).
Addi ionally, a ecen s udy ound ha he T cell-dependen B cell
ma u a ion p ocess is dependen on C3a and C5a signaling. Speci ically,
ge minal cen e B cells down egula e hei su ace inhibi o s excep o
CD59, which inc eases complemen ac i a ion on hei su ace while
s ill p o ec ing hem om cell lysis (Cumpelik e al., 2021). T cell-
dependen an ibody p oduc ion was educed in C1q-de icien mice,
sugges ing he impo ance o he CP. T cell-independen B cell esponses
may also be dependen on anaphyla oxin signaling and in pa icula AP
ac i a ion (Cumpelik e al., 2023). O no e, an in e ac ion be ween C3
agmen s and complemen ecep o s in luences he h eshold o B cell
ac i a ion (Melche s e al., 1985; Kulik e al., 2011; Ko ´
acs e al., 2021).
4. Complemen egula o s
The complemen sys em’s powe ul unc ions can ha m he hos ,
especially when ac i a ed inapp op ia ely du ing condi ions like issue
ischemia and epe usion. To p e en damage o hos cells while e ec-
i ely a ge ing o eign ma e ials, mammals ha e de eloped a ious
inhibi o y p o eins o egula e complemen ac i i y.
C1 inhibi o (C1INH) inac i a es C1 and C1s in he CP and MASP-1
and MASP-2 in he LP, hus inhibi ing he ini ia ion o hese wo pa h-
ways (Da is e al., 2010). Complemen ac o H (FH) and complemen
ac o I (FI) a e key egula o s o he AP, wi h FI inac i a ing C3b by
o ming iC3b in he p esence o co ac o s such as FH (Ro e si e al.,
2011). FH also compe es wi h FB o binding o C3b and he e o e ac-
cele a es he decay o he C3 con e ase complex (Fe ei a e al., 2010).
Memb ane co ac o p o ein (MCP, CD46) ac s as a co ac o o FI,
acili a ing he clea age o C3b and C4b (Liszewski e al., 1991). Decay-
accele a ing ac o (DAF, CD55) enhances he dissocia ion o C3 con-
e ases o all h ee pa hways (Hou cade e al., 2002). CR1 ac s by
emo ing opsonized immune complexes and has a co ac o ac i i y o
FI (Khe a and Das, 2009). Th ombomodulin enhances FI-media ed
inac i a ion o C3b and can des-a gina e anaphyla oxins, u he
modula ing complemen ac i i y (Del aeye e al., 2009). Vi onec in
binds o C5b-7 and C9, p e en ing hei inco po a ion in o memb anes
and inhibi ing polyme iza ion (P eissne e al., 1989). Clus e in binds o
C5b-7, C8 and C9 and simila ly inhibi s polyme iza ion wi hou
comple ely p e en ing MAC assembly (Tschopp e al., 1993). CD59 is a
key egula o o he e minal pa hway and blocks he associa ion o C9
wi h C5b-8 o p e en MAC o ma ion (Fa kas e al., 2002).
5. Complosome
In ecen yea s, no el insigh s in o complemen biology ha e un-
eiled he concep o cell-au onomous and in acellula complemen ,
e med he "complosome" (A bo e e al., 2016). This eme ging pa adigm
posi ions he complosome as a c ucial o ches a o o no mal cell
physiology, in luencing essen ial p ocesses such as mi ochond ial ac-
i i y, glycolysis, oxida i e phospho yla ion, cell su i al, and gene
egula ion. I s impac s ex end beyond immune cells, encompassing non-
immune cells like ib oblas s, as well as endo helial cells (Mahajan e al.,
2021) and epi helial cells (Kulka ni e al., 2019). Gi en hese oles, he
complosome eme ges as a cen al playe in main aining cell homeos asis
and egula ing e ec o esponses. The comp ehensi e e iew by Wes
and Kempe (Wes and Kempe , 2023) se es as an excellen esou ce,
p o iding de ailed in o ma ion on he signi icance o in acellula
complemen in cellula unc ions.
Addi ionally, C3 unc ions as a senso o in acellula pa hogens,
ac i a ing cell-in insic immuni y when a C3-bound pa hogen en e s he
cells (B ock and Pa mely, 2017). Fo ins ance, C3 bound o Lis e ia
monocy ogenes du ing an in ec ion o in es inal epi helial cells, acili a es
he clea ance o pa hogens by inducing au ophagy o he hos in es inal
epi helial cell (So ba a e al., 2018). These pieces o e idence demon-
s a e in acellula oles o C3 when ac i a ed C3/C3b is b ough in o
he cy osol by in asi e pa hogens. E asion mechanisms ela ed o
in acellula complemen ha e no ye been ex ensi ely desc ibed.
A.A. Nowacka e al.
Immunobiology 230 (2025) 153126
3
5.1. A oidance o ecogni ion – disguise
5.1.1. Dis up ion o an ibody-complemen in e ac ions
Th ough e olu ion, pa hogens ha e de eloped s a egies o a oid
ecogni ion by he complemen sys em. The ideal solu ion o pa hogens
is o a oid immune de ec ion in he i s place. Examples o s uc u al
ba ie s ha help o disguise pa hogens can be ound in Table 1. A
commonly used ea u e is molecula mimic y, de ined as he sha ing o
an igenic de e minan s be ween he pa hogen and hos (Fishelson,
1991). The pa hogen is hus ecognized by he hos ’s immune sys em as
a sel -s uc u e and limi ed immune esponse is igge ed. Molecula
mimic y s a egies a e also well desc ibed causes o au oimmuni y
(Cusick e al., 2012). Fo example, he M p o ein o S. pyogenes elici s he
o ma ion o au oan ibodies ha c oss- eac wi h hea myosin which
can cause hea damage (Fig. 1A) (Whi on and Feue , 2004).
