Prominent Role of FnBPs of Mycobacterium Tuberculosis in Cell Adhesion, Immune Invasion and Pathogenesis

An asymmetrical sharing of adhesion molecules throughout the cell surface of the Staphylococcus aureus and their significant associative role in host-pathogen interaction remains elusive. The continual researches in host-pathogen interaction mechanism revealed certain potential adhesins that facilitates mycobacterium adherence to host cells surface. The adhesion proteins like fibronectin binding protein (fnbp) are expressed by PE_PGRS a polymorphic GC-repetitive sequence belong to subfamily in Staphylococcus aureus which have a potential role in cell-attachment, entry, and immune evasion. This review addresses the adhesion property of fnbp in Staphylococcus aureus and their role in cell-cell adhesion process. Additionally modulation of host’s cells signaling to promotes adhesion and host-pathogen interaction events. Likewise, this study highlights the prominent role of fnbp that may further act as a potent source of antigenic variation lead to evoke immune response during mycobacterium infection. So, increasing in our current understanding in these selective fnbp (adhesion proteins) and by targeting these Staphylococcus aureus expressive genes could help us for development of novel drug that will further valuable for therapeutics.

Abbreviation

Staphylococcus aureus: Mycobacterium Tuberculosis; PE_PGRS: Proline-Glutamic Polymorphic GC-rich Repetitive Sequence; fnbp: fibronectin binding protein; fn: fibronectin; Staphylococcus aureus: Staphylococcus aureus; MSCRAMMs: Microbial Surface Component Recognize Adhesive Matrix Molecules; FAK: Focal Adhesion Kinase; PLC-γ: Phospholipase C-γ; IP3: Inositol Triphosphate- 3; Th1: T-helper cell 1; (MHC) class II (MHC-II): Major Histocompatibility Complex

Introduction

Tuberculosis (TB) one of the mortal disease caused by Mycobacterium Tuberculosis (Staphylococcus aureus) and, spreading the mortality rate throughout the world. It is estimated that, there were 9.0 million people infected with mycobacterium but only 10% of them break down with this disease, while 90% remains clinically latent followed by approximately 1.5 million TB deaths in worldwide [1]. In Staphylococcus aureus infection the virulence and molecular events are still largely unknown, and additionally the unique and chemical entity present in the cell envelope of this bacillus participate equally followed by disease succession [2]. Staphylococcus aureus’s cell envolpe contain complex lipids like mycolic acid (a long fatty acid and strong hydrophobic chain in nature), lipoarmanon, arbinogalacton and glycoproteins which have virulent potency into disease progression and tissue damaging. In particular, the greater understanding of adhesion molecules is required in host-pathogen interaction together with its potential role in cell-attachment, entry, and immune evasion. The adhesion of microorganisms to the host cell surface or tissue is a key constituent in initial stage of infection [3].

Previous studies explore different adhesion molecules which exhibits specific affinity toward particular host cell receptor that further influences disease progression [4]. Moreover, the entry of Staphylococcus aureus into the macrophage and its survival strategy within hostile environment are very specific for internalization [5]. The adherence of the pathogen with the host is highly dependent upon adhesions like cell adhesion molecules (CAMs), which are mycobacterium cell surface protein involved in binding with other cells and/or with the Extracellular Matrix (ECM) via adhesion specific receptor.

Interestingly, fibronectin binding protein (Fnbp) of Staphylococcus aureus exhibits binding with fibronectin (Fn) derived by the host. It has been demonstrated that, Fn is a versatile cell adhesive glycoprotein capable of interacting with macromolecule including fibrin, collagen, proteoglycan as well as cell bearing specific fibronectin receptor on their surfaces [6]. Fn exists as a protein dimer with identical monomer linked with disulfide bond. Fn present in two forms, one is soluble found in blood plasma and other found in extracellular matrix in insoluble forms. The RGD (Arginine, Glycine, Aspartate) sequence is the major binding site of cell attachment of Fn via α5β1 integrin. Knowledge about the entry mechanism of Staphylococcus aureus into targeted cell via specific adhesion proteins are limited, thus exploration of these adhesion molecules in mycobacterium may provide new strategy to develop novel approaches that could help to reduce TB prevalence. Though intercalating with macromolecule and receptor armed cells, Fn also exhibits interaction with a large number of microorganism including bacteria, fungi, and protozoa. Additionally, in studies it has also shown that Fn binding antigens are the major secreted constituents in short term culture supernatants of Staphylococcus aureus, that exhibits high binding affinity to fnbp [7].

Our current study aim to summarize the significant role of multifunctional Fnbp that involve not only in adhesion event but also directly participate in host cell signaling alteration of the host that may further act as a potential source of antigenic variation. It was demonstrated that, ECM and cell-cell interaction play crucial role in many physiological and pathological events because matrix components also have the ability to alter cell functioning which is facilitated by cell adhesion molecule [8]. The extracellular matrix/region contains a variety of multi-functional collagen, super family molecule and non-collagen matrix molecule [9,10]. Furthermore, in past studies it has been reported that, the GC-repetitive sequence (PGRS) subfamily expresses Fnbp in Staphylococcus aureus which exhibits binding property with Fn. Mycobacterium expresses a range of fnbps proteins for instance, antigen 85 complex (The complex consists of three proteins termed 85A, 85B and 85C), which are known to be a major secreted proteins in Staphylococcus aureus infection. As in prior studies it was investigated that attachment of fnbp to Fn is considered to be important proteins involved in phagocytosis of various bacterium like Staphylococcus aureus, Mycobacterium bovis (M. bovis), Mycobacterium kansasii (M. kansasii), Mycobacterium avium (M. avium) and Mycobacterium leprae (M. leprae) in epithelial cells [11,12]. In support of this, it has been also recognized that, Fnbp are most prominent secreted antigen that alters macrophage cellular functions. Staphylococcus aureus infection brings macrophage activation that further developed a variety of inflammatory cytokines that mediate intracellular infection which causes apoptosis via Tumor Necrosis Factor (TNF-α) dependent mechanism [13,14]. It has also shown that, TNF-α additionally implicated in many of the immune-pathological features in TB infection.

Fibronectin binding proteins in cell adhesion

Microorganism infection begins with adherence, which is the most common phenomenon to invade the host tissue [15]. Both Gram positