Review Article

Innate
Journal of J Innate Immun 2018;10:432–441 Received: January 31, 2018
Immunity DOI: 10.1159/000487756 Accepted after revision: February 14, 2018
Published online: April 11, 2018

Neutrophils and Bacterial Immune

Evasion
Scott D. Kobayashi Natalia Malachowa Frank R. DeLeo
Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases,
National Institutes of Health, Hamilton, MT, USA

Keywords physical barriers, antimicrobial peptides, freely secreted

Bacterial pathogenesis · Virulence · Phagocytosis · antimicrobial proteins present in the blood, mucous se-
Neutrophil · Host defense · Innate immunity cretions, and interstitial fluid, and leukocytes. Together,
these innate immune system elements protect against in-
fection from many types of microorganisms, including
Abstract bacteria.
Neutrophils are an important component of the innate im- The skin is an important physical barrier to microor-
mune system and provide a front line of defense against bac- ganisms, and skin cells (or other cell types within or
terial infection. Although most bacteria are killed readily by around the skin) produce many antimicrobial molecules
neutrophils, some bacterial pathogens have the capacity to that contribute to the host defense against bacteria [1].
circumvent destruction by these host leukocytes. The ability Most skin antimicrobial peptides, such as β-defensins
of bacterial pathogens to avoid killing by neutrophils often and cathelicidins, are comprised of approximately 15–20
involves multiple attributes or characteristics, including the amino acid residues, and have a net positive charge. These
production of virulence molecules. These molecules are di- peptides interact readily with the negatively charged sur-
verse in composition and function, and collectively have the face of bacteria, and, in turn, inhibit growth and/or are
potential to alter or inhibit neutrophil recruitment, phagocy- bactericidal [1, 2]. Individuals with defects in the regula-
tosis, bactericidal activity, and/or apoptosis. Here, we review tion of these peptides are more susceptible to skin infec-
the ability of bacteria to target these processes. tions [2]. Microorganisms, whether commensal or patho-
© 2018 S. Karger AG, Basel genic, can gain access to normally sterile host tissues and
the bloodstream by way of an entry portal. Such portals
include breaches in the skin barrier, e.g., abrasions, lac-
Introduction erations, and burns, and also access through mucous
membranes. Importantly, invading bacteria trigger the
The human innate immune system is comprised of release of proinflammatory molecules that amplify the in-
many components that function in concert to defend flammatory response and, in turn, the innate immune re-
against microorganisms. These components include sponse.

© 2018 S. Karger AG, Basel Dr. Frank R. DeLeo

Laboratory of Bacteriology, Rocky Mountain Laboratories, NIAID/NIH
903 South 4th Street
E-Mail [email protected]
Hamilton, MT 59840 (USA)
www.karger.com/jin E-Mail fdeleo @ niaid.nih.gov
 The complement system, antibody, collectins, ficolins, Bacterial Strategies to Evade Neutrophil Function
and pentraxins are important noncellular antimicrobial
factors that contribute significantly to the host defense Neutrophil Recruitment
against invading microbes [3, 4]. For example, individu- Pathogen recognition and the subsequent recruitment
als with complement deficiencies are more susceptible to of neutrophils to sites of infection are key elements of the
recurrent bacterial infections than people with a fully host defense against bacterial disease. Neutrophil recruit-
functional complement system [4, 5]. The complement ment is a multistep process that includes extravasation of
membrane attack complex (C5b-C9) forms a cytolytic bloodstream neutrophils to distal sites of infection and/
pore in the bacterial cell envelope membrane, and thus or injury, mobilization of neutrophils from bone marrow
has direct bactericidal activity [4]. Other complement reserves, and increased hematopoiesis as needed. Invad-
fragments, including C3b and iC3b, bind the surface of ing pathogens and their signature pathogen-associated
bacteria and, in the context of antibodies, promote effi- molecular patterns (PAMPs) are recognized by host pat-
cient phagocytosis by macrophages, monocytes, and neu- tern recognition receptors (PRRs), which include Toll-
trophils [4]. Thus, it should be no surprise that some bac- like receptors (TLRs) and nucleotide-binding oligomer-
terial pathogens have evolved molecules that inhibit com- ization domain (NOD) proteins. Receptor ligation trig-
ponents of the complement cascade and/or sequester or gers the production of a variety of proinflammatory host
degrade antibodies. cytokines and chemokines, such as interleukin (IL)-8, IL-
Proinflammatory molecules such as chemokines and 1α, and IL-β, CXCL1 (GROα), CXCL2 (MIP2α), CXCL5
bacterial molecules recruit leukocytes to sites of infection. (ENA78), tumor necrosis factor (TNF), granulocyte-col-
Phagocytic leukocytes, i.e., polymorphonuclear leuko- ony stimulating factor (G-CSF), or granulocyte-macro-
cytes (PMNs or neutrophils) and mononuclear phago- phage colony stimulating factor (GM-CSF). These mol-
cytes (monocytes, macrophages, and dendritic cells), are ecules serve as chemoattractants and promote neutrophil
critical for defense against invading microorganisms. recruitment to infected tissues.
These cells ingest and kill bacteria, or provide a link be- Neutrophil migration is also driven by pathogen-de-
tween innate and adaptive immunity that is important for rived molecules such as N-formylated peptides (e.g., for-
long-term protection against reinfection. Among phago- myl-methionyl-leucyl-phenylalanine, fMLF) that are by-
cytic leukocytes, PMNs are the most numerous and have products of bacterial protein synthesis. Besides a handful
arguably the greatest bactericidal capacity. PMNs kill bac- of resident immune cells, the majority of neutrophils have
teria by using oxygen-dependent and oxygen indepen- to be recruited from blood, and this involves a process
dent processes [6]. Oxygen-dependent bactericidal activ- known as extravasation. Neutrophil extravasation is di-
ity involves the production of superoxide by an enzyme vided into 4 major phases: rolling, adhesion, crawling,
complex known as NADPH oxidase [6]. Superoxide is and transmigration. Each step is tightly regulated by
converted to other reactive oxygen species (ROS) that are cross-talk between lymphocytes and endothelium, and
effective at killing bacteria. PMNs from individuals with involves the interaction of numerous integrins and adhe-
genetic defects in NADPH oxidase are susceptible to se- sion molecules. Neutrophil exposure to host- and patho-
vere and recurrent bacterial and fungal infections [6]. In gen-derived proinflammatory molecules as well as inter-
addition to the production of ROS, PMNs possess an ar- actions with activated endothelia primes these phago-
ray of antimicrobial peptides and proteins that have bac- cytes for enhanced function. Historically, priming was
tericidal activity. These molecules are contained within defined as the ability of primary agonists such as lipopoly-
cytoplasmic granules and are typically delivered to bacte- saccharide to enhance ROS production by a secondary
ria-containing vacuoles (phagosomes) following phago- stimulus. During this process, neutrophils undergo mo-
cytosis. PMN ROS and granule proteins work together to bilization of secretory vesicles, partial mobilization of
kill ingested microbes. specific granules, and partial assembly of NADPH oxi-
Although PMNs are highly effective at killing most dase which enhances neutrophil function in response to
bacteria, some pathogens have evolved means to evade a second stimulus [7].
killing by these leukocytes. A comprehensive review of Pathogen success is often highly dependent on the
the immune evasion molecules produced by all types of ability to avoid recognition and killing by the host im-
microbes is beyond the scope of this article. Instead, we mune system. To that end, a number of bacterial patho-
highlight selected molecules used by bacteria to circum- gens produce molecules that have the ability to dampen
vent killing by neutrophils. neutrophil recruitment. Some of these molecules target

Neutrophils and Bacterial Immune J Innate Immun 2018;10:432–441 433

Evasion DOI: 10.1159/000487756
chemoattractants. For example, Streptococcus pyogenes [20]. The OspF phosphatase of Shigella represses the tran-
produces secreted peptidases known as ScpA and ScpC/ scription of multiple genes involved in the immune re-
SpyCEP that degrade C5a and IL-8, respectively [8, 9], sponse, including IL-8, a potent neutrophil chemoattrac-
and the streptococcal secreted esterase Sse, which inacti- tant [21]. Moreover, the Shigella virulence factor IpgD
vates platelet-activating factor [10, 11]. Inhibition of neu- induces phosphatidylinositol 5-phosphate (PI5P) pro-
trophil recruitment is enhanced in hypervirulent S. pyo- duction. The high levels of PI5P trigger ICAM-1 internal-
genes strains by mutation/deletion in CovRS, a 2-compo- ization and degradation in infected epithelial cells, and
nent gene regulatory system that controls the expression significantly affect neutrophil trafficking during infection
of multiple virulence factors, including SpyCEP and SsE [22].
[11, 12]. Streptococcus pneumoniae employs a slightly dif-
ferent mechanism to block neutrophil recruitment. This Phagocytosis
pathogen produces pneumococcal zinc metalloprotein- The ability of neutrophils to ingest and subsequently
ase C (ZmpC), which targets the initial rolling step of kill invading microbes is essential for the maintenance of
neutrophil extravasation by cleavage of the N-terminal host health. Neutrophils remove bacterial and fungal
domain of P-selectin glycoprotein 1 (PSGL-1) [13]. pathogens through a process known as phagocytosis.
Staphylococcus aureus, one of the most prominent Recognition of invading microbial pathogens is mediated
gram-positive pathogens, possesses an arsenal of viru- by receptors present on the neutrophil surface, such as
lence factors that have the ability to counteract the initial PRRs (e.g., TLRs) and opsonic receptors, which recognize
steps of the innate immune response. For example, neu- host proteins that are deposited on the microbial surface.
trophil activation and chemotaxis can be inhibited by the The ligation of PRRs initiates a complex series of molecu-
chemotaxis inhibitory protein of S. aureus (CHIPS), lar signals that modulate effector functions such as en-
which binds to the C5a receptor and formyl peptide re- hanced phagocytosis, killing, and the regulation of in-
ceptor (FPR), thereby blocking ligand interaction [14]. flammation via cytokine production. Phagocytosis is
FPR and its homolog formyl peptide receptor-like 1 are most efficient in the presence of opsonins such as spe-
additionally blocked by the S. aureus-secreted proteins cific immunoglobulin (Ig)G and complement factors that
known as FPRL1 inhibitory protein (FLIPr) and FLIPr- directly mediate uptake (opsonophagocytosis). IgG or
like protein [15, 16]. Staphylococcal superantigen-like IgM bound to the microbial surface is recognized by C1q
protein (SSL3) inhibits TLR2, an important PRR for the which activates the classical complement pathway. In ad-
recognition of S. aureus. Moreover, SSL5 and SSL11 and dition, complement can be deposited on the microbial
staphylococcal enterotoxin-like toxin X (SElX) inhibit surface following activation of the alternative or man-
neutrophil extravasation by blocking the interaction of nose-binding lectin pathways. PMNs express distinct re-
PSGL-1 and P-selectin on the endothelium [17]. Recent- ceptors for IgG (FcγRI, FcγRII, and FcγRIII) and opson-
ly, SSL1 and SSL5 were shown to inhibit neutrophil ma- ic complement molecules C3b and iC3b (CR1, CR3, and
trix metalloproteinases (MMP8 and MMP9), which sub- CR4). Efficient particle-binding is enhanced by simulta-
sequently inhibit MMP-dependent IL-8 cleavage to pre- neous or sequential engagement of receptors on the
vent potentiation and inhibit neutrophil migration [18]. phagocyte surface and precedes the internalization of
Gram-negative pathogens often employ a flagellar and pathogens. Actin polymerization is a requisite for phago-
translocation-associated type III secretion system (T3SS) cytosis and, in conjunction with progressive FcR binding,
to evade the host immune system, including neutrophil it provides the cytoskeletal framework to advance the
recruitment. The T3SS is a plasmid-encoded and contact- plasma membrane of neutrophils over the particle and
dependent translocation mechanism that allows bacteria sequester them in phagosomes prior to killing.
to inject effector molecules into host cell cytoplasm [19]. Inasmuch as the process of phagocytosis is predicated
Pathogenic bacteria use this route to introduce virulence by PMN recognition of microbial pathogens, it is not sur-
factors into host cells and as an adaptation to favor patho- prising that pathogens have evolved strategies to limit or
gen intracellular survival. Several bacterial factors con- prevent binding and uptake. One of the primary mecha-
tribute to the evasion of the immune system by impairing nisms to prevent recognition is through the masking of
NF-κB signaling, and thereby altering the production of surface epitopes, thereby preventing the binding of anti-
interleukins. For example, Bordetella effector BopN has bodies and the deposition of complement on the bacte-
the ability to stimulate the production of anti-inflamma- rial surface. The ability of bacterial pathogens to prevent/
tory IL-10, which in turn inhibits neutrophil recruitment evade complement deposition and subsequent activation

