Adhesive mechanism of different Salmonella fimbrial adhesins

Microbial Pathogenesis 137 (2019) 103748

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Adhesive mechanism of different Salmonella fimbrial adhesins☆ a,1

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Tayyab Rehman , Lizi Yin , Muhammad Bilal Latif , Jiehao Chen , Kaiyu Wang , Yi Geng , Xiaoli Huangb, Muhammad Abaidullaha, Hongrui Guoa, Ping Ouyanga,∗ a b c

Department of Basic Veterinary, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, 611130, Sichuan, China Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, Sichuan, China Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, 44195, Ohio, USA

A R T I C LE I N FO

A B S T R A C T

Keywords: Adhesion Assembly pathways Fimbriae Salmonella

Salmonellosis is a serious threat to human and animal health. Salmonella adhesion to the host cell is an initial and most crucial step in the pathogenesis of salmonellosis. Many factors are involved in the adhesion process of Salmonella infection. Fimbriae are one of the most important factors in the adhesion of Salmonella. The Salmonella fimbriae are assembled in three types of assembly pathways: chaperon–usher, nucleation–precipitation, and type IV fimbriae. These assembly pathways lead to multiple types of fimbriae. Salmonella fimbriae bind to host cell receptors to initiate adhesion. So far, many receptors have been identified, such as Toll-like receptors. However, several receptors that may be involved in the adhesive mechanism of Salmonella fimbriae are still un-identified. This review aimed to summarize the types of Salmonella fimbriae produced by different assembly pathways and their role in adhesion. It also enlisted previously discovered receptors involved in adhesion. This review might help readers to develop a comprehensive understanding of Salmonella fimbriae, their role in adhesion, and recently developed strategies to counter Salmonella infection.

1. Introduction Salmonellosis has health and economic significance because of the costs associated with the surveillance, control, and treatment of Salmonella-caused diseases [1]. Salmonella-associated gastroenteritis is the most common sickness among all cases of salmonellosis globally, with 93.8 million patients resulting in 155,000 deaths annually [2,3]. Salmonella strains show diverse tolerance mechanisms and diversity of responses under high-pressure processing [4]. About 2600 serotypes of Salmonella have been identified with a wide host range including humans [5]. The two most important serovars of S. enterica are S. Typhimurium and S. Enteritidis, which contribute approximately about 80% of the total non-typhoid salmonellosis infections [8]. The adhesion to the host cell is considered a key factor during bacterial pathogenesis. Specialized protein structures present on the surface of bacteria and complementary receptors on the host cell surface often facilitate bacterial attachment to the host cell [9]. In eukaryotic cells, various cellular components have been identified for adhesion by microorganisms, many of them characterized as

proteoglycans. Some studies also suggest that bacteria use a novel strategic approach in which carbohydrate-based molecules facilitate bacterial adhesion on the surface of eukaryotic cells [10,11]. During attachment, the bacterial surface protein–binding site (adhesin) binds with polyhydroxylated glycan present on the host cell surface. In some cases, bacterial adhesins bind to glycosaminoglycans (GAGs) present on the host cell [12–14]. Recent studies suggest that diverse factors are involved in enhancing the adhesiveness of bacteria with the host cell [15]. Different binding forces involved in the adhesive mechanism are van der Walls forces and hydrogen bonding. The binding occurs when the adhesin is opposite to the respective glycan [16,17]. Mostly, cell membrane receptors are made up of oligosaccharide residues from glycolipids and glycoproteins [18]. Salmonella pathogenesis is implicated by many virulent factors, including different types of secretion systems, capsule, plasmid, and flagella. With these different virulence factors, Salmonella has developed many fimbrial adhesins through which it establishes various strategies to attach to the host cell, resulting in Salmonella infection in some cases [9]. The term fimbria (for fibers in Latin) is preferably used to