An ibodies a e esponsible o many essen ial unc ions in he im-
mune sys em, and as such many pa hogens a emp o a oid an ibody
ecogni ion. The e is he e o e a s ong selec ion p essu e o pa hogens
o conceal neu alizing epi opes om human an ibodies. Common
mechanisms o an ibody escape include an igenic d i , epi ope shield-
ing and immune edi ec ion o dominan bu non-p o ec i e epi opes
(Qe qez e al., 2023). One s a egy o e ade an ibody binding is he
exp ession o highly immunogenic bu non-p o ec i e decoy epi opes
(Hsieh e al., 2021). The p ima y cha ac e is ics o decoy epi opes
in ol e edi ec ing he humo al esponse away om impo an epi opes
and p omo ing he p oduc ion o non-neu alizing an ibodies agains
non-essen ial epi opes. Ano he way o p o ec neu alizing epi opes is
by glycosyla ion. Fo ins ance, he human immunode iciency i us 1
(HIV-1) en elope is deco a ed wi h >25 N-linked glycosyla ion si es ha
shields neu alizing epi opes (Kim e al., 2015). Ano he s a egy is he
s uc u al blockade o neu alizing epi opes. In se e e acu e espi a o y
synd ome co ona i us (SARS-CoV) -1 and -2 he c oss- eac i e an ibody,
CR3022, binds a c yp ic epi ope ha is e ealed only in a speci ic
con o ma ion o ecep o -binding domain (RBD). This way he epi ope is
concealed om CR3022 un il binding o he ACE2 ecep o (Yuan e al.,
2020).
Ano he mechanism o p e en an ibody binding is he exp ession o
Fc ecep o s o Fc-binding p o eins on he pa hogen su ace. These
molecules engage he Fc egion o human IgG, which hus blocks
an ibody-dependen mechanisms. Fo ins ance, i uses belonging o he
amilies He pes i idae and Co ona i idae exp ess ecep o s ha esul
in he binding o non-speci ic IgG o he i uses o i us-in ec ed cells,
esul ing in he s e ic hind ance o i us-speci ic immune IgG (Dowle
and Vel i, 1984). In some cases an an ibody may bind o bo h he su -
ace epi opes and i al Fc ecep o s, called an ibody bipola b idging
e ec , which hinde s i us binding. This e ec i ely inhibi s mos
an ibody-dependen immune mechanisms (F ank and F iedman, 1989).
Some pa hogens can also clea an ibody-an igen complexes om hei
su aces as in he case o alphahe pes i us pseudo abies i us (PRV)
(Fa o eel e al., 1999), o pa asi es such as T ypanosoma (Balbe e al.,
1979; F e e and Reinwald, 1990).
5.1.2. Hiding o su ace molecules c ucial o complemen ecogni ion
Se e al pa hogens e ade complemen a ack by masking he moie ies
on hei su ace ha lead o complemen ac i a ion in he hos . Hiding
om an ibodies is desc ibed in sec ion A1.
Fo example, he binding o FH o he p e en ion o IgM binding o
hos cell su aces due o p esence o glycosaminoglycans may inhibi
complemen ac i i y (Dudek e al., 2022). Non ypeable Haemophilus
in luenzae s ains show ha a de ec in hei abili y o sialyla e LPS leads
o less i ulen s ains. This e ec is shown o be FH independen
(Figuei a e al., 2007) in con as o he FH media ed e ec o sialyla ed
Neisse ia gono hoeae (Ram e al., 1998). As such, se e al bac e ia ha e
adap ed s a egies o ei he syn hesize hei own sialic acids o u ilize
hos ’s machine y o sialyla e hei su aces, p e ending o be hos by
molecula mimic y (Fig. 1B) (Vim e al., 2004).
Mu an s o he ungal Aspe gillus species lacking genes associa ed
wi h pigmen a ion, display highe complemen deposi ion on i s su ace,
sugges ing a ole o melanin in he masking o complemen -ac i a ing
moie ies (Spe h and Rambach, 2012; Tsai e al., 1997; Tsai e al., 1998).
5.1.3. Capsules as ba ie agains complemen
Capsules shield bac e ia om ecogni ion and des uc ion by he hos
immune esponse. The capsule o Neisse ia meningi idis p e en s an i-
body media ed C1q ec ui men o he bac e ial su ace and inhibi s he
ini ia ion o he CP (Aga wal e al., 2014). The capsule also masks sub-
Table 1
S uc u al ba ie s.
Mic obial
class
Species Mechanism Complemen a ge E ec Li e a u e
Vi us SARS-CoV-1/-2 Epi ope masking Likely CP
ac i a ion
“Down” con o ma ion masks epi ope om an ibody
ecogni ion
(Yuan e al., 2020)
He pes i idae and
Co ona i idae
S e ic hind ance by binding
non-speci ic an ibodies
Likely CP
ac i a ion
S e ic hind ance by binding non-speci ic an ibodies (Dowle and Vel i,
1984; F ank and
F iedman, 1989)
HIV-1 Glycosyla ion o su ace Likely CP
ac i a ion
Glycosyla ion p e en s ecogni ion by hos ’s an ibodies,
p e en ing CP ac i a ion
(Ra ho e e al., 2017)
Fungi A. umiga us P e en ion o complemen
deposi ion
Complemen
agmen
deposi ion
Melanin migh mask complemen -ac i a ing moie ies on
he su ace o ungus
(Spe h and Rambach,
2012; Tsai e al., 1997;
Tsai e al., 1998)
Bac e ia Neisse ia
meningi idis
P e en ion o C3b deposi ion
and ac i a ion o CP
Inhibi s CP and
ampli ica ion loop
Capsule p e en s ac i a ion o CP and deposi ion o C3b,
hus p e en ing bo h CP and ampli ica ion loop.
(Aga wal e al., 2014;
Robe s, 1996)
Neisse ia gono hea Sialyla ion o LOS inhibi s all
ac i a ion pa hways
Inhibi s all
ac i a ion
pa hways
Sialyla ion o LOS in e e es wi h IgG binding, MBL
ecogni ion and ep esses AP ac i a ion h ough
enhanced FH binding and he e o e inhibi s all h ee
complemen pa hways
(Elkins e al., 1992;
Gula i e al., 2002)
S ep ococcus
pyogenes
Binding o human p o eins o
M-p o ein o a oid
complemen ac i a ion
Inhibi s all
ac i a ion
pa hways
M-p o ein in e ac s wi h many human p o eins such as
FH, IgG Fc domain and albumin o p e en complemen
deposi ion and phagocy osis
(Whi on and Feue ,
2004)
P o is Leishmania spp. Inhibi ion o MAC media ed
killing by su ace
MAC media ed
killing
Dis up ion o glycocalyx inhibi s suscep ibili y o MAC-
media ed killing
(Puen es e al., 1950;
Sp¨
a h e al., 2003)
A.A. Nowacka e al.
Immunobiology 230 (2025) 153126
4
capsula a ge s o C3b deposi ion, esul ing in he in e up ion o he
AP ampli ica ion loop (Robe s, 1996). The complex s uc u e o he
capsule he e o e s e ically hinde s he binding o C3b molecules o
complemen ecep o s on immune cells.
Fu he mo e, some bac e ia like Klebsiella pneumonieae, modi y hei
capsule composi ion by emo ing hamnobiose and mannobiose,
he eby inhibi ing ecogni ion by he LP (Fig. 1C) (Sahly e al., 2009).
The lipooligosaccha ide (LOS) in N. gono hea con ains a lac o-N-
neo e aose moie y which can be sialyla ed by he enzyme LOS sialyl-
ans e ase (Gilbe e al., 1996). The sialyla ion o LOS in e e es wi h
IgG binding, MBL ecogni ion, and ep esses AP ac i a ion h ough
enhanced FH binding, and he e o e inhibi s all h ee complemen
pa hways (Elkins e al., 1992; Gula i e al., 2002).
E ec i e complemen ac i a ion is c ucially dependen on p oximi y
o he pa hogen. Fo ins ance, IgG-C1q assembly elies on op imal an-
igen epi ope dis ibu ion, and p oximi y is necessa y o subsequen CP
ac i a ion (Diebolde e al., 2014). In addi ion o inhibi ing he binding
o C1q and o he complemen componen s o he bac e ial su ace, he
elonga ed O-an igen o Klebsiella pneumoniae inhibi s he e minal
complemen pa hway since any deposi ed C3b is oo a away om he
memb ane o allow u he ac i a ion o s abiliza ion a he su ace
(Me ino e al., 1992).
Acine obac e baumannii is a G am-nega i e bac e ium enowned o
i s excep ional esis ance o complemen -media ed killing, a key aspec
o i s se um esis ance. A cen al p o ec i e s uc u e is i s exopoly-
saccha ide capsule, which is composed o long-chain polysaccha ides
o med om epea ing ca bohyd a e uni s, and i s syn hesis is go e ned
by genes loca ed in he capsule locus. To da e, o e 128 capsule locus
ypes ha e been iden i ied, con ibu ing o signi ican s uc u al and
composi ional di e si y o capsula polysaccha ides among A. baumannii
s ains (Magda e al., 2025). This s uc u al a iabili y plays a c i ical
ole in immune e asion. The capsule ac s as a physical shield, p e en ing
he e ec i e deposi ion o inse ion o complemen componen s like
C3b, C4b, and he MAC in o he bac e ial su ace. No ably, al hough
MAC deposi ion can occu , especially in some capsule ypes,
A. baumannii o en su i es despi e MAC p esence, sugges ing incom-
ple e inse ion o in e e ence wi h po e o ma ion (Monem e al., 2020).
5.2. A oidance o e adica ion – emo al
5.2.1. Remo ing complemen agmen s om he pa hogen’s su ace
In case he pa hogen is unable o a oid ecogni ion, complemen
agmen s success ully deposi on i s su ace (Table 2). Many pa hogens,
howe e , ha e acqui ed he abili y o shed hese agmen s o a oid
des uc ion. A se um- esis an s ain o Salmonella (Salmonella minneso a
S218) emo es he MAC om i s su ace a e addi ion o C8 and C9
(Fig. 2A) hanks o an inabili y o he complex o inse in o he hy-
d ophobic ou e memb ane o he pa hogen (Joine e al., 1982).
5.2.2. P o ease-dependen mechanisms o complemen e asion
The neu aliza ion o complemen componen s h ough deg ada ion
in o smalle , non- unc ional agmen s ep esen s a key e asion s a egy
o en u ilized by bac e ia. Two mechanisms o p o eoly ic clea age o
complemen p o eins a e desc ibed. Fi s ly, he dis up ion o he com-
plemen cascade h ough pa hogen-exp essed p o eases. Secondly, he
acquisi ion and ac i a ion o hos -de i ed plasminogen o indi ec
plasmin-media ed complemen deg ada ion (E me e al., 2019).
Pa hogenic p o eases ha e a wide ange o subs a es in he com-
plemen cascade. The clea age o immunoglobulin and C1q by e.g.,
Pseudomonas elas ase (PaE) o alkaline p o ease (PaAP), in e e es wi h
he ac i a ion o he CP by p e en ing he o ma ion o o de ed IgG Fc
hexame s. This, in u n, comp omises he s uc u al pla o m needed o
s ong Fc–C1q in e ac ions, e ec i ely blocking downs eam comple-
men ac i a ion (Rooijakke s and Van S ijp, 2007).
A
CP
sel -looking
an igen
sel an igen
1) no an ibodies a e p oduced -> no classical pa hway ac i a ion
2) au oan ibodies a e p oduced -> au oimmuni y
Two possible ou comes:
C5b-9
B
C3b C5b
C5b-9
C3b C5b
iC3b
ac o H
sialic
acid
C
LP
saccha ide
emo al
C5b-9
LP
Fig. 1. A oidance o ecogni ion–disguise. (A) Unde no mal condi ions, ac i a ion o he CP ia an ibody-an igen in e ac ions wi h C1q lead o p ope clea ance o
pa hogens. Howe e , some pa hogens, such as S ep ococcus pyogenes, can p esen an igens ha esemble hos an igens, hus disguising hemsel es as sel ; a key
example is he M p o ein, a majo i ulence ac o ha mimics hos an igens h ough molecula mimic y, pa icula ly in i s N- e minal egion, enabling he bac e ia
o e ade he hos ’s immune sys em by appea ing simila o hos issues. (B) Complemen ac i a ion leads o he po en ac i a ion o he memb ane a ack complex.
Sialic acid enhances he binding o FH o hos cells (and hus complemen inhibi ion), and hus he deco a ion o hos ’s sialic acids ei he by s ealing o de no o
syn hesis is a common s a egy o complemen egula ion. (C) Modula ion o complemen -ac i a ion molecules om pa hogen’s su ace is ano he common
mechanism o e ade complemen a ack. Fo example, K. pneumonia lacking mannose-poo O an igens a e less suscep ible o killing by poly-
mo phonuclea leukocy es.
A.A. Nowacka e al.
Immunobiology 230 (2025) 153126
5

Many pa hogens deg ade C3 as a cen al componen o he comple-
men cascade, ci cum en ing he downs eam complemen unc ions
like opsoniza ion, phagocy osis, signaling h ough anaphyla oxin e-
cep o s and MAC o ma ion. S. pyogenes exo oxin B (SpeB), a cys eine
p o ease and an impo an i ulence ac o in G oup A S ep ococcus
(GAS) in ec ions, deg ades se um C3 and enables GAS o esis com-
plemen damage, opsoniza ion and p e en s phagocy osis (Kuo e al.,
2008). The clea age o C3 by he au o anspo e NaIP om Neisse ia
meningi idis occu s ou amino acids ups eam om he na u al C3
clea age si e and p oduces sho e C3a-like and longe C3b-like ag-
men s (Del To dello e al., 2014). The C3b-like agmen has highe a -
ini y o deg ada ion by hos complemen egula o s, FH and FI, and
does no lead o C3b deposi ion on he bac e ial su ace (Del To dello
e al., 2014).
S aphylococcus au eus elies on a whole a senal o i ulence ac o s o
escape he hos immune esponse including he six se ine-p o ease-like
p o eins, SplA o SplF. No ably, SplB unc ions as a po en and b oad-
spec um p o ease ha a ge s mul iple complemen componen s,
e ec i ely comp omising he in eg i y o he en i e complemen sys em
(Dasa i e al., 2022). I inac i a es C3, C4 and ac i a ion agmen s C3b
and C4b by p e e en ially clea ing hei alpha chains. Mo eo e , i can
clea e he componen s o he e minal complemen pa hway, C5, C6, C7,
C8 and C9 (Dasa i e al., 2022). Thus, h ough he exp ession o one
mul i unc ional p o ease S. au eus escapes wo majo unc ions o he
complemen sys em, he C3b-media ed phagocy osis as well as he MAC
deposi ion on he bac e ial su ace.
No only bac e ia e ade complemen ac i a ion h ough p o ease
exp ession. The p esence o he complemen -deg ading ungal se ine
p o ease Alp1 was shown in he supe na an o Aspe gillus umiga us
cul u es in ce eb ospinal luid (CSF) (Rambach e al., 2010). Alp1 has a
clea age a ini y o he complemen p o eins C1q, C3, C4, C5, MBL, and
FD (Rambach e al., 2010; Behnsen e al., 2010).
T ypanosoma c uzi displays a su ace complemen egula o y p o ein
(CRP) which binds C3b. I is belie ed ha he CRP-C3b complex is hen
clea ed by he pa asi ic cys eine p o ease educing bo h C3 con e ase
o ma ion and C3b opsoniza ion on he pa hogen’s su ace (Fig. 2B)
(No is, 1996a; No is, 1996b).
5.2.3. Use o enzymes o he coagula ion cascade o e asion
In addi ion o hos -de i ed complemen egula o s, pa hogens can
also hijack hos p o eases o a enua e complemen ac i a ion, e.g.
plasminogen ia plasminogen binding p o eins. Once bound o such a
mic obial ecep o , plasminogen becomes accessible and can be ac i-
a ed by ei he human o mic obial ac i a o s esul ing in o i s ac i e
o m, plasmin. Plasmin supp esses complemen a he le el o C3 and C5,
by clea ing hese cen al p o eins (Fig. 2C) (Po empa and Po empa,
2012). Plasminogen is, as a componen o he coagula ion sys em,
abundan and hus omnip esen in he ci cula ion, u ning i in o an
easily accessible a ge o many human pa hogens including: Haemo-
philus in luenzae (Ba hel e al., 2012), Pseudomonas ae uginosa (Kune
e al., 2007), Bo elia bu gdo e i (B isse e e al., 2009), S ep ococcus
pneumoniae (Be gmann e al., 2004), S. au eus (Koch e al., 2012), and
Candida albicans (Luo e al., 2009). Ano he well s udied example o
plasminogen acquisi ion and ac i a ion is Lep ospi a. A leas eigh
p o eins ac as plasminogen-binding ecep o s o Lep ospi a, including
he majo ou e memb ane p o ein, LipL32 (Viei a e al., 2010). Ac i-
a ion o plasminogen ei he happens h ough mic obial p o eins on he
su ace o Lep ospi a o hos -de i ed ac i a o s, like u okinase- ype
Table 2
Shedding o des uc ion.
Mic obial
class
Species Mechanism Complemen a ge E ec Li e a u e
Vi us
Alphahe pes i us
Pseudo abies i us,
Clea ance o an ibody-an igen
complex CP ac i a ion Clea ance o an ibody-an igen complex
p e en s ecogni ion by CP (Fa o eel e al., 1999)
Fla i i us P omo ing clea age o C4 C4
NS1 p omo es clea age o C4 in o C4b,
and also p omo es he ec ui men o
C4BP, inac i a ing C4.
(A i u nan e al.,
1950)
RSV
Rhino i us, Polio 2
Vi us
C3 deg ading p o eases C3
C3 deg ading p o eases inhibi s
in acellula opsoniza ion by
complemen .
(Tam e al., 2014)
Bac e ia
K. pneumoniae Remo al o suga moie ies LP ecogni ion Remo al o suga moie ies on capsule
p e en s ecogni ion by LP (Sahly e al., 2009)
Pseudomonas spp. Pa hogen p o eases clea ing
complemen C1q Clea age o C1q a ge s he CP (Rooijakke s and Van
S ijp, 2007)
Salmonella spp. Shedding complemen om he
pa hogen’s su ace Assembling MAC Complemen ac i a ion impai ed (Joine e al., 1982)
S ep ococcus pyogenes Deg ada ion o C3 by p o ease
S ep ococcal py ogenic exo oxin B C3 Impai s opsoniza ion and all
complemen pa hways (Kuo e al., 2008)
S ep ococcus pyogenes Release o complemen -deg ada ing
p o eins om pa hogen su ace C5a Releases a C5a pep idase, inhibi ing
chemo ac ic po en ial o C5a.
(Be ge and Bj¨
o ck,
1995)
Neisse ia meningi idis NalP clea es C3 C3 and downs eam
opsoniza ion
Impai s opsoniza ion and he
anaphyla oxin e ec s o C3a.
(Del To dello e al.,
2014)
S aphylococcus au eus
Se ine p o ease-like p o ein B (SplB)
clea es C3-C9, and FB and ac i a ion
agmen s o C3 and C4
C3-C9, FB and
ac i a ion agmen s o
C3 and C4.
Blocks all complemen pa hways (Dasa i e al., 2022)
Fungus Aspe gillus umiga us Alp1 deg ades C1q, C3, C4, C5, MBL,
FD
C1q, C3, C4, C5, MBL,
FD
Reduced opsoniza ion and
phagoyc osis.
(Rambach e al., 2010;
Behnsen e al., 2010)
P o is T ypanosoma spp.
Clea ance o an ibody-an igen
complex CP ac i a ion Clea ance o an ibody-an igen complex
p e en s ecogni ion by CP
(Balbe e al., 1979;
F e e and Reinwald,
1990)
Clea age o C3b Remo al o C3b om
su ace
Binding o C3b o complemen egula o
y p o ein ende s i suscep ible o
clea age
(No is, 1996b)
A.A. Nowacka e al.
Immunobiology 230 (2025) 153126
6
plasminogen ac i a o (uPA) (Viei a e al., 2009). The bac e ia-
associa ed plasmin p e en s IgG and C3b deposi ion on he lep ospi al
su ace h ough clea age and inc eases su i al upon in ec ion.
The mala ia pa asi e, Plasmodium alcipa um, also binds human
plasminogen which hen ge s con e ed o plasmin, and leads o he
clea age o C3b, ul ima ely inhibi ing MAC ac i i y (Reiss e al., 2021).
5.2.4. Chemical modi ica ions o complemen p o eins
In addi ion o p o ease o pep idase clea age, some pa hogens ha e
also acqui ed he abili y o inhibi complemen by chemical modi ica-
ions. Fo example, he Leishmanial enzyme LPK-1, an ou wa d acing
su ace p o ein kinase, which is a e in euka yo ic cells, can cause C3
and C5 phospho yla ion, which is belie ed o inhibi clea age o hese
p o eins (Fig. 2D) (He moso e al., 1991).
5.2.5. Dis ac ing complemen ac i a ion o he mic obe
A sec e ed and hen ex acellula cys eine p o ease (SCP) o
S. pyogenes leads o he ac i a ion o complemen in he su oundings o
S. pyogenes, bu dec eased complemen deposi ion on he su ace o he
bac e ia (Be ge e al., 1997). As a seconda y mechanism o S. pyogenes,
SCP also eleases a C5a pep idase ha diminishes he e ec s o com-
plemen ac i a ion in he icini y o he bac e ia (Be ge and Bj¨
o ck,
1995). This is simila o he e ec s o pneumolysin om S. pneumoniae
which also causes complemen ac i a ion away om he su ace o he
mic obe (Fig. 2E) (Mi chell and And ew, 1997).
In one s udy, galac osaminogalac an (GAG), a molecule sec e ed by
Aspe gillus du ing co-cul u e wi h human pla ele s, was shown o induce
complemen ac i a ion and deposi ion on he pla ele s, he eby educing
hei iabili y. Howe e , i emains unclea whe he his p ocess also led
o educed complemen deposi ion on he Aspe gillus i sel , as his aspec
was no add essed in he s udy (Deshmukh e al., 2020). Pla ele loss can
po en ially lead o a highe hemo hage and consequen ly o mo e ac-
cess o ee heme o he ungus, a key sou ce o i on.
T ypanosoma b ucei e ades hos immuni y h ough he apid in e -
naliza ion and ecycling o i s dense coa o a ian su ace glycop o eins
(VSG). This high u no e is c ucial o he emo al o hos immune
e ec o s, including an ibodies and o he co alen ly bound complemen
p o eins. These p o eins a e a ge ed o deg ada ion and hus p e en ed
C3b C3b C3b
C3b
C3b C3b
iC3b
C3b
C3b C3b
iC3b
iC3b iC3b iC3b
iC3b
iC3b
iC3b
C3b
C3b C3b
iC3b
iC3b
iC3b
C3b
C3b C3b
iC3b
iC3b
esponse esponse
diminished
C3b
iC3b
complemen
ecep o s
C3b
iC3b
C3b
iC3b
C3b
iC3b
complemen
deple ion
C1q
S ep ococcus
pneumoniae
pneumolysin
CP
C5b-9
plasminogen
plasminogen plasmin
C3, C5
9
9
-9
-9
9
9
9
C3b
C5b
C3
C5
C3-con e ase
C5-con e ase
P
C3
C5
Pphospho yla ed
o ms a e esis an
o clea age
P
C5b-9
C3b C5b
C5b-9
C6, C7
C5b-7
C8, C9
C3b C5b
C6, C7
C5b-7
C8, C9 C5b-9
C3b C5b
C5b-9
C3b
T p-CRP
AB
CD
EF
C
5
b
-
9
T p-CP
T p-CP
PA
uPa
Fig. 2. A oidance o e adica ion– emo al. (A) Se um- esis an Salmonella minneso a S218 sheds he MAC om i s su ace a e addi ion o C8 and C9 as he nascen
complex canno inse in o he hyd ophobic ou e memb ane o he pa hogen. (B) T ypanosoma c uzi displays CRP which binds C3b he e and he CRP-C3b complex is
hen clea ed by he pa asi ic cys eine p o ease CP downmodula ing complemen ac i a ion. (C) Pa hogens can hijack hos p o eases o a enua e complemen
ac i a ion, e.g. plasminogen ia pa asi ic plasminogen binding p o eins. Once bound, plasminogen can be ac i a ed by ei he human o mic obial ac i a o s o i s
ac i e o m, plasmin, which clea es C3 and C5 ia he ac ion o C5 and C3 con e ases. (D) Leishmanial su ace p o ein kinase LPK-1 can phospho yla e C3 and C5,
he eby inhibi ing hei clea age. (E) S. pneumoniae pneumolysin is eleased and hen causes complemen ac i a ion away om he su ace o he pa hogen. (F)
Complemen coa ed non-en eloped i uses induce in acellula complemen sensing leading o in lamma ion, whe eas en eloped i uses, such as RSV, lea e he C3b
on he ou side o he cell when engul ed, esul ing in a diminished complemen ac i a ion.
A.A. Nowacka e al.
Immunobiology 230 (2025) 153126
7
om ecycling back o he su ace. In doing so, he pa asi e minimizes
e ec i e opsoniza ion and complemen -media ed lysis, he eby a oid-
ing ecogni ion and clea ance by mac ophages du ing ch onic in ec ion.
In addi ion, he cons an shedding o VSG molecules ac s as a decoy
mechanism, di e ing complemen ac i a ion away om he pa asi e
and leading o ine ec i e complemen consump ion and po en ial
hypocomplemen emia (Onyilagha and Uzonna, 2019).
5.2.6. E ading a ack o in acellula complemen
The mechanism o in acellula complemen sensing is now ecog-
nized as a po en an i-mic obial mechanism in mammalian cells o sense
pa hogens ha ha e been agged by complemen and in e nalized (Tam
e al., 2014). En eloped i uses, such as espi a o y syncy ial i us
(RSV), a e belie ed o be esis an o in acellula complemen sensing
since hei opsoniza ion in he ex acellula space should occu on he
Table 3
Rec ui men o p o ec ion.
Mic obial
class
Species Mechanism Complemen a ge E ec Li e a u e
Vi us Sindbis Vi us Sialic acid on pa hogen su ace FH ec ui men Quan i y o sialic acid and subsequen
ec ui men o FH in luence AP ac i i y
(Hi sch e al., 1983; Hi sch
e al., 1950)
HIV-1 CD46, CD55 and CD59
inco po a ed in o HIV-1 pa icles
and unc ion o p o ec i ions
om complemen -media ed
des uc ion
CD46, CD55, CD59 P o ec s om complemen media ed
des uc ion by complemen - egula ing
mechanisms
(Mon e io i e al., 1994;
Sai uddin e al., 1995)
Human
Cy omegalo i us
Up egula ion o CD46 and CD55
on he in ec ed cells
CD46, CD55 Inhibi ion o all pa hways (Spille e al., 1996)
Vaccinia i us Inco po a ion o CD46, CD55, and
CD59 in o he ou e en elope
CD46, CD55, CD59 Inhibi ion o all pa hways (Vande plasschen e al.,
1998)
Bac e ia Neisse ia gono hoeae Glycosyla ion o pa hogen su ace FH Glycosyla ion enhances binding o FH
o pa hogen su ace, esul ing on
inhibi ion o complemen by FH
(Ram e al., 1998; Vim e al.,
2004)
Pseudomonas
ae uginosa,
Mycoplasma
hyopneumoniae
Binding o hos ’ FH and/o
plasminogen
FH Binding o FH and plasminogen leads
C3b deg ada ion and clea age o
plasminogen subs a es
(Kune e al., 2007; Yu e al.,
2020)
Bo elia bu gdo e i Binding o FH, FHL-1,
plasminogen
FH, FHL-1,
plasminogen, C7, C9
Enhances FH-media ed C3 inac i a ion,
inhibi s MAC, and deg ades
plasminogen subs a es
(Ha e al., 2018; Siegel
e al., 2008; Ha mann e al.,
2006)
Binding o FH, FH-L1 wi h
complemen egula o acqui ing
su ace p o eins
FH, FHL-1 Inhibi ion o C3 ac i a ion & C3
con e ase o ma ion, e mina ion o
he assembly and inally he in eg a ion
o he MAC in o he bac e ial
memb ane
(Locke, 2019)
Acine obac e
baumannii
Rec ui men o FI leads o
o ma ion o complex and
deg ada ion o C3b and C4b
C3, C3b, C4b, C5, FB,
FD & esp. FI
Inhibi ion o all h ee complemen
pa hways.
(Ries e al., 2022)
Lep ospi a sp. Once bound o he lep ospi al
su ace, FH and C4BP e ain
co ac o ac i i y o FI in he
clea age o C3b and C4b
FH, FH-like-1, C4BP,
Vi onec in
Binding o i onec in supp esses
polyme iza ion o C9
(F aga e al., 2016)
Fungus Candida albicans,
Aspe gillus umiga us
Rec ui men o FH and o he
complemen egula o s o su ace
FH, FHL-1, C4BP,
plasminogen
A oids ac i a ion o complemen (Kenno e al., 2018; Dasa i
e al., 2019; Me i e al., 2002;
Luo e al., 2011)
P o is T ypanosoma c uzi T ans e o hos cell sialic acids P omo es nega i ely
cha ged su ace
inhibi ing AP.
A oids ac i a ion o complemen -
media ed lysis and enhances
in acellula in asion
(Tomlinson e al., 1950;
Wea he ly e al., 2016; Dc-
Rubin and Schenkman, 2012)
Plasmodium spp. Rec ui men o C1-INH o he
su ace P MSP3.1 p o ein
C1-INH Inhibi ion o ac i a ing p o eases o he
complemen cascade C1s, MASP1, and
MASP2
(Kennedy e al., 1950)
Plasmodium alcipa um Glideosome-associa ed p o ein 50
(GAP50) binds o FH
FH, Binds FH and uses su ace-bound FH o
inac i a e C3b
(Schmid e al., 2015; Simon
e al., 2013)
Inhibi ion o e minal
complemen pa hway by CD59
ec ui men
P PIG-M P e en ion o MAC o ma ion on
pa hogen-in ec ed ed blood cells
(Kiyuka e al., 2020; Rashidi
e al., 2022; Wiesne e al.,
1997; Kim and Hong, 2007)
Inhibi ion o C3-con e ases by
C4BP ec ui men
Ci cumspo ozoi e
p o ein (CSP)
(Kha ab e al., 2022)
T ichomonas aginalis Inhibi ion o e minal
complemen pa hway by CD59
ec ui men
unknown P e en ion o MAC o ma ion and
pa hogen lysis
(Ib´
a˜
nez-Esc ibano e al.,
2015)
Leishmania species C4bBP ecep o Accele a ion o C3-con e ases decay (Pe ei a-Filho e al., 2023)
En amoeba his oly ica Rec ui men o CD46, CD55, and
CD59 by ogocy osis
Inhibi ion o all h ee pa hways (Mille e al., 2022)
Toxoplasma gondii Rec ui men o C4BP, FH o he
su ace o inac i a e su ace-
bound C3 and limi o ma ion o
he MAC
FH, C3b, C4BP Blockade o AP ampli ies complemen
ac i a ion & killing o T. gondii
(Rashidi e al., 2022; Siko ski
e al., 2020; Siko ski e al.,
2021)
A.A. Nowacka e al.
Immunobiology 230 (2025) 153126
8
lipid memb ane and hus be le behind in he p ocess o memb ane
usion (Fig. 2F) (Tam e al., 2014). Ano he impo an mechanism o
e ade in acellula complemen sensing is by he exp ession o C3
deg ading p o eases by i uses, such as human hino i us o polio i us 2
(Tam e al., 2014). This hen down egula es opsoniza ion o neu ali-
za ion in he ex acellula space and may also p e en in acellula
sensing once in e nalized. This appea s o be a common e asion s a egy
among i uses.
5.3. A oidance o ac i a ion and unc ion – Inhibi ion
5.3.1. In e up ion o complemen ac i a ion
The mos di ec s a egy o ab oga e complemen ac i a ion lies in
he in e up ion o he speci ic p o ein-p o ein in e ac ions ha
o ches a e he complemen cascade. Fo his pu pose, many pa hogens
exp ess p o eins ha ac as complemen inhibi o s ha can ei he block,
ca ch o des abilize complemen (Table 3).