434 J Innate Immun 2018;10:432–441 Kobayashi/Malachowa/DeLeo

DOI: 10.1159/000487756
has 3 potential consequences for pathogen survival: (1) it As indicated above, evasion of neutrophil recognition
serves as a mechanism to limit direct complement medi- is a common and successful strategy employed by many
ated lysis/killing of the microbe; (2) (and perhaps more bacterial pathogens to survive in the host. Alternatively,
pertinent for interactions with PMNs) it prevents direct some pathogens have developed methods to actively in-
recognition and opsonophagocytosis of the pathogen and hibit phagocytosis following neutrophil recognition.
consequent exposure to intracellular neutrophil microbi- Many gram-negative pathogens use a T3SS to deliver ef-
cidal agents; and (3) it interferes with downstream com- fector proteins into the host cell to promote the establish-
plement signaling cascades (e.g., an inflammatory re- ment of infection. Among the type III effector molecules,
sponse). One of the most common strategies for bacterial the GTPase activating proteins (GAPs) such as Yersinia
pathogens to mask surface antigens is by simply express- YopE are capable of targeting small RhoA family G pro-
ing an enveloping polysaccharide capsule [23]. There are teins, leading to the impairment of the actin cytoskeleton,
many examples of encapsulated bacteria that have been and thus actively inhibiting phagocytosis. Salmonella en-
described as inhibiting neutrophil phagocytosis includ- terica SptP and P. aeruginosa ExoS are similar GAPs that
ing Streptococcus spp., Neisseria meningitidis, Klebsiella target the actin cytoskeleton. Yersinia expresses an ad-
spp., Escherichia coli, Pseudomonas aeruginosa, and Hae- ditional type III effector protein tyrosine phosphatase
mophilus influenzae. Bacterial pathogens also mask epit- (PTPase), YopH, that blocks immediate early Ca2+ signal-
opes through structural modifications that prevent rec- ing in neutrophils and impairs phagocytosis [30], and,
ognition by PRRs. For example, several gram-negative together with YopE, has recently been shown to interfere
bacterial pathogens such as Yersinia spp. and Salmonella with neutrophil degranulation [31].
typhimurium modify lipid A structure to inhibit recogni-
tion by TLR4. Bacteria can also interfere with comple- Bactericidal Activity
ment regulatory proteins as an evasion strategy to limit Neutrophils use oxygen-dependent and oxygen inde-
opsonization. For example, the sequestration of comple- pendent processes to kill ingested microorganisms. The
ment regulatory factor H by N. meningitidis impairs com- phagocytosis of bacterial pathogens leads to the forma-
plement activation by the alternative pathway which fa- tion of potent antimicrobial ROS, such as superoxide rad-
vors bacterial survival [24]. Furthermore, the surface M icals, hydrogen peroxide, hypochlorous acid, hydroxyl
protein of S. pyogenes impairs the binding of opsonic radicals, and chloramines. In addition, cytoplasmic gran-
fragment C3b to the cell surface by inhibiting comple- ules fuse with bacteria-containing phagosomes and en-
ment regulatory proteins, such as C4b-binding protein, rich the vacuole lumen with antimicrobial peptides and
factor H, and factor H-like protein [25]. S. pyogenes also proteases. Thus, the potent antimicrobial activity of the
secretes Mac/IdeS, a host-receptor mimetic of the leuko- neutrophil is a collaborative effort between highly proteo-
cyte β2-integrin Mac-1 that has 2 distinct immune eva- lytic and degradative enzymes, cationic molecules, and
sion properties that function in concert to inhibit opso- ROS.
nophagocytosis [26, 27]. Mac/IdeS interacts with CD16 In activated neutrophils, a membrane-bound NADPH-
and Mac-1 at the neutrophil plasma membrane to block dependent oxidase generates high levels of superoxide. In
the binding of IgG to CD16, and streptococcal Mac is a unstimulated neutrophils, subunits of the NADPH oxi-
cysteine protease that degrades IgG. S. aureus produces a dase complex are separated in cytosol (p40phox, p47phox,
number of complement inhibitors that interfere with op- p67phox, and Rac2) and membrane compartments (fla-
sonophagocytosis, including staphylococcal complement vocytochrome b558, Rap1A). During phagocytosis, the cy-
inhibitor (SCIN), extracellular complement-binding pro- tosolic components translocate to the plasma and/or
tein (Ecb), and staphylococcal superantigen-like protein phagosome membrane and associate with flavocyto-
(SSL7). Bacterial pathogens can also interfere with anti- chrome b558, a transmembrane heterodimer comprised of
body opsonization through protease degradation of im- gp91phox and p22phox, to form the active oxidase. The
munoglobulin by factors such as SpeB and the aforemen- oxidase transfers electrons from cytosolic NADPH to in-
tioned IdeS, albeit interference by proteolytic activity re- traphagosomal molecular oxygen to produce superoxide.
quires high concentrations of proteins in vivo [28]. In Superoxide anion is short-lived and dismutates rapidly to
addition, some bacteria can produce immunoglobulin- hydrogen peroxide and forms other secondary products,
binding proteins (e.g., SpA and Sbi of S. aureus) that are such as hypochlorous acid, hydroxyl radical, and singlet
capable of sequestering antibodies [29] and thus, poten- oxygen, which are effective microbicidal compounds.
tially, inhibiting opsonophagocytosis. ROS are cytotoxic and cause damage to proteins, mem-