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Mailing address: College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, Sichuan, China. Corresponding author. E-mail addresses: [email protected] (T. Rehman), [email protected] (L. Yin), [email protected] (M.B. Latif), [email protected] (J. Chen), [email protected] (K. Wang), [email protected] (Y. Geng), [email protected] (X. Huang), [email protected] (M. Abaidullah), [email protected] (H. Guo), [email protected], [email protected] (P. Ouyang). 1 These authors contributed equally to this work. ∗

https://doi.org/10.1016/j.micpath.2019.103748 Received 29 April 2019; Received in revised form 10 September 2019; Accepted 11 September 2019 Available online 12 September 2019 0882-4010/ © 2019 Elsevier Ltd. All rights reserved.

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demonstrate the non-flagellar filamentous apparatus [19]. Fimbriae are extracellular appendages with 0.5–10 μm length and 2–8 nm width. They are typically involved in adhesion and many other functions, including interaction with macrophages, biofilm formation, intestinal persistence, and bacterial aggregation [20–26]. A few fimbriae are limited to some specific serovars and may play specific roles not required by other serovars. Salmonella fimbrial gene clusters (FGCs) usually consist of 4–15 genes and encode for their assembly, structure, and regulatory proteins required for the production of extracellular fimbriae. A total of 38 unique FGCs have been identified so far in 111 sequenced genomes from 34 different serovars [27]. Under laboratory conditions, most of the fimbriae are poorly expressed, and their functional redundancy makes their studies complicated [27]. However, fimbriae are considered as key factors to understand the pathogenesis of Salmonella [28]. Salmonella fimbrial adhesins have different assembly pathways: including chaperone–usher (CU) pathway, extracellular nucleation–precipitation (N/P) pathway, and, like type II secretion system, a special system for type IV (T4) fimbriae. The diverse fimbriae are produced through these three types of assembly pathways [27]. The best-characterized type 1 fimbrial adhesin FimH resembles several fimbrial adhesins structurally and functionally [9]. This study enlisted all types of Salmonella fimbriae, their role in adhesive mechanism, and their assembly pathways to understand the pathogenesis of salmonellosis.

structural and functional activation/alteration of different host defense mechanisms, providing clues to develop new therapeutic strategies to combat infections [46–50]. Fimbriae have been identified as an important virulence factor in many bacteria. Salmonella fimbriae have an affinity to bind to various host cell receptors [9,54], which play many important functions during Salmonella pathogenesis [51–53]. The presence of fimbriae in the extracellular matrix makes them a potential antigen for developing vaccines against salmonellosis [55]. Fimbriae also play an important role in identifying Salmonella through different molecular techniques [56–62]. The discrimination among non-Salmonella and Salmonella species is possible with the presence of fimbrial genes [63]. Moreover, the unique patterns of fimbrial genes are useful for differentiating among different Salmonella serovars. Fimbriae are also an important factor for the development of new therapeutic drugs against Salmonella infection. Further understanding of fimbriae may reveal new insights on Salmonella pathogenesis. 3. Types of fimbriae in Salmonella In humans, salmonellosis is mostly caused by the S. enterica spp. I, and most of the sequenced serovars also belong to the spp. I. Moreover, 27 out of 38 FGCs belong to spp. I. Furthermore, using phylogenetic analysis, spp. I was subdivided into five different classes. The serovars that mostly cause gastroenteritis were grouped in class IA; the main serovar of this class was Typhimurium. Serovars with similar FGCs and O-antigens, including Pullorum, Gallinarum, Dublin, and Enteritidis were grouped in class IB. Class C consisted of Paratyphi C and Choleraesuis serovars, and human-specific Typhi and Paratyphi serovars were categorized into class ID. With the highest number of FGCs, different serovars, including Heidelberg, Virchow, and Hadar formed the separate branch of IA class. The serovars mostly isolated from edible plants, such as Kentucky, Tennessee, Montevideo, Welterveden, Javiana, and Schwarzengrund, belonged to IE class [64,65]. In 1966, fimbriae were classified into seven types (types 1–6 and F) depending on their morphology and hemagglutination patterns. Later on, another classification better predicted the genetic relatedness of fimbrial antigens based on serology. According to the modern classification, fimbriae have been divided into different types based on their assembly pathway: CU, N/P, and T4 fimbriae [27,66]. The CU assembly is characterized by interaction among the subunits—a periplasmic chaperone and an outer membrane usher—for the biogenesis of mature fimbriae. In the extracellular environment, a nucleator forms an aggregate of fibers through the N/P pathway. T4 fimbriae need ATP for their assembly and use a complex machinery for fimbrial formation. Moreover, T4 fimbriae have an ability to retract and reverse fimbrial assembly [66]. In the Salmonella genome, CU fimbriae are the most common. Curly fimbriae assemble through the nucleation–precipitation pathway and are present in the genome of all types of Salmonella. T4 fimbriae are the least common among the Salmonella serovars. Fimbriae

2. Importance of fimbriae in Salmonella infection Salmonellosis is acquired from the oral ingestion of contaminated food items. It initiates after the adhesion of Salmonella to the host cell, leading to its colonization and infection [32]. The first obstacle that affects Salmonella infectivity after oral ingestion is the stomach. Fimbriae, which are involved mainly in the attachment, do not play a role in Salmonella motility compared with flagella. Different factors, including food, also protect Salmonella in many ways in the stomach [33,34]. After entering the intestine, Salmonella fimbriae traverse the mucous layer to invade the epithelium of the host [35–38]. Salmonella fimbriae help invade non-phagocytic enterocytes in the epithelium of the intestine and then adhere to the epithelium [39,40]. Salmonella fimbriae attach to microfold (M) cells, which are specialized intestinal epithelial cells with less mucous covering, glycocalyx, and small microvilli [41,42]. Moreover, some recent studies suggest that Salmonella fimbriae in various serovars preferably adhere to enterocytes instead of M cells [43]. The adherence of Salmonella preferably to M cells probably helps Salmonella in entering intestinal epithelial cells through the basement of epithelial cells. The epithelial cells shed them in the intestinal lumen where they possibly replicate, which is required for their survival. This mechanism is probably important for the intestinal colonization of Salmonella, leading to an acute infection [44,45]. The diverse strategic approach followed by Salmonella fimbriae leads to the

Fig. 1. Different types of Salmonella fimbriae. Green boxes show the main three types of fimbriae produced by these assembly pathways. They have a diverse distribution among different serovars. Blue boxes show the division and subdivision of Salmonella fimbriae. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

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Table 1 Distribution of different types of Salmonella fimbriae among different serovars. Fimbriae

CU clade

Adhesin

Fimbrial gene cluster

Distribution

Receptor/Affinity/Host

Reference

Tcf Sdf Sdg Stj Bcf Fim Lpf Sdd/Smf Stg Sth Sti Saf Sde Sef Mrk Peg Peh Sba Sdh Sdi Sdj Sta Stb Stc Stk Fae/Skf Pef Sbc/Spf Sbb/Sbf Sdk Sdi Std Ste Stf Sdc/Sas Csg Pil

α β β β γ1 γ1 γ1 γ1 γ1 γ1 γ1 γ3 γ3 γ3 γ4 γ4 γ4 γ4 γ4 γ4 γ4 γ4 γ4 γ4 γ4 κ κ κ π π π π π π σ Curli Type IV

TcfD SdfD SdgG StjA BcfD FimH LpfD SddD StgD SthE StiH SafD SdeD SefD MrkD PegD PehD SbaH SdhG SdiD SdjD StaG StbD StcD StkG FaeD PefD SbcF SbbD SdkD SdiD StdD SteG StfH SdcE – PilD

tcfABCD sdfABCDEF sdgABCDEFG stdABCD bcfABCDEFGH fimAICDHFZYW lpfABCDE sddABCDF stgABCD sthABCDE stiABCH safABCD sdeABCDE sefABCDR MrkABCDJI pegABCDE pehABCDE sbaABCDEFGH sdhABCDEFG stiABCD sdjABCD_yhoN staABCDEFG stbABCDEF stcABCD_yhoN stkABCDEFG faeBCDEFGHIJKA pefBACDEFI sbcABCDEFGH sbbABCD sdkABCD sdiABCD stdABCD steABCDEFGHIJ stfABCDEFGH sdcABCDE ——— ————

