Evasion of the Host Innate Immune System by Pathogenic Bacteria

Naoko Matsunaga
Independent Researcher and Consultant, San Diego, California 92111, USA
Correspondence to: yff33165@gmail.com

DOI: https://doi.org/10.70389/PJS.100046

Additional information

• Ethical approval: N/a
• Consent: N/a
• Funding: No industry funding
• Conflicts of interest: N/a
• Author contribution: Naoko Matsunaga – Conceptualization, Writing – original draft, review and editing
• Guarantor: Naoko Matsunaga
• Provenance and peer-review:
  Commissioned and externally peer-reviewed
• Data availability statement: N/a

Keywords: Pathogenic bacteria, Immune evasion, ­Pattern recognition receptors, Bacterial effector proteins, Complement system.

Peer Review
Received: 4 December 2024
Revised: 21 December 2024
Accepted: 22 December 2024
Published: 30 December 2024

Abbreviations

IL, interleukin; TLR, Toll-like receptor; TIR, Toll/IL-1 receptor; PAMPs, pathogen-associated molecular patterns; PRRs, pattern recognition receptors; TRAFs, tumor necrosis factor receptor-associated factors; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based ­inhibitory motif; SHP, Src homology 2 domain-containing tyrosine phosphatases

Highlights

• In the early stage of bacterial infection, pattern recognition receptors (PRRs), antibodies, and complement components bind to the bacterial surface to trigger an antibacterial immune response.
• Pathogenic bacteria can avoid opsonization and recognition by the host by changing their cell surface structures.
• Pathogenic bacteria can mimic host molecules to manipulate the antibacterial signaling pathways and elude host defense responses.
• Pathogenic bacteria can change posttranslational modification of host transcription factors and signaling molecules to suppress inflammation.
• Pathogenic bacteria can degrade complement components to avoid host phagocytes.

Introduction

Bacteria, formerly Eubacteria, are unicellular organisms classified as prokaryotes. They lack a nuclear membrane or membrane-bound organelles. It is estimated that bacteria account for more than three- quarters of all species of organisms on Earth. These diverse organisms can be categorized into three main groups based on their cell wall structures: Gram-negative bacteria, Gram-positive bacteria, and mycobacteria (Figure 1).

The schematic comparison of the cell walls (or cell envelopes) of Gram-negative bacteria, Gram-positive bacteria, and mycobacteria illustrates the major classes of structural glycoconjugates and their locations. Each envelope type possesses peptidoglycan located outside the cytoplasmic membrane as a major component conferring shape and integrity to the cell wall. In Gram-negative bacteria, a selectively permeable asymmetric outer membrane (OM) usually contains lipopolysaccharides. In Gram-positive bacteria, the much thicker peptidoglycan layer is augmented by covalently linked wall teichoic acids and a variety of lipoglycans (including lipoteichoic acids) embedded in the cell membrane. Mycobacteria also possess an “outer membrane,” but it is much different from the Gram-negative OM. The major lipid components are long-chain mycolic acids, linked via a branched arabinogalactan structure to the peptidoglycan. Mycobacterial walls possess a wide diversity of lipoglycans in the cytoplasmic and OMs. All three wall types may be covered with capsular and extracellular polysaccharides Essentials of Glycobiology 4th edition, Chapter 21, Eubacteria. © 2022 The Consortium of Glycobiology Editors, La Jolla, California; published by Cold Spring Harbor Laboratory Press

Because of the short generation times, bacteria can quickly adapt to diverse environmental changes through mutation followed by natural selection. Pathogenic bacteria have evolved various mechanisms to evade the host’s defense system, enabling them to survive within the host.¹ Some of these ­strategies include modifying their surface structures, producing effector proteins using secretion system (SS), suppressing antibacterial signaling pathways, inactivating the complement system, and escaping from phagocytes. On the other hand, humans have developed innate and adaptive immune systems to combat microbial infections. The innate immune system provides immediate and rapid defenses against bacteria and other pathogenic microorganisms, while adaptive immunity develops more slowly but offers a targeted response over time. We scrutinized publications on PubMed and selected papers that describe how bacteria evade host innate immune responses during the early stages of infection. We organized the host defense mechanisms and corresponding bacterial anti-immune strategies based on key topics related to antibacterial immune responses, arranged chronologically from the initial moment of infection. The examples chosen highlight clinically significant pathogenic bacteria.

The first step of host antibacterial response is the recognition of pathogens. Pattern recognition receptors (PRRs) recognize molecular structures or molecules that are common to pathogenic microorganisms, known as pathogen-associated molecular patterns (PAMPs). Complement and antibodies can also recognize potential pathogens. We summarize the bacterial evasion of immune recognition by changing their surface structure in Section 1. The next step is the activation of cellular signaling pathways to induce inflammation. During the activation of proinflammatory signaling pathways, host molecules with specific protein structures or motifs control the immune responses. These specific structures include toll/interleukin 1 receptor (TIR) domain, tyrosine-based activation motif (ITAM), and immunoreceptor tyrosine-based inhibitory motif (ITIM). They act as the interface between receptors and signaling pathways. Since pathogenic bacteria have unique systems that exploit these protein structures, we discuss TIR domain-containing proteins in Section 2 and ITAM/ITIM-bearing receptors in Section 3, showing interesting examples.

The PRR-dependent inflammatory responses are regulated by posttranslational modification such as phosphorylation, polyubiquitination, and acetylation.² In Section 4, we focus on posttranslational modification of inflammatory signaling molecules and their modulation by pathogenic bacteria. Following the activation of inflammatory signaling pathways, a variety of cytokines and chemokines are produced. These chemoattractants recruit effector cells to kill bacteria. Neutrophils are the leading effector cells of the innate immune system. They are recruited by those chemoattractants, including complement components. Complement pathways are as important as PRR-signaling pathways in the early phase of bacterial infection. We discuss how pathogenic bacteria manipulate complement pathways in Section 5.

1. Escape Recognition by Changing Cell Surface

Host Defense Mechanism

Macrophages and neutrophils express PRRs, which include Toll-like receptors (TLRs), NOD-like receptors, C-type lectin receptors, and RIG-I-like receptors.³ They recognize PAMPs. The bacteria are also recognized by antibodies and complement components, called opsonization. Opsonization is to tag pathogenic bacteria so that phagocytes can recognize them. In this section, we highlight the host recognition by PRRs and antibodies in the first stage of infection. For the recognition by complement components, please see Section 5.

Bacterial Immune Evasion

To avoid recognition by the host, bacteria have modified their PAMPs. Lipopolysaccharide (LPS), a chief component of Gram-negative bacterial cell walls (Figure 1), is one of the well-known PAMPs that is recognized by the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) complex. LPS is a potent agonist for the TLR4/MD-2 complex in general; however, Yersinia pestis has evolved an alternative form of LPS resulting in a weak antagonist of TLR4/MD-2 signaling.4 The transmission of Y. pestis, the causative agent of plaque, to humans occurs through the bite of infected fleas. When the temperature increases from flea temperature (21–27°C) to human temperature (37°C), a tetra-acylated lipid A-LPS is generated over hexa-acylated lipid A-LPS. The tetra-acylated lipid A-LPS have lower stimulatory activity on TLR4/MD-2 signaling, thereby evading the host’s inflammatory response to combat infection. In addition, the tetra-acylated lipid A-LPS also potentiates plasminogen activator protease, which is also the key virulence factor.⁵ This temperature-dependent remodeling of lipid A is critical for the virulence of Y. pestis.

Likewise, Shigella flexneri, the cause of bacterial dysenteries or shigellosis, modifies the degree of acylation of the lipid after internalization and proliferation within cells.6 These enteropathogenic bacteria have hexa-acylated lipid A-LPS with an optimal inflammatory activity when they are grown in laboratory medium such as trypticase soy broth. Once they invade the intestinal epithelial cells, they generate hypoacylated LPSs including tetra- and tri-acylated lipid A-LPS. Changes in the lipid A acylation have a decisive impact on the binding of the lipid A to TLR4/MD-2 complex. Consequently, S. flexneri in cytosol eludes the host’s antibacterial response.

Staphylococcus aureus (S. aureus) is a pathogenic Gram-positive bacterium that can colonize the anterior nares and become a frequent cause of bacteremia. Gram-positive bacteria lack outer membranes and have thick peptidoglycan cell walls (Figure 1). One of the cell components in S. aureus lipoteichoic acid (LTA) is recognized by TLR2,⁷ mannose-binding lectin (MBL), and scavenger receptors.⁸ Another cell wall component, wall teichoic acid (WTA), is recognized by MBL.⁹ In addition to IgG antibody, S. aureus can utilize TarP to modify their cell wall structure.¹⁰ TarP is a glycosyltransferase encoded on a prophage in some clones of S. aureus. TarP glycosylates WTA polymers that are major surface antigens of S. aureus. This enzyme transfers N-acetylglucosamine to a different hydroxyl group of the ribitol phosphate of WTA compared with the standard enzyme TarS.^11,12 As a result, S. aureus with TarP-glycosylated WTA can avert the host’s immune recognition because a major part of human antibodies against S. aureus ­targets the glycoantigen WTA. In fact, S. aureus with mutant WTA lacking glycosylation showed diminished binding of human antibodies, and this defect was able to be recovered by expression of TarS.¹³ The binding of human antibodies to the surface of S. aureus promotes engulfment by macrophages and neutrophils. In this way, S. aureus avoids the host’s immune recognition and following phagocytosis.

2. Mimic Host TIR Domains

Host Defense Mechanism

After recognizing the invading bacteria, the host starts an antibacterial inflammatory response. TLRs initiate their signaling by dimerization of the cytoplasmic TIR domain. TIR domain-containing proteins are distributed across all domains of life, including mammals, bacteria, and plants¹⁴ (Figure 2). TIR domains predominantly function through homotypic interactions, including self-association or association with other TIR domains of downstream signaling molecules. The assembly of TIR domain can produce inflammatory cytokines and chemokines to combat the intruders.

TIR domains of the human (TLR1, IL-1R9, MAL, MyD88, and SARM1), lower metazoan Hydra magnipapillata (TRR-2), plant (RPP1 and ROQ1), and bacterial (TcpB) proteins with their corresponding PDB IDs are shown. All the TIR domains show a central core of five β-strands (βA–βE) surrounded by five α-helices (αA–αE). The functionally important BB-loop in each TIR is labeled Nimma S et al. Front. Immunol. 12:784484. © 2021 Nimma, Gu, Maruta, Li, Pan, Saikot, Lim, McGuinness, Zaoti, Li, Desa, Manik, Nanson and Kobe

Bacterial Immune Evasion

Bacteria can produce proteins containing similar motifs to the intracellular TIR domains (Figure 2) and hijack this assembly system. These eukaryotic-like proteins produced in bacteria have diverse functional roles. Some bacterial TIR domain-containing proteins have nicotinamide adenine dinucleotide (NAD+)-hydrolyzing activity and contribute to bacterial defense mechanisms against phage attack. In this section, we selected examples of TIR domain-containing proteins that function as a means of bacterial immune evasion.

Salmonella enterica serovar Enteritidis (S. Enteritidis) is a Gram-negative bacteria, which possess a protein similar to mammalian TIR domains, named TIR-like protein A (TlpA). TlpA suppresses NF-κB activation induced by stimuli with TLR4, myeloid differentiation primary response gene 88 (MyD88), and IL-1β, which have TIR domains. A main feature of TIR domain signaling is weak and transient TIR–TIR interactions. TlpA can occupy the docking sites of the similar proteins and inhibit the binding of the host original proteins with the TIR domain, thereby disrupting the normal signaling complex formation. TlpA also promotes activation of the protease caspase-1, resulting in host cell apoptosis.¹⁵ Thus, TlpA is required for the evasion of the host’s immune response to show full virulence. Similarly, T3SS1-related protein containing a TIR domain and a CC domain (TcpS) from S. Enteritidis interferes with TLR signaling by impeding MyD88/ TIR-domain-containing adapter-inducing interferon-β (TRIF)-mediated immune responses. TcpS promotes S. Enteritidis survival by evading the innate immune system, which leads to inflammation storms, tissue damages, and ultimately poor survival outcomes in mouse infection models.¹⁶

The two Gram-negative bacteria, Brucella melitensis (B. melitensis), a cause of human brucellosis, and uropathogenic Escherichia coli (UPEC), the primary cause of urinary tract infections, have TIR domain- containing proteins called TIR domain-containing protein B (TcpB) and C (TcpC), respectively. These proteins directly bind to MyD88 and TLR4, which impairs TLR signaling triggered by bacterial infection.^17,18 TcpC also impairs NOD-like receptor protein 3 (NLRP3) inflammasome by binding to both NLRP3 and caspase-1.19 For that reason, TcpC is the multifunctional virulence factor in UPEC that suppresses innate immune response in the host urinary tract and increases persistence in the kidneys. The TIR domain-containing protein can also be found in S. aureus. The database research identified staphylococcal TIR domain protein (TirS) in S. aureus MSSA476.²⁰ TirS attenuates host cell signaling ­pathways mediated by TLR2, MyD88, and TIR domain- containing adaptor protein. It suppresses c-Jun N-terminal kinase phosphorylation, NF-κB activation, and downstream cytokines and chemokines expression.

3. Exploit ITAM/ITIM-Bearing Receptors

Host Defense Mechanism

Macrophages, dendritic cells, and NK cells are also involved in the early stage of the bacterial infections. The key immune responses can be triggered by the Fc receptors21 (Figure 3) and other PRRs such as sialic acid-binding immunoglobulin-type lectin (Siglec) family,²² killer cell immunoglobulin-like receptors,²³ and C-type lectin-like receptors.^24,25 Those receptors possess a conserved short sequence called ITAM and ITIM in the cytoplasmic domains. ITAMs deliver activating signals via dual phosphorylation and following recruitment of tyrosine kinases, while ITIMs deliver inhibitory signals by recruiting phosphatases. Incomplete phosphorylation of ITAM tyrosines generates inhibitory signals,^26,27 which is called an ITAMi (Figure 3). These ITAM/ITIM-bearing receptors exquisitely control the quality, magnitude, and balance of immune responses.

The PLCγ converts PI(4,5)P2 into IP3 and DAG. IP3, a soluble inositol phosphate, leads to Ca2+ mobilization while DAG activates MAPK.PI3K, which converts PI(4,5)P2 to PI(3,4,5)P3 allowing recruitment of signal intermediates through their pleckstrin homology (PH) domain (Middle), co-ligation between an activating heterologous receptor (e.g., the BCR) and the inhibitory FcR (i.e., FcγRIIB) induces phosphorylation of the tyrosine present within the ITIM motif by Lyn (5), leading to the phosphorylation and recruitment of phosphatases (SHIP or SHP). The phosphatases PTEN and SHIP1/2 regulate cellular levels of PI(3,4,5)P3 by hydrolyzing it to PI(4,5)P2 and PI(3,4)P2, respectively. These dephosphorylations inhibit cell proliferation. (Right), monovalent targeting of FcR bearing ITAM motif (e.g., FcγRIIA) induces the phosphorylation of the last tyrosine residue of the ITAM motif by Lyn responsible for transient recruitment of Syk followed by that of SHP-1, which abrogates the activation signal Ben Mkaddem S et al. Front. Immunol. 10:811 © 2019 Ben Mkaddem, Benhamou and Monteiro

Bacterial Immune Evasion

The interactions of ITAM- and ITIM-bearing proteins are attractive targets for bacteria to elude the host’s antibacterial defense. Streptococcus agalactiae, or group B Streptococcus (GBS), is a species of Gram-positive bacteria that causes serious bacterial infections in human newborns. Capsular polysaccharide (CPS), located in the outer layer of the cell wall (Figure 1), is the key virulence factor. CPS contains a terminal α2-3-linked N-acetylneuraminic acid, which is recognized by Siglec-5 and Siglec-9.28 These Siglecs, also known as CD33-related Siglecs, have ITIMs.29 In addition to CPS, GBS β protein also binds to Siglec-5.30 Both Siglec-5 and Siglec-9 can recruit Src homology 2 domain-containing tyrosine phosphatases (SHP)-1, -2 and inhibit immune responses such as phagocytosis, extracellular trap formation, and oxidative burst. In such a way, GBS hijacks ITIM-bearing receptors to avert host antibacterial immune response.