Neutrophils and Bacterial Immune J Innate Immun 2018;10:432–441 435

Evasion DOI: 10.1159/000487756
brane lipids, and nucleic acids. The NADPH oxidase is dants to detoxify ROS and reduce damage caused by oxi-
essential for the host defense against bacterial and fungal dative stress. For example, superoxide dismutases such as
pathogens, as inherited defects in components of this en- SodA and SodM produced by S. aureus are enzymes that
zyme system predispose individuals to severe and/or fatal catalyze the dismutation of superoxide to hydrogen per-
infections. oxide. Hydrogen peroxide can be further decomposed to
Inasmuch as ROS are a critical component of neutro- water and oxygen by catalases (e.g., S aureus KatA, and E.
phil killing of bacterial pathogens, it is not unexpected coli KatE and KatG). In addition, ROS can be broken
that there are diverse mechanisms to either inhibit ROS down by enzymes of the thioredoxin system such as the
production or to detoxify these molecules. As discussed S. pneumoniae thiol peroxidase TpxD [38], and those of
above, NADPH oxidase is a multicomponent complex the glutathione system such as the S. pyogenes glutathione
that is unassembled and inactive in resting cells. The oxi- peroxidase [39].
dase components are translocated to the plasma or phago- Oxygen independent microbicidal systems utilize an-
somal membrane upon activation, and the subunits are timicrobial peptides and enzymes to facilitate the killing
assembled into a functional complex. Several bacterial and degradation of ingested microbes. In neutrophils, the
pathogens have exploited the complexity of the assembly antimicrobial peptides and proteins are stored primarily
process, to either inhibit ROS production or misdirect the in azurophilic granules and specific granules in the cyto-
oxidase complex away from the phagosome. Anaplasma plasm. Neutrophil phagocytosis promotes mobilization
phagocytophilum is one of the few obligate intracellular of these granules, which subsequently fuse with phago-
pathogens with a tropism for neutrophils; part of its suc- somes or the plasma membrane (exocytosis). Fusion of
cess is attributed to its ability to evade NADPH oxidase- azurophilic granules with phagosomes enriches the vacu-
mediated killing. A. phagocytophilum does not elicit a ole lumen with a diversity of antimicrobial peptides, in-
pronounced increase of intracellular ROS upon neutro- cluding α-defensins, cathepsins, proteinase-3, elastase,
phil uptake, and it has been shown to inhibit the delivery azurocidin, and lysozymes. Neutrophil α-defensins (HNP
of flavocytochrome b558 to the phagosomal/vacuolar 1–4) are highly abundant in azurophilic granules and ex-
membrane [32]. The intracellular pathogen Francisella hibit potent antimicrobial activity. The defensins are rel-
tularensis also excludes flavocytochrome b558 from the atively small cationic polypeptides (3–5 kDa) that interact
neutrophil phagosome, resulting in pronounced inhibi- with negatively charged molecules at the pathogen sur-
tion of ROS production [33]. By contrast, neutrophil face and contribute to the permeabilization of bacterial
phagosomes containing Opa-negative N. gonorrhoeae ac- membranes. In addition, PMN α-defensins and other an-
cumulate flavocytochrome b558, but exhibit defects in the timicrobial peptides serve as an important bridge be-
recruitment of p47phox and p67phox, thus resulting in a tween the innate and adaptive immune systems, and are
reduced production of ROS [34]. Helicobacter pylori em- known to contribute to processes such as chemotaxis,
ploys a somewhat different strategy and, following phago- wound repair, and stimulation of histamine release. De-
cytosis, targets localization of the NADPH oxidase to the granulation also enriches phagosomes with specific gran-
neutrophil outer membrane, thus directing ROS to the ule constituents such as flavocytochrome b558 (mem-
extracellular space [35]. Pathogenic Yersiniae utilize the brane) and lactoferrin (lumen), further contributing to
T3SS to deploy effector molecules into the neutrophil cy- antimicrobial potential. Lactoferrin sequesters iron need-
toplasm to interfere with NADPH oxidase. As discussed ed for bacterial growth, and supplies iron required to gen-
above, YopE is a GTPase-activating protein and the mol- erate neutrophil hydroxyl radicals. Lysozyme is univer-
ecule has recently been shown to inactivate Rac2, a key sally recognized for the ability to degrade bacterial pepti-
regulatory GTPase for activation of the NADPH oxidase doglycan, and is ubiquitous among the granule subtypes.
[36]. The P. aeruginosa type III cytotoxic effector ExoS Azurocidin, elastase, cathepsin G, and proteinase 3 are
inhibits ROS production in human neutrophils, and, sim- collectively known as serprocidins, a family of antimicro-
ilar to Yersinia YopE, functions as a GTPase-activating bial proteins with a structural homology with serine pro-
protein. However, ExoS is a bifunctional protein that also teases. The proteins exhibit direct antimicrobial activity
contains a C-terminal ADP ribosyltransferase domain. and, except for azurocidin (also known as CAP37), are
ExoS has recently been shown to ADP-ribosylate RAS to serine proteases. Neutrophil elastase has been shown to
inhibit PI3K signaling for the activation and assembly of cleave the outer membrane protein A (OmpA) of E. coli,
the neutrophil NADPH oxidase [37]. Bacterial pathogens thus disrupting membrane integrity and resulting in cell
are capable of producing numerous enzymatic antioxi- death [40]. Collectively, the oxygen-dependent and oxy-