1C, 1D, and 1E – – IA and IE Absent in IV Only absent in S. bongori Only absent in ID IE, II, IIIa, and IV Bongori, ID Absent in IIIa and IIIb Absent in ID Spp. I IE IB and D Only present in Montevideo Bongori, IB, IC, IIIa, and VI Only present in Montevideo Only in Bongori IE IIIb, diarizonae IIIb, diarizonae ID I, II, and IIIb IA, IB, and ID IE IB and IE Only in IA, IC, and bongori IV, VI, and bongori Bongori IIIb and VI IIIb diarizonae II, IIIa, Absent in gallinarum Absent in IA and IE Absent in ID and IE IIIa and Arizona All Salmonella ID, IE, and S. bongori

Unknown Unknown Unknown Unknown Unknown Mannose residue, erythrocyte, glycoprotein-2 in the murine model Peyer's patches Unknown Permeabilization of macrophage-like cells and Hep-2 epithelial cells Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Lewis X blood group antigen Unknown Unknown Unknown Unknown α (1,2)-Fucose Unknown Unknown Unknown Unknown Unknown

[65] [65] [65] [69] [31,70] [71,72] [31,73] [65] [65,74] [31,65] [65,75] [76] [65] [77] [65] [78] [65] [65] [65] [65,79] [65] [70] [31,70] [31,65,73] [21] [65] [73] [65] [65,79] [65] [65] [31,65] [65] [65,71] [65] [65] [65]

are divided into different clades and subclades, such as α, β, γ, κ, π, and σ, as shown in Fig. 1 and Table 1. The representatives of all the different six phylogenetic clades are observed in Salmonella. Among these clades, lpf, fim, and sef genes belong to the γ1 and γ3 subclades, while pef and sdc belong to the κ and σ clades, respectively [67]. The largest and highly conserved clade (fim, bcf, and sth) with 22 FGCs belongs to the γ1 clade. The γ4 clade is considered as the most diverse clade. The sdc is the only representative FGC of the σ clade found in S. enterica IIIa subspecies. The seven FGCs, curli fimbriae, and CU fimbriae (std, stb, stc, sth, bcf, and fim) represent the conserved fimbriae. Fim fimbriae are present in all strains of S. enterica, but absent in S. bongori. In CU fimbriae, a classical shape is formed by the repetition of major subunits that emerge through the usher and attach to the outer cellular membrane. These emerged major subunits are accompanied by some minor subunits and/or adhesins [27]. An aggregated shape of fimbriae produced through the N/P pathway is highly stable and hardly depolymerized due to the precipitation of major subunits together [68]. Furthermore, T4 fimbriae subunits for pilus formation anchor in the inner membrane through the periplasm and reach the outer membrane as intact fimbriae [9].

structural attributes. GAGs, such as dermatan sulfate and hyaluronan, construct the polysaccharide part and link covalently with proteins to form proteoglycans [80]. The other protein components of ECM include laminin, elastin, collagen, fibronectin, and so forth. ECM plays various roles besides adhesion, such as cytoskeleton contractility, tensile strength, gene expression, and tissue integrity. Salmonella fimbrial adhesins attach to host ECM components to enter the suitable niche. In addition, Salmonella can adhere to blood group antigens present mainly on erythrocytes. Glycosphingolipids present on erythrocytes carry characteristic terminal ends in their saccharide chains. However, blood group antigens are also present in dermal epithelia and on mucosal surfaces. Their curial role as ligands for different pathogen adhesins represents one of the factors for evolving the heterogeneity of structure found in the glycans that cover the digestive tract [9]. Although Salmonella fimbriae differ in their assembly methods, the various fimbriae assembled through these assembly methods have the same adhesive mechanism (Fig. 2). Mature fimbriae have sticky fimbrial adhesins at their tip. These Salmonella fimbrial adhesins have an affinity to bind to various ECMs of the host cells. The following sections describe diverse assembly methods and the adhesive mechanism in S. enterica. The molecular basis of adhesive systems should be understood to develop new strategies for preventing and treating severe disease outcomes of Salmonella infection [81–84].

4. Adhesive mechanism of Salmonella fimbriae Salmonella fimbriae interact with proteins present on the host cell receptor and adhere to host cells, most often leading to intestinal colonization and acute and chronic salmonellosis. The host has extracellular space comprising a complex meshwork of proteins and polysaccharides. Fimbriae activate stromal fibroblasts to secrete extracellular matrix (ECM) components, which possess adhesive and

4.1. CU-assembled fimbrial adhesins The CU assembly pathway has been studied in great detail among different assembly pathways [85]. The CU fimbriae biogenesis starts with the production of the subunits in the cytoplasm and their export 3

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Fig. 2. Adhesive mechanism of Salmonella fimbriae. The CU, N/P and T4 fimbriae pathways are used by Salmonella. Different fimbrial adhesins are produced by different fimbrial assembly pathways. Salmonella interacts with the host intestinal cells. Several diverse receptors are present on the host intestinal cells and other host cells. The fimbrial adhesins attach to the receptors that facilitate their colonization and invasion in the host cells.

act synergistically in each serovar [70,96]. The adaptations of different serovars to various niches are likely to be reflected by the varied distribution of fimbrial operon. However, different fimbrial operons were not expressed in vivo due to the identification and function of many fimbrial adhesins, which is still a challenge [71]. The expression of heterologous E. coli strains, as detected by electron microscopy or flow cytometry, can help analyze different fimbrial functions, which were not expressed in vitro previously because of the involvement of the stc fimbrial operon [71,97]. In Salmonella infection, the antibodies against different fimbriae could be detected in mice or various other species, indicating in vivo fimbrial expression [30,98]. The function of fimbrial adhesin has already been proved using in vivo experimental approaches. Long polar fimbriae (lpf), one of the chromosomal encoded fimbriae in the S. Typhimurium, enhance recognition of, and adherence to, M cells. In S. Typhi, the addition of different CU fimbriae in afimbrial strains seems to have significant effects on the adhesion and invasion of epithelial cells [40]. Apart from host cell attachments in the bacterium [99], fimbriae are also involved in colonization [71] and biofilm formation [23]. Typhi colonization factor (tcf) fimbriae play an important role in host specification and intestinal colonization [44,45]. Generally, the receptors on the host cell may be a lipid structure, sugar residues, or a distinct membrane protein. A receptor-binding site is present on fully developed fimbriae, which makes Salmonella capable of adhering to the host cell by recognizing specific receptors [27,100–102]. Fim fimbriae are the members of type 1 fimbriae family.

through the inner membrane via the general secretory pathway (GSP) [9,86,87]. The GSP usually uses the SecYEG complex and proteins SecDF/YajC. The accessory factor SecA targets the prepilin after its production, which is translocated to SecA by SecB. SecYEG translocation is energized by ATP hydrolysis catalyzed by SecA. The transport of prepilin to the periplasm is triggered by the use of ATP accompanied by the proton motive force. The peptidase in periplasm cleaves N-terminal signal peptides during the translocation across the membrane [86,88]. The interaction among specific chaperones prevents the rapid degradation through proteases and premature assembly of fimbrial subunits in the periplasm [89]. Fimbrial subunits are also directed by chaperones to the usher that consists of outer membrane integral proteins, which coordinate fimbrial assembly on the surface [90]. In vivo, the subunit transmission from the usher to the chaperone occurs very rapidly. In vitro, a slow and insufficient assembly was detected in the absence of the usher. These findings showed that the uncapping of the chaperone is necessary for the efficient assembly of mature fimbriae [89,91,92]. The morphology and dimensions of fully mature fibers of CU fimbriae depend mainly on the interactions among subunits and their composition. The diverse distribution of CU fimbrial subunits contribute to the virulence of Salmonella [93]. The unique molecular mechanism of CU fimbrial biogenesis may reveal new insight into the CU pathway [94]. S. enterica CU fimbriae widely differ in their composition and structure [95]. Diverse combinations of fimbriae are characterized to 4

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The accessory proteins CsgF and CsgE are accompanied by CsgG. The CsgE protein is a specific factor that closes the periplasmic space by the formation of a monomeric adaptor or by CsgG binding. The CsgA uptake by the CsgG protein is optimized in the presence of CsgE. The CsgB nucleation activity is supported by CsgF. However, CsgF depends on CsgG and CsgE for stability [122,123]. The crucial role of curli fimbriae during pathogenesis is not completely clear. However, evidence about the involvement of curli fimbriae in the infection process reveals its importance. Amyloid fibrils are recognized mainly for their important role in biofilm formation and detection by the immune system [124]. Different conditions, such as low temperature, low osmolarity, and nutrition limitation, affect the assembly and expression of curli fimbriae [125–127]. Various ECM proteins might allow the attachment of curli fimbriae to host cells, such as laminin, fibronectin, and fibrinogen [119,126,128]. The interaction of curli fimbriae with many host proteins is proposed to facilitate bacterial propagation through the host. Curli fimbriae bind to plasminogen. Plasminogen is activated from a proenzyme form that degrades fibrin and soft tissues. The binding of curli fimbriae to plasminogen results in the activation of plasmin. Bacteria might get a chance to invade into the host cell because plasmin degrades soft tissue. The identification of Curli-positive Salmonella is aided by the ability of curli fimbriae to attach to Congo Red dye [120]. Curli is required for the successful adhesion to cultured epithelial cells of the intestine in mouse and other inorganic surfaces such as stainless steel [129–131]. CsgA and bcsA genes contribute to biofilm formation and virulence of S. Pullorum [132]. The curli fimbriae regulator, csgD, is involved in the biofilm formation, while human bile promotes the regulation of curli fimbriae [133]. S. Typhimurium and E. coli have 74% similarity in the polypeptide sequence with similar functions of major subunits of CsgA. However, the N/P fimbrial pathway is still poorly understood. The assembly pathway and different fimbrial adhesins produced as a result of this pathway need further investigation.

They are characterized by mannose-sensitive hemagglutination and binding to host cells [21]. FimH present at the tip of fim fimbriae is characterized by the adherence to the host cell receptor [103]. The beststudied FimH encoded by the fim operon is a bi-domain protein highly specific for mannose residues. The C-terminal domain is used for the integration of FimH into the organelle, while the other N-terminal domain attaches to receptors of the host. The fim fimbriae, present in all Salmonella serovars, except in S. bongori, can be expressed in laboratory media [70,71]. FimH in Salmonella adheres to enterocytes, whereas FimH in E. coli adheres preferentially to epithelial cells of the bladder [104]. Moreover, FimH in Salmonella also has an affinity to bind to glycoprotein-2 expressed on M cells [105,106]. However, Salmonella exhibits lectin at the tip of all characterized fimbrial adhesins that have the affinity to bind to a variety of host cell receptors. StdA and PefA bind to α (1–2) fucosylated receptors and LewisX blood group antigen, respectively [29,107]. Allelic variations direct diverse host tropisms of serovars [9,108]. Although FimH variants have a slight difference in their sequences, the binding pattern varies for different Salmonella strains and serovars [109,110]. Fimbriae of S. Gallinarum and S. Pullorum represent a “non-adhesive” type 1 fimbriae variant; they are often categorized as type 2 fimbriae [111]. FimH variants in S. Gallinarum and S. Pullorum have slight amino acid substitutions compared with S. Typhimurium, which makes fimbriae incapable of binding to human and murine cell lines or to mannose [112–114]. Furthermore, S. Gallinarum type 2 fimbriae bound to leukocytes in chicken. The mannose-resistant interaction suggested the adaptation of serovars to a specific avian host and revealed distinct receptors in the avian host tissue [112,115]. Chicken granuloma cells showed a diverse antibacterial response against invasive Salmonella serovars [116]. In response to salmonellosis, several defense mechanisms of macrophages have been shown to limit the infection [117]. Recent studies reveal that many poultry-associated Salmonella strains have become multi-drug resistant [53,118]. The FimH variations in binding specificities are not limited to different serovars. Instead, even the derivatives of FimH strains of the same serovars can show diverse binding strategies. The two FimH variants, “low adhesive” and “high adhesive,” are found in S. Typhimurium [23,112]. The higher affinity is shown by highly adhesive forms, while the lower affinity is shown by less adhesive forms of FimH fimbriae to epithelial cells in humans [23]. S. Typhimurium shows the low-adhesive variant of FimH with similar properties as S. Enteritidis. Therefore, both mannose-sensitive adherent variants bind to bladder cells of humans in addition to human intestinal cell lines [113]. Highly adhesive FimH variants can efficiently differentiate between types of cells, compared with less adhesive FimH variants.

4.3. T4 fimbriae T4 fimbriae are another class of fimbrial adhesins that exist in many bacterial pathogens. They comprise single-pili repeated subunits and usually range from 1 to 5 μm in length. T4 fimbriae use a complex machinery for their assembly. They form an apparatus comprising various proteins that facilitate the anchoring of fibers and provide energy for fimbrial assembly. Many other proteins are also encoded by gene clusters with different functions, in addition to the fimbrial assembly proteins. T4 fimbriae with a similar mechanism of assembly and structure are mostly compared with the type II secretory system. The transportation of pilin subunits to the periplasm occurs through the GSP, and then they are anchored to the inner membrane [134]. T4 fimbriae in Neisseria gonorrhoeae have been extensively studied; Salmonella pili have a minor difference of a single peptide in the mature sequence [135]. The PilE and PilS pilus subunits in N. Gonorrhoeae and S. Typhi, respectively, are transported through the GSP to the periplasm and anchored to the inner membrane. The N-terminal leader sequence is cleaved by the prepilin peptidases PilD and PilU in N. Gonorrhoeae and S. Typhi. The assembly ATPase provides the energy required for the polymerization of the pilus. In N. Gonorrhoeae, the protrusion of the assembled pilus occurs through the action of secretin PilQ. The depolymerization of the pilus mediated by ATPase leads to a movement known as “twisting motility.” The movement mediated by this mechanism is along the surfaces as pili are still adhered to target surface during retraction [135]. Besides gliding and twitching motility [136], T4 fimbriae also revealed many processes involved in pathogenesis, including adhesion to host cells, DNA uptake, microcolony formation, and biofilm formation [135]. The major bacterial virulence-associated adhesins, T4 fimbriae, promote bacterial attachment to host cells. In Salmonella, the T4 fimbriae pathway has not been fully characterized yet. T4b fimbriae are