A i al example o he supp ession o complemen ac i a ion h ough
C1q binding is he coa p o ein o human As o i us ype 1 (HAs V-1)
h ough he eplacemen o he C1 C1s e ame (Bonapa e e al., 2008;
Hai e al., 2010). Mo eo e , he HAs V-1 coa p o ein can bind MBL and
he e o e s ops LP ac i a ion. Since he C3 con e ase plays a cen al
ole in he cascade, i has become an ob ious a ge o pa hogenic in-
ade s. P ope din (FP), is a posi i e AP egula o , is blocked om
binding o bac e ial su ace by LPS (E me e al., 2019). The glyco-
p o ein C (gC) o He pes simplex i us 1 (HSV-1) impedes complemen
om wo si es: one gC domain blocks FP and C5 binding o C3b, and
ano he disables C3 and i s agmen s (Fig. 3A) (F ies e al., 1950; Hung
e al., 1994; Kos a asili e al., 1950).
Inhibi ion o he LP is ano he a ge o human pa hogens. Fo example,
T. c uzi u ilizes N- and O-glycosyla ed molecules on i s su ace o bind L-
and H- icolins, and MBL and he eby impedes MASP-1 and 2-induced C2
and C4 clea age (Kahn e al., 1996; Ces a i and Rami ez, 2010; Ribei o
e al., 2015). Addi ionally, he T. c uzi CRP binds he collagenous pa o L-
icolin and inhibi s he LP ini ia ion (Sosoniuk e al., 2014).
5.3.2. In e e ence wi h anaphyla oxin gene a ion and MAC assembly
In e e ence wi h MAC o ma ion ep esen s he inal oppo uni y o
pa hogens o e ade complemen -media ed lysis, and nume ous mic o-
o ganisms ha e e ol ed mechanisms o exploi his s age o he cascade.
CspA is a su ace-exposed p o ein o B. bu gdo e i ha inhibi s he
e minal complemen pa hway by di ec ly binding o he complemen
componen s C7 and C9, he eby blocking MAC o ma ion on he bac-
e ial su ace and in solu ion (Halls ¨
om e al., 2013). The lep ospi al
su ace p o ein LcpA binds o he human se um componen i onec in
and he eby supp esses polyme iza ion o C9 (F aga e al., 2016). The
S aphylococcus supe an igen-like 7 (SSL-7) p o ein p e en s MAC o -
ma ion a an ea lie s ep: i binds C5 and blocks i s in e ac ion wi h he
C5 con e ase leading o a lack o C5b (Bes eb oe e al., 2010).
Inac i a ing mechanisms o he anaphyla oxins a e also p esen in
bac e ia, such as S ep ococcus h ough ScpA (Lynskey e al., 2017). The
p o ein chemo axis inhibi o y p o ein o S. au eus (CHIPS) inhibi s
chemo axis o neu ophils and monocy es owa ds C5a by binding
di ec ly o C5aR1, hus p e en ing he chemo ac ic ac i i y o C5a
(Pos ma e al., 2004; de Haas e al., 2004).
MAC o ma ion on i us-in ec ed cells can lowe he i al load. Fo
ins ance, Zika i us inhibi s MAC o ma ion and complemen -media ed
lysis by binding e minal complemen componen s o i s i al E p o ein
(Malekshahi e al., 2020).
The sec e ed p o ein P a1 om C. albicans can bind C3a (as well as
o he C3 agmen s) and p e en e ec o mechanisms (Luo e al., 2018).
The ex acellula cys eine p o einase o he p o ozoa En amoeba
his oly ica deg ades he anaphyla oxins C3a and C5a, hus p e en ing he
immunomodula o y e ec s o he anaphyla oxins (Fig. 3B) (Reed e al.,
1950).
5.4. Employmen – hijacking and mimic y o hos complemen
componen s
5.4.1. Employmen o complemen egula o s o mic obial p o ec ion
Fo he hos s, complemen egula o s a e c ucial o p e en ing
damage o hos issue, hijacking o complemen egula o unc ions a e
widely used as a mechanism o e asion (Table 4). Mo eo e , as many
egula o s sha e s uc u al ea u es, pa hogens can syn hesize a small
a senal o ec ui a ious egula o s, hus p o iding a low-cos solu ion
o e ading hos ’ complemen (Lamb is e al., 2008). One pa icula ly
common and sha ed mechanism is he employmen o FH, FH like
p o ein-1 and FH- ela ed p o eins o inhibi complemen ac i a ion
ea ly in he cascade (Moo e e al., 2021).
An al e na i e s a egy o u ilizing he hos ’ complemen egula o
a senal is o encode p o eins ha mimic he unc ion o hos ’ p o eins.
Mimic y o hos molecules can be used in a p o ec i e way, an agg essi e
C3b C5bC3
C3a C5a
C3aR C5aR1
p o ease
A
B
C3b C5b
gC p o ein
in ec ed
hos cell
C5
b
-9
Fig. 3. A oidance o ac i a ion and unc ion–inhibi ion. highly speci ic p o ein-p o ein in e ac ions a e he key ea u e o he complemen cascade, and hei
ab oga ion is a common ea u e o pa hogen e asion s a egies. (A) A p ominen example o his e asion s a egy is he ma u e He pes simplex i us (HSV)
glycop o ein C (gC) ha inhibi s he ac i a ion o he complemen cascade by binding C3b and by blocking binding o p ope din and C5 o C3b, he eby in e e ing
wi h he gene a ion o he memb ane a ack complex (MAC) and he lysis o in ec ed hos cells. (B) The pa hogen-de i ed complemen -ac i e p o eases om
En amoeba his oly ica and s ep ococci bac e ia can deg ade he anaphyla oxins C3a and C5a consequen ly blocking he ac i a ion o anaphyla oxin ecep o s C5aR
and C3aR and hei downs eam assigned e ec o unc ions.
A.A. Nowacka e al.
Immunobiology 230 (2025) 153126
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