436 J Innate Immun 2018;10:432–441 Kobayashi/Malachowa/DeLeo

DOI: 10.1159/000487756
gen independent neutrophil microbicidal systems oper- The primary mechanisms of serine protease resistance
ate as an efficient system to prevent bacterial infection. used by bacterial pathogens are the modification of serine
Antimicrobial peptides (AMPs) are important in the host protease substrates and the production of serine protease
defense against microbial pathogens and a key compo- inhibitors [43].
nent of the human innate immune response. There are 2 Neutrophil extracellular traps (NETs) are web-like
major AMP families in mammals: the cathelicidins (LL- structures that consist of strands of decondensed chro-
37 is the sole member in humans), and the defensins (the matin decorated with the contents of neutrophil granules
α and β families). Prototypical AMPs have a net positive [44]. NETs can be released from either live or dying cells
charge to facilitate interaction with the net negative and, importantly, they have been reported to ensnare and
charge of bacterial surfaces. These cationic AMPs target kill various bacterial pathogens [45]. Although NETs
anionic lipids (e.g., phosphatidylglycerol and cardio- have the potential to augment the innate host defense,
lipins) and other anionic components (e.g., lipopolysac- most bacterial pathogens produce nucleases (e.g., Sda of
charide and lipoteichoic acid) of the cell membrane. Once S. pyogenes) that can destroy cell-free DNA that forms
associated with the microbial surface, the amphipathic NETs [46].
nature of the cationic AMPs enables insertion into the cell
membrane, thereby disrupting membrane integrity and Apoptosis
leading to osmotic lysis of the microbial cell. Inasmuch as As discussed above, the high toxicity of ROS and en-
AMPs are ubiquitous and are encountered frequently by zymes from the neutrophil granules enables the immune
bacterial pathogens, several different mechanisms have system to successfully defend the host from a wide range
evolved for the evasion of AMP-mediated killing, such as of bacterial pathogens. However, these molecules have
alteration of the microbial surface charge, sequestration the potential to cause collateral damage to adjacent host
of AMPs by secreted and cell surface-associated mole- tissue, if not tightly controlled. In steady-state conditions,
cules, energy-dependent membrane efflux pumps, and aged or spent neutrophils are destined to undergo consti-
degradation by peptidases. tutive (spontaneous) apoptosis [47]. Neutrophils under-
In general, bacterial surfaces are more negatively go multiple changes during spontaneous apoptosis, in-
charged than those of the eukaryotic host, and thus the cluding chromatin condensation, DNA fragmentation,
cationic AMPs exhibit a higher degree of attraction to the vacuolization of the cytoplasm, exposure of phosphatidyl
bacterial cell. One of the most commonly employed serine on the surface of the cell, diminished proinflam-
mechanisms of AMP resistance is through alteration of matory and antimicrobial capabilities, and metabolic
the surface charge with cationic molecules, thus promot- changes [48]. Intact apoptotic neutrophils are safely re-
ing electrostatic repulsion. Gram-negative bacteria typi- moved by macrophages via a nonphlogistic uptake pro-
cally alter the surface charge by remodeling lipid A and cess known as efferocytosis [48]. Two neutrophil apop-
the addition of phosphatidylethanolamine and 4-amino- totic pathways have been described: (i) the intrinsic or
4-deoxy-L-arabinose. Gram-positive bacteria often mod- stress-induced pathway associated with death-mediated
ify cell wall teichoic acids by D-alanylation to reduce the by neutrophil mitochondria, and (ii) the extrinsic path-
negative surface charge and enhance electrostatic repul- way activated by death receptor FAS (CD95) or TNF in-
sion and AMP resistance. Bacteria can also reduce the teractions. Spontaneous apoptosis relies heavily on the
deleterious effects of AMPs by the use of efflux pumps. proapoptotic B cell lymphoma (Bcl-2) family of proteins
For example, the multiple transferable resistance trans- and typically is associated with the intrinsic pathway.
porter of N. gonorrhoeae provides resistance to LL-37 and Upon apoptosis, Bcl-2-associated X (Bax) protein trans-
other AMPs [41]. AMPs can also be rendered inactive by locates from the cytosol to the mitochondria and interacts
bacterial proteases. Numerous studies demonstrate that with the BH3-interacting domain death agonist (Bid). Bid
the cathelicidin LL-37 is degraded by metalloproteases induces conformational changes, oligomerization, and
such as S. aureus aureolysin, Proteus mirabilis ZapA, S. the anchoring of Bax that creates pores in the outer mito-
pyogenes SpeB, P. aeruginosa elastase, and Enterococcus chondrial membrane. These pores allow the release of mi-
faecalis gelatinase [42]. In addition to AMP resistance, tochondrial proapoptotic intermembrane space proteins
pathogenic bacteria have also developed mechanisms to that activate caspase-9 and displace the X-linked inhibi-
evade targeting by other neutrophil granule constituents, tor of apoptosis (XIAP) [49]. In the extrinsic pathway, the
including serine proteases such as neutrophil elastase, ca- activation of death receptors leads to the recruitment and
thepsin G, proteinase 3, and neutrophil serine protease-4. activation of caspase-8 by the death-inducing signaling

Neutrophils and Bacterial Immune J Innate Immun 2018;10:432–441 437

Evasion DOI: 10.1159/000487756
 Table 1. Selected bacteria and associated immune evasion molecules

Process blocked or targeted Bacteria (selected) Selected molecules involved

Phagocytosis Streptococcus pyogenes M protein, Mac

Klebsiella pneumoniae capsular polysaccharide
Yersinia YopE, YopH
Recruitment Staphylococcus aureus CHIPS, FLIPr, SSL3, SElX
S. pyogenes ScpA, ScpC, Sse, ZmpC
Bordetella pertussis BopN
Shigella flexneri OspF
Antimicrobial peptide actions S. aureus aureolysin
S. pyogenes SpeB
Antibody function S. aureus SpA, Sbi
S. pyogenes SpeB, IdeS
NADPH oxidase activation Francisella tularensis FevR
and/or assembly Yersinia spp. YopE, YopH
Pseudomonas aeruginosa ExoS
Apoptosis/cell lysis Anaplasma phagocytophilum Ats-1
F. tularensis lipoproteins
P. aeruginosa pyocyanin
S. pyogenes streptolysin O/streptolysin S
S. aureus LukGH, PVL
Lysosome or granule-phagosome S. pyogenes M protein
fusion Yersinia pseudotuberculosis YopE, YopH

complex (DISC). Of note, caspase-8 can be activated in- pathogen survival and is necessary to evade the host im-
dependently from the extrinsic pathway, and can activate mune system. A. phagocytophilum, the etiological agent
caspase-9 as a downstream effect of cleavage and the ac- of human granulocytic anaplasmosis, and Chlamydia
tivation of Bid, thus demonstrating the interconnection pneumoniae, a cause of acute respiratory disease, are ex-
between the intrinsic and extrinsic pathways. Moreover, amples of pathogens that can survive and replicate within
both pathways converge at the effector caspase-3 level neutrophils [52, 53]. The delay of neutrophil apoptosis by
[47]. A. phagocytophilum is mediated in part by the increased
During bacterial infection, neutrophil ingestion of mi- phosphorylation of p38 mitogen-activated protein kinase
crobes prompts cells to undergo apoptosis in a process (MAPK) and activation of phosphatidylinosytol 3-kinase
termed “phagocytosis-induced cell death” (PICD) [47]. (PI3K)/Akt [54, 55]. Apoptosis is delayed by affecting 2
PICD is highly dependent on ROS, Mac-1 (CD11b/ main antiapoptotic proteins. Specifically, infected neu-
CD18), and Fcγ receptor signaling [50, 51]. Nonlytic pro- trophils maintain the expression of Mcl-1, a Bcl-2 family
grammed cell death is highly advantageous to the host, antiapoptosis protein that directly prevents Bax translo-
since it allows the safe removal of effete neutrophils con- cation, and the enhanced expression of cellular inhibitor
taining killed bacteria, and promotes the resolution of in- of apoptosis (cIAP2), which regulates caspase activity by
fection. In general, a select group of bacterial pathogens direct binding. Furthermore, infected neutrophils in-
can either delay apoptosis to prolong host cell survival, or crease IL-8 production, which promotes neutrophil sur-
accelerate and/or redirect apoptosis causing cell lysis, and vival in an autocrine/paracrine manner [55]. F. tularensis
leading to prolonged inflammation and surrounding tis- is another intracellular bacterial pathogen that delays
sue destruction. There are very few intracellular patho- neutrophil apoptosis by affecting Bcl-2 family proteins.
gens that are neutrophil-tropic, attributed, primarily, to Namely, the pathogen impairs the processing and activa-
the short neutrophil lifespan. Nonetheless, the delay of tion of caspase-8 and Bid, and significantly inhibits apop-
neutrophil apoptosis is a crucial strategy for intracellular tosis by impairing translocation of Bax into the mito-