4.2. N/P pathway Different fimbriae, such as “thin aggregative fimbriae” (agf), are assembled through a unique assembly pathway, the N/P pathway. Curli fimbriae were first discovered in E. coli in the Enterobacteriaceae family. In E. coli, FGC for curli is known as csg (curli subunit gene), compared with agf in Salmonella, but now the commonly used term for Salmonella is csg. Csg are fimbrial adhesins in Salmonella that lead to auto-aggregation, adhesion to various surfaces, and biofilm formation [119,120]. The biogenesis of curli fimbriae depends mainly on diverse operons, including csgBAC and csgDEFG. Genes csgBAC, csgB, and csgA encode for the nucleator and subunit, but csgC encodes for oxidoreductase. The gene csgDEFG encodes for the operon transcription regulator (csgD) and for the assembly protein located in the periplasm (CsgE) or in the outer membrane (CsgG and CsgF) [121]. The exportation and precipitation of the subunit characterize the assembly mechanism for curli fimbriae. The GSP is used by curli proteins for exportation via the inner membrane to the periplasm. Then, the CsgG lipoprotein secretes two proteins CsgA and CsgB. The subunit and nucleator pass through the pores formed by CsgG in the outer membrane. 5

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present in Salmonella with a completely known structure. T4b fimbriae have been detected in human-adapted Salmonella serovar Typhi. T4 fimbriae require 11 genes for assembly, adhesion, and uptake in intestinal cells of humans, which are encoded in pil operon localized on Salmonella pathogenicity island (SPI) 7 [137,138]. The initial binding and uptake occur through the only known ECM receptor cystic fibrosis transmembrane conductance regulator (CFTR) [139,140]. S. Typhi uptake efficiency is correlated with the CFTR level on the surface [140]. Pre PilS could attach to the CFTR fragment and thus facilitate adhesion to the membrane of epithelial cells in the gut [141,142]. FimH fimbriae use their entire fimbrial tip adhesin for attaching to host receptors. In contrast, T4 fimbriae use a disulfide-bonded loop region to bind to receptors, although adhesins located at the fimbriae tip also take part in the binding process. Interestingly, CFTR facilitates the attachment of only S. Typhi in the host intestine, not S. Typhimurium. However, the T4 fimbrial pathway is still poorly understood. More research is needed to understand the assembly pathway and different fimbrial adhesins produced through this pathway.

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5. Conclusions Salmonellosis is a big challenge to human and animal health. Salmonella adhesion to host cells is an initial and most crucial step in the pathogenesis of salmonellosis. Salmonella has many types of fimbrial and afimbrial adhesins. Fimbrial adhesins are assembled through three assembly mechanisms: CU, N/P, and T4 fimbriae. CU fimbriae have been studied in great detail, compared with the other two types of fimbrial assembly mechanisms. The current knowledge of fimbriae is limited, which can be attributed to their inability to express pathogenicity under laboratory conditions. More research is needed to understand N/P and T4 fimbrial assembly mechanisms. It was generally believed that Salmonella attached to M cells, but recent studies show that fimbrial adhesins prefer attaching to enterocytes instead of M cells during infection. It can be concluded that some of Salmonella adhesive mechanisms have not been discovered yet, as recent studies have provided the clues about novel mechanisms adopted by Salmonella. Salmonella fimbrial adhesins adhere to corresponding host cell receptors. Many receptors are present on the cell surface of the host. Fimbrial adhesins have an affinity to attach to respective receptors to initiate Salmonella infection. Besides understanding adhesive mechanisms, further studies are needed to know the ways to block the receptors or the Salmonella fimbrial adhesin to prevent Salmonella infection. Most Salmonella strains have become multi-drug resistant due to the excessive use of antibiotics [56,143–146]. For the prevention and control of salmonellosis, active ingredients of drugs capable of blocking the binding site of fimbrial adhesins to disrupt the attachment of Salmonella with host cells should be investigated. Moreover, molecular mechanisms of the action of drugs should be elucidated in detail to cope with salmonellosis. In this review, types of fimbriae, molecular targets, and mechanisms of adhesion were summarized. The findings might help pharmacists and a broad community of scientists in understanding and building strategies against salmonellosis. Competing interest The authors declare no competing interests. Author contributions TR and LZY wrote and designed the manuscript. MBL, JHC, PO, XLH, MA, and HR G contributed through their intellectual inputs. KYW, YG, and PO read and corrected the contents. Acknowledgments This study was supported by a project funded by the National 6

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