E. coli is commonly found in the lower intestine and can cause foodborne illness. E. coli is known to bind to FcγRIII directly in an antibody-independent manner, though a specific ligand has not been identified yet. This ITAM-bearing receptor, FcγRIII, also called CD16, is expressed on NK cells, neutrophils, monocytes, macrophages, and a subset of T cells. The low-avidity interaction between E. coli and FcγRIII results in FcRγ phosphorylation, followed by SHP-1 recruitment to macrophage receptor with collagenous structure (MARCO) and phosphatidylinositide-3 kinase dephosphorylation.³¹ MARCO, a class A scavenger receptor, mediates phagocytosis. Since MARCO is suppressed by SHP-1, E. coli can avoid phagocytosis.

Enteropathogenic E. coli (EPEC) is a cause of diarrhea in children especially under 2 years of age. Enterohemorrhagic E. coli (EHEC) is a zoonotic ­pathogen that can lead to hemorrhagic colitis and hemolytic uremic syndrome. EPEC and EHEC are also called enteric (A/E) pathogens. They express translocated intimin receptor (Tir) to adhere to intestinal epithelial cells. Tir is delivered by type III secretion system (T3SS) (Figure 4) and migrates into the host intestinal epithelial cells during infection to act as a receptor for intimin, a bacterial adhesin protein. This effector protein, Tir, shares sequence similarity with ITIMs, which mimic an endogenous innate immunoregulatory mechanism.³² Tir interacts with β-arrestin 233 and recruits host phosphatase SHP-1 and SHP-2,^34,35 or inositol phosphatase SHIP236 to suppress antibacterial host defense signaling such as TLR signaling. SHP-1 prevents activation of TRAF6, which results in the suppression of proinflammatory cytokines that include TNF-α, ll-6, Il-12, and Il-1β.

In this simplified view only the basics of each secretion system are sketched. HM: Host membrane; OM: outer membrane; IM: inner membrane; MM: mycomembrane; OMP: outer membrane protein; MFP: membrane fusion protein. ATPases and chaperones are shown in yellow Tseng TT et al. BMC Microbiol 2009, 9 (Suppl 1), S2 © 2009, Tseng et al; licensee BioMed Central Ltd Another example of a bacterial effector protein with ITIM-like motifs is the cytotoxin-associated gene A (CagA) from Gram-negative bacteria Helicobacter pylori (H. pylori), a cause of chronic gastritis. CagA was the first identified bacterial effector protein containing tyrosine-based motifs similar to ITIMs. Once attached, H. pylori injects CagA into the host cells. The CagA in the cells form a physical complex with SHP-2 in a phosphorylation-dependent manner, which leads to the activation of phosphatase.³⁷ That leads to the dephosphorylation of activated epidermal growth factor receptor and transcription factor signal transducer and activator of transcription 1, which suppresses the antibacterial response.

4. Modify Host Cell Signaling Pathways by Posttranslational Modification

Host Defense Mechanism

PRRs can trigger the activation of NF-κB and inflammasomes, which lead to the production of proinflammatory cytokines such as TNF-α and chemokines. NF-κB is a well-studied transcription factor that plays a central role in the PRR signaling. The activity of NF-κB and related signaling molecules is regulated tightly by posttranslational modifications, i.e., ubiquitination, phosphorylation, and glycosylation.

Bacterial Immune Evasion

Bacteria express several virulence factors after attaching to the host cells. They are called effector proteins. The transport systems of the effector proteins are known as SS and are essential for bacterial pathogens to secrete virulence factors.38 Pathogenic bacteria use dedicated SS, which can be classified into different types based on their structures and mechanisms (Figure 4). In this section, we highlight how the bacterial effector proteins manipulate NF-κB and related inflammatory signaling pathways. Pathogenic Yersinia species, i.e., Y. enterocolitica, Y. pseudotuberculosis, and Y. pestis, need plasmid- encoded Yersinia outer proteins (Yops) to survive in host cells. Yops are injected by T3SS (Figure 4) to translocate into the cytosol of the host cells. The transported effector Yops represses signaling initiated by PRRs and phagocytosis. One of the effector proteins, YopJ, has intrinsic deubiquitinating protease activity. It deubiquitinates K48- and K63-linked ubiquitin conjugates that are required for the activation of antibacterial response molecules including NF-kB, tumor necrosis factor receptor-associated factor (TRAF) 3, and TRAF6,39 thereby inhibiting NF-kB signaling, MAPK signaling, and IFN response.

Likewise, one of the T3SS effector proteins, OspI, a deamidase, secreted by S. flexneri, inhibits the formation of K63-linked ubiquitin chains by deamidating the glutamine residue in the E2-conjugating enzyme Ubc13.^40,41 This leads to inhibition of ubiquitin transfer from Ubc13 to TRAF6. As a result, TRAF6 auto-polyubiquitination and downstream antibacterial inflammatory responses are dampened by OspI. Shigella secretes multiple effector proteins with a variety of enzymatic activities.⁴² Another effector protein, OspG, shares sequence similarity with eukaryotic protein kinases.⁴³ It has been shown to associate with ubiquitin and ubiquitin-conjugating enzymes to activate its kinase activity. OspG suppresses the degradation of IκBα, thereby inhibiting NF-κB translocation to the nucleus. Recently, unbiased phosphoproteomics screening identified Cullin-associated and neddylation-dissociated 1 (CAND1) as a major target of OspG.⁴⁴ OspG promotes ubiquitination of septins, a class of cytoskeletal proteins, which inhibits septin assembly and the formation of cage-like structures that entrap cytosolic bacteria.

A/E pathogens also produce multiple effectors with enzymatic activities: NleB, one of the effector proteins that have glycosyltransferase activity; NleB transfers N-acetylglucosamine (GlcNAc) onto glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which hinders GAPDH-TRAF2 complex formation and TRAF2 polyubiquitination. As a result, NleB inhibits NF-κB activation induced by tumor necrosis factor (TNF) receptor 1-signaling complex.⁴⁵ NleB also can transfer GlcNAc to signaling molecules containing death domains such as Fas-associated death domain protein (FADD), TNF receptor type 1-associated death domain protein (TRADD), and receptor-interacting protein kinase 1.^46,47 The attached GlcNAc interferes with death domain oligomerization and subsequent TNF death receptor complex formation. Therefore, NleB inhibits TNF-induced immune response and subsequent inflammatory mediator production.

5. Manipulate Complement Pathways

Host Defense Mechanism

The complement system is activated by three extracellular pathways: classical, lectin, and alternative pathways (Figure 5). The classical pathway is activated by the binding of antibody–antigen complexes to C1q. The lectin pathway is triggered by the binding of MBL to the carbohydrate motifs on pathogens. Activation of the alternative pathway occurs when C3b recognizes pathogens. The activation of these pathways results in the formation of the membrane attack complex, which lyses the bacterial cells, promotion of phagocytosis, and inflammation to recruit additional phagocytes that are mainly neutrophils.

Gray boxes identify initiation and terminal pathways with complement components identified along the arrows. The classical pathway is activated by antigen/antibody complexes, recognized by C1q in complex with C1r and C1s. Proteases C1r and C1s cleave C4 and C2 to generate the classical pathway C3 convertase C4b2a. The lectin pathway is triggered by binding of MBL or ficolins to carbohydrates on the target membrane. The MBL-associated serine proteases (MASPs) then cleave C4 and C2 generating the C3-convertase C4b2a. The alternative pathway, an amplification loop, is triggered when the C3b protein directly binds a microbe, foreign material, or damaged tissue. C3b also binds factor B (fB) to form C3bB. FB is cleaved by factor D (fD) to form alternative pathway C3 convertase, C3bBb. This convertase is stabilized by properdin (P). C3b opsonizes targets for phagocytosis and B-cell activation. All three initiation pathways converge on C3 with distinct C3 convertases, which cleave C3 to generate the anaphylatoxin C3a, and more C3b to form the C5 convertases (C4b2a3b and C3bBb3b). C5 convertase then cleaves C5 into C5a and C5b. C3a and C5a can attract and activate inflammatory cells and contract smooth muscle through receptors (C3aR, C5aR1, and C5aR2). C5b binds C6, C7, C8, and multiple copies of C9 forming the membrane attack complex (MAC). MAC pores can cause cell death by osmotic flux Girardi G et al. Front. Immunol. 2020;11:1681 © 2020 Girardi, Lingo, Fleming and Regal

Bacterial Immune Evasion

As described in Section 1, bacteria can suppress the activation of complement pathways by modifying their surface structures. Besides, bacteria can produce proteases that degrade complement components. In this section, we discuss examples of how bacteria skillfully manipulate the complement pathways. Pseudomonas aeruginosa (P. aeruginosa), a common Gram-negative bacterium causing nosocomial bacteremia, secretes proteases to degrade the complement component system in addition to their contribution to the complement resistance by their O-antigen and capsule polysaccharide.48 These exoproteases include alkaline protease A (AprA), elastase B (LasB), and protease IV (PIV). AprA inhibits the activation of the classical and lectin pathways by degrading C2 (Figure 5). Subsequently, AprA inhibits C3b and C5a formation and neutrophil recruitment, allowing the bacteria to escape phagocytes.49 LasB cleaves C1q and C350 as well as inactivates the purified components C5, C5a, C8, and C9. PIV degrades C3 and C1q.

Gram-positive bacteria Streptococcus pyogenes, or group A Streptococcus (GAS), GBS, and S. pneumoniae have a polysaccharide capsule that is poorly immunogenic in humans. In addition to their capsule, which already makes them difficult targets for a complement attack, they produce cell-envelope proteases. GAS produces SpyCEP and ScpA, GBS produces CspA and ScpB. These proteases are expressed on the cell surface or released and cleave multiple chemokines including CXCL8, complement component C5a, and fibrinogen.51 CXCL8 and C5a (Figure 5) are neutrophil-recruiting chemokines. By degrading these chemokines, GAS and GBS block the recruitment of neutrophils to the sites of infection. Similarly, S. pneumoniae produces PspC, which binds factor H, a complement regulatory protein, and inhibits complement activation.⁵² The cell surface protein of S. aureus SdrE also binds factor H to inhibit activation of the alternative pathway,⁵³ which is one of their strategies to facilitate immune evasion.

Concluding Remarks

Human immune cells deploy a series of antibacterial defense mechanisms to eliminate the pathogens and prevent serious infections. On the other hand, pathogenic bacteria have developed an arsenal of virulence factors that have evolved to favor their survival. In this review, we attempt to take a unique perspective on the bacterial immune evasion and host innate immune responses in the very early phase of infection. Giving several examples corresponding to the host immune responses, interesting strategies used by pathogenic bacteria to manipulate or evade host immune responses are highlighted. Bacterial infections can be transmitted and spread throughout the human body, potentially leading to serious conditions such as sepsis and organ failure. Although a variety of effective antibiotics have been developed in recent decades, treatment options for antimicrobial-resistant bacteria remain limited, highlighting a critical need for new therapeutic interventions. Understanding the complex and dynamic interaction between host and pathogenic bacteria by novel approaches may possibly offer innovative solutions to treat these bacterial infections, for instance, new treatment modalities targeting host molecules or new types of vaccines. Vaccines are useful and promising tools to fight against bacterial antibiotic resistance.