438 J Innate Immun 2018;10:432–441 Kobayashi/Malachowa/DeLeo

DOI: 10.1159/000487756
 Fig. 1. Bacteria produce molecules that target (inhibit) key neutrophil processes. The bacterial molecules shown
are examples of those that inhibit or alter the indicated neutrophil function. See text for details.

chondria [56, 57]. More recently, it has been suggested tolytic path or cause direct cell lysis by secreted toxins.
that F. tularensis-secreted bacterial lipoproteins play a Some ingested S. aureus or S. pyogenes strains survive
role in apoptosis inhibition via a TLR-2 dependent route within human neutrophils and cause premature lysis that
[58]. leads to the dissemination of viable bacteria, thus per-
Common bacterial pathogens such as E. coli, P. aeru- petuating the disease process. Lysis of PMNs infected
ginosa, and S. aureus induce neutrophil apoptosis follow- with S. aureus resembles necroptosis [60]. This process
ing phagocytosis. In general, PICD is a host-driven pro- is typically dependent on an interaction between recep-
cess that promotes pathogen removal and the resolution tor-interacting serine/threonine kinase (RIPK-1 and
of inflammation; however, some bacterial pathogens RIPK-3) and mixed-lineage kinase like protein (MLKL).
have evolved means by which to exploit this process to Necroptosis induced by S. aureus is primarily dependent
their benefit. For example, P. aeruginosa secretes a phen- on RIPK3 activation, but is inhibited by necrostatin-1
azine exotoxin, pyocyanin, that rapidly accelerates neu- (Nec-1), an antagonist of RIPK-1 [61]. In addition, neu-
trophil apoptosis. This pathogen-driven premature trophils with ingested bacteria increase the expression of
apoptosis of neutrophils interferes with the ability of the CD47 (a “don’t eat me” signal) that interferes with mac-
immune system to eliminate invading bacteria. Pyocya- rophage efferocytosis and cytokine production [60].
nin-induced apoptosis is a ROS-dependent process that Furthermore, S. aureus and S. pyogenes produce several
mediates dysfunction of the phagosome and leads to the leukotoxins (e.g., streptolysins O and S, and the staph­
release of cathepsin D, permeabilization of the mito- ylococcal leukotoxins HlgAB, LukDE, LukGH, and Pan-
chondrial membranes and, subsequently, reduced levels ton-Valentine leukocidin [PVL]) that form pores in the
of Mcl-1 [59]. Moreover, pathogens such as S. aureus neutrophil membrane and cause subsequent cytolysis
have the ability to redirect neutrophil fate towards a cy- [62, 63].

Neutrophils and Bacterial Immune J Innate Immun 2018;10:432–441 439

Evasion DOI: 10.1159/000487756
 Concluding Comment develop vaccines or immunotherapies that target these
molecules for a number of human pathogens, but more
Many bacterial species, whether primary pathogens or work is needed in this area.
commensal microbes, have the capacity to produce im-
mune evasion molecules. The fundamental role played by
Acknowledgements
these molecules is similar, to avoid detection and/or im-
mune clearance by the host. A diverse array of bacterial We thank Ryan Kissinger (NIAID) for assistance with Figure
immune evasion molecules exist, and they can potential- 1. The authors are supported by the Intramural Research Program
ly inhibit or moderate key host immune processes (Table of the National Institute of Allergy and Infectious Diseases, Na-
tional Institutes of Health.
1; Fig. 1). In an era of increasing antibiotic resistance of
bacteria, especially among commensal microbes that are
opportunistic pathogens, alternative therapeutics and/or
Disclosure Statement
vaccines are needed. Targeting bacterial immune evasion
molecules is one such approach. Efforts are ongoing to The authors declare no conflicts of interest.

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