Indeed, omics approaches have significantly contributed to recent vaccine and antibiotic discoveries by providing comprehensive insights into the molecular mechanisms of host–pathogen interactions. These omics approaches will potentially provide novel target molecules. The research on host–pathogen interactions will teach us how host pathways are exploited by bacterial pathogens, which is a fascinating aspect of immunology and microbiology. In addition, artificial intelligence gives us powerful leverage with the exploration of chemical spaces to discover a new class of antibiotics. Developing new antibiotics that can effectively target drug-resistant bacteria is imperative. Furthermore, non-traditional therapies, such as antibodies, bacteriophages, anti-virulence agents, microbiome-modulating agents, and immune-modulating agents, are emerging. These recent advancements in technology will accelerate the discovery of new antibiotics and innovative therapeutic strategies.

Acknowledgment

The author would like to thank the support from Mr. Claude A Duncan for providing great work environment and infrastructure.

References

1 Finlay BB, McFadden G. Anti-immunology: Evasion of the host immune system by bacterial and viral pathogens. Cell. 2006;124(4):767-82.
https://doi.org/10.1016/j.cell.2006.01.034
 
2 Ji F, Zhou M, Zhu H, Jiang Z, Li Q, Ouyang X, et al. Integrative proteomic analysis of multiple posttranslational modifications in inflammatory response. Genomics Proteomics Bioinformatics. 2022;20(1):163-76.
https://doi.org/10.1016/j.gpb.2020.11.004
 
3 Li D, Wu M. Pattern recognition receptors in health and diseases. Signal Transduct Target Ther. 2021;6(1):291.
https://doi.org/10.1038/s41392-021-00687-0
 
4 Matsuura M. Structural modifications of bacterial lipopolysaccharide that facilitate Gram-Negative bacteria evasion of host innate immunity. Front Immunol. 2013;4:109.
https://doi.org/10.3389/fimmu.2013.00109
 
5 Suomalainen M, Lobo LA, Brandenburg K, Lindner B, Virkola R, Knirel YA, et al. Temperature-induced changes in the lipopolysaccharide of yersinia pestis affect plasminogen activation by the pla surface protease. Infect Immun. 2010;78(6):2644-52.
https://doi.org/10.1128/IAI.01329-09
 
6 Paciello I, Silipo A, Lembo-Fazio L, Curcurù L, Zumsteg A, Noël G, et al. Intracellular shigella remodels its LPS to dampen the innate immune recognition and evade inflammasome activation. Proc Natl Acad Sci U S A. 2013;110(46):E4345-54.
https://doi.org/10.1073/pnas.1303641110
 
7 Musilova J, Mulcahy ME, Kuijk MM, McLoughlin RM, Bowie AG. Toll-like receptor 2-dependent endosomal signaling by Staphylococcus aureus in monocytes induces type i interferon and promotes intracellular survival. J Biol Chem. 2019;294(45):17031-42.
https://doi.org/10.1074/jbc.RA119.009302
 
8 Weidenmaier C, Peschel A. Teichoic acids and related cell-wall glycopolymers in Gram-positive physiology and host interactions. Nat Rev Microbiol. 2008;6(4):276-87.
https://doi.org/10.1038/nrmicro1861
 
9 Park KH, Kurokawa K, Zheng L, Jung DJ, Tateishi K, Jin JO, et al. Human serum mannose-binding lectin senses wall teichoic acid glycopolymer of Staphylococcus aureus, which is restricted in infancy. J Biol Chem. 2010;285(35):27167-75.
https://doi.org/10.1074/jbc.M110.141309
 
10 Gerlach D, Guo Y, De Castro C, Kim SH, Schlatterer K, Xu FF, et al. Methicillin-resistant Staphylococcus aureus alters cell wall glycosylation to evade immunity. Nature. 2018;563(7733):705-9.
https://doi.org/10.1038/s41586-018-0730-x
 
11 Brown S, Xia G, Luhachack LG, Campbell J, Meredith TC, Chen C, et al. Methicillin resistance in Staphylococcus aureus requires glycosylated wall teichoic acids. Proc Natl Acad Sci U S A. 2012;109(46):18909-14.
https://doi.org/10.1073/pnas.1209126109
 
12 Guo Y, Pfahler NM, Völpel SL, Stehle T. Cell wall glycosylation in Staphylococcus aureus: Targeting the tar glycosyltransferases. Curr Opin Struct Biol. 2021;68:166-74.
https://doi.org/10.1016/j.sbi.2021.01.003
 
13 Kurokawa K, Jung DJ, An JH, Fuchs K, Jeon YJ, Kim NH, et al. Glycoepitopes of staphylococcal wall teichoic acid govern complement-mediated opsonophagocytosis via human serum antibody and mannose-binding lectin. J Biol Chem. 2013;288(43):30956-68.
https://doi.org/10.1074/jbc.M113.509893
 
14 Essuman K, Milbrandt J, Dangl JL, Nishimura MT. Shared TIR enzymatic functions regulate cell death and immunity across the tree of life. Science. 2022;377(6605):abo0001.
https://doi.org/10.1126/science.abo0001
 
15 Newman RM, Salunkhe P, Godzik A, Reed JC. Identification and characterization of a novel bacterial virulence factor that shares homology with mammalian Toll/interleukin-1 receptor family proteins. Infect Immun. 2006;74(1):594-601.
https://doi.org/10.1128/IAI.74.1.594-601.2006
 
16 Xiong D, Song L, Geng S, Jiao Y, Zhou X, Song H, et al. Salmonella coiled-coil- and TIR-containing TcpS evades the innate immune system and subdues inflammation. Cell Rep. 2019;28(3):804-18.e7.
https://doi.org/10.1016/j.celrep.2019.06.048
 
17 Cirl C, Wieser A, Yadav M, Duerr S, Schubert S, Fischer H, et al. Subversion of toll-like receptor signaling by a unique family of bacterial toll/interleukin-1 receptor domain-containing proteins. Nat Med. 2008;14(4):399-406.
https://doi.org/10.1038/nm1734
 
18 Yadav M, Zhang J, Fischer H, Huang W, Lutay N, Cirl C, et al. Inhibition of TIR domain signaling by TcpC: Myd88-dependent and independent effects on Escherichia coli virulence. PLoS Pathog. 2010;6(9):e1001120.
https://doi.org/10.1371/journal.ppat.1001120
 
19 Waldhuber A, Puthia M, Wieser A, Cirl C, Dürr S, Neumann-Pfeifer S, et al. Uropathogenic Escherichia coli strain CFT073 disrupts NLRP3 inflammasome activation. J Clin Invest. 2016;126(7):2425-36.
https://doi.org/10.1172/JCI81916
 
20 Askarian F, van Sorge NM, Sangvik M, Beasley FC, Henriksen JR, Sollid JU, et al. A Staphylococcus aureus TIR domain protein virulence factor blocks TLR2-mediated NF-κB signaling. J Innate Immun. 2014;6(4):485-98.
https://doi.org/10.1159/000357618
 
21 Ben Mkaddem S, Benhamou M, Monteiro RC. Understanding fc receptor involvement in inflammatory diseases: From mechanisms to new therapeutic tools. Front Immunol. 2019;10:811.
https://doi.org/10.3389/fimmu.2019.00811
 
22 Bornhöfft KF, Goldammer T, Rebl A, Galuska SP. Siglecs: A journey through the evolution of sialic acid-binding immunoglobulin-type lectins. Dev Comp Immunol. 2018;86:219-31.
https://doi.org/10.1016/j.dci.2018.05.008
 
23 Medjouel Khlifi H, Guia S, Vivier E, Narni-Mancinelli E. Role of the ITAM-bearing receptors expressed by natural killer cells in cancer. Front Immunol. 2022;13:898745.
https://doi.org/10.3389/fimmu.2022.898745
 
24 Scur M, Parsons BD, Dey S, Makrigiannis AP. The diverse roles of C-type lectin-like receptors in immunity. Front Immunol. 2023;14:1126043.
https://doi.org/10.3389/fimmu.2023.1126043
 
25 Reis E, Sousa C, Yamasaki S, Brown GD. Myeloid C-type lectin receptors in innate immune recognition. Immunity. 2024;57(4):700-17.
https://doi.org/10.1016/j.immuni.2024.03.005
 
26 Wang L, Gordon RA, Huynh L, Su X, Park Min KH, Han J, et al. Indirect inhibition of toll-like receptor and type i interferon responses by ITAM-coupled receptors and integrins. Immunity. 2010;32(4):518-30.
https://doi.org/10.1016/j.immuni.2010.03.014
 
27 Pinheiro da Silva F, Aloulou M, Benhamou M, Monteiro RC. Inhibitory ITAMs: A matter of life and death. Trends Immunol. 2008;29(8):366-73.
https://doi.org/10.1016/j.it.2008.05.001
 
28 Carlin AF, Uchiyama S, Chang YC, Lewis AL, Nizet V, Varki A. Molecular mimicry of host sialylated glycans allows a bacterial pathogen to engage neutrophil Siglec-9 and dampen the innate immune response. Blood. 2009;113(14):3333-6.
https://doi.org/10.1182/blood-2008-11-187302
 
29 Crocker PR, Paulson JC, Varki A. Siglecs and their roles in the immune system. Nat Rev Immunol. 2007;7(4):255-66.
https://doi.org/10.1038/nri2056
 
30 Carlin AF, Chang YC, Areschoug T, Lindahl G, Hurtado-Ziola N, King CC, et al. Group B Streptococcus suppression of phagocyte functions by protein-mediated engagement of human Siglec-5. J Exp Med. 2009;206(8):1691-9.
https://doi.org/10.1084/jem.20090691
 
31 Pinheiro da Silva F, Aloulou M, Skurnik D, Benhamou M, Andremont A, Velasco IT, et al. CD16 promotes Escherichia coli sepsis through an FcR gamma inhibitory pathway that prevents phagocytosis and facilitates inflammation. Nat Med. 2007;13(11):1368-74.
https://doi.org/10.1038/nm1665
 
32 Vieira MFM, Hernandez G, Zhong Q, Arbesú M, Veloso T, Gomes T, et al. The pathogen-encoded signalling receptor Tir exploits host-like intrinsic disorder for infection. Commun Biol. 2024;7(1):179.
https://doi.org/10.1038/s42003-024-05856-9
 
33 Chen Z, Zhou R, Zhang Y, Hao D, Wang Y, Huang S, et al. β-arrestin 2 quenches TLR signaling to facilitate the immune evasion of EPEC. Gut Microbes. 2020;11(5):1423-37.
https://doi.org/10.1080/19490976.2020.1759490
 
34 Yan D, Wang X, Luo L, Cao X, Ge B. Inhibition of TLR signaling by a bacterial protein containing immunoreceptor tyrosine-based inhibitory motifs. Nat Immunol. 2012;13(11):1063-71.
https://doi.org/10.1038/ni.2417
 
35 Yan D, Quan H, Wang L, Liu F, Liu H, Chen J, et al. Enteropathogenic Escherichia coli Tir recruits cellular SHP-2 through ITIM motifs to suppress host immune response. Cell Signal. 2013;25(9):1887-94.
https://doi.org/10.1016/j.cellsig.2013.05.020
 
36 Smith K, Humphreys D, Hume PJ, Koronakis V. Enteropathogenic Escherichia coli recruits the cellular inositol phosphatase SHIP2 to regulate actin-pedestal formation. Cell Host Microbe. 2010;7(1):13-24.
https://doi.org/10.1016/j.chom.2009.12.004
 
37 Higashi H, Tsutsumi R, Muto S, Sugiyama T, Azuma T, Asaka M, et al. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science. 2002;295(5555):683-6.
https://doi.org/10.1126/science.1067147
 
38 Green ER, Mecsas J. Bacterial secretion systems: An overview. Microbiol Spectr. 2016;4(1). Doi:10.1128/microbiolspc.VMBF-0012-2015.
https://doi.org/10.1128/microbiolspec.VMBF-0012-2015
 
39 Sweet CR, Conlon J, Golenbock DT, Goguen J, Silverman N. YopJ targets TRAF proteins to inhibit TLR-mediated NF-kappaB, MAPK and IRF3 signal transduction. Cell Microbiol. 2007;9(11):2700-15.
https://doi.org/10.1111/j.1462-5822.2007.00990.x
 
40 Sanada T, Kim M, Mimuro H, Suzuki M, Ogawa M, Oyama A, et al. The Shigella flexneri effector OspI deamidates UBC13 to dampen the inflammatory response. Nature. 2012;483(7391):623-6.
https://doi.org/10.1038/nature10894
 
41 Nishide A, Kim M, Takagi K, Himeno A, Sanada T, Sasakawa C, et al. Structural basis for the recognition of Ubc13 by the shigella flexneri effector OspI. J Mol Biol. 2013;425(15):2623-31.
https://doi.org/10.1016/j.jmb.2013.02.037
 
42 de Jong MF, Alto NM. Cooperative immune suppression by Escherichia coli and shigella effector proteins. Infect Immun. 2018;86(4):00560-17.
https://doi.org/10.1128/IAI.00560-17
 
43 Kim DW, Lenzen G, Page AL, Legrain P, Sansonetti PJ, Parsot C. The shigella flexneri effector OspG interferes with innate immune responses by targeting ubiquitin-conjugating enzymes. Proc Natl Acad Sci U S A. 2005;102(39):14046-51.
https://doi.org/10.1073/pnas.0504466102
 
44 Xian W, Fu J, Zhang Q, Li C, Zhao YB, Tang Z, et al. The shigella kinase effector OspG modulates host ubiquitin signaling to escape septin-cage entrapment. Nat Commun. 2024;15(1):3890.
https://doi.org/10.1038/s41467-024-48205-4
 
45 Gao X, Wang X, Pham TH, Feuerbacher LA, Lubos ML, Huang M,
 
et al. NleB, a bacterial effector with glycosyltransferase activity, targets GAPDH function to inhibit NF-κB activation. Cell Host Microbe. 2013;13(1):87-99.
https://doi.org/10.1016/j.chom.2012.11.010
 
46 Pearson JS, Giogha C, Ong SY, Kennedy CL, Kelly M, Robinson KS,
 
et al. A type III effector antagonizes death receptor signalling during bacterial gut infection. Nature. 2013;501(7466):247-51.
https://doi.org/10.1038/nature12524
 
47 Li S, Zhang L, Yao Q, Li L, Dong N, Rong J, et al. Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains. Nature. 2013;501(7466):242-6.
https://doi.org/10.1038/nature12436
 
48 González-Alsina A, Mateu-Borrás M, Doménech-Sánchez A, Albertí S. Pseudomonas aeruginosa and the complement system: A review of the evasion strategies. Microorganisms. 2023;11(3):664.
https://doi.org/10.3390/microorganisms11030664
 
49 Laarman AJ, Bardoel BW, Ruyken M, Fernie J, Milder FJ, van Strijp JA, et al. Pseudomonas aeruginosa alkaline protease blocks complement activation via the classical and lectin pathways. J Immunol. 2012;188(1):386-93.
https://doi.org/10.4049/jimmunol.1102162
 
50 Mateu-Borrás M, Zamorano L, González-Alsina A, Sánchez-Diener I, Doménech-Sánchez A, Oliver A, et al. Molecular analysis of the contribution of alkaline protease A and elastase B to the virulence of Pseudomonas aeruginosa bloodstream infections. Front Cell Infect Microbiol. 2021;11:816356.
https://doi.org/10.3389/fcimb.2021.816356
 
51 McKenna S, Huse KK, Giblin S, Pearson M, Majid Al Shibar MS, Sriskandan S, et al. The role of streptococcal cell-envelope proteases in bacterial evasion of the innate immune system. J Innate Immun. 2022;14(2):69-88.
https://doi.org/10.1159/000516956
 
52 Pathak A, Bergstrand J, Sender V, Spelmink L, Aschtgen MS, Muschiol S, et al. Factor H binding proteins protect division septa on encapsulated Streptococcus pneumoniae against complement C3b deposition and amplification. Nat Commun. 2018;9(1):3398.
https://doi.org/10.1038/s41467-018-05494-w
 
53 Sharp JA, Echague CG, Hair PS, Ward MD, Nyalwidhe JO, Geoghegan JA, et al. Staphylococcus aureus surface protein SdrE binds complement regulator factor H as an immune evasion tactic. PLoS One. 2012;7(5):38407.
https://doi.org/10.1371/journal.pone.0038407

Cite this article as:
Matsunaga N. Evasion of the Host Innate Immune System by Pathogenic Bacteria. Premier Journal of Science 2024;5:100046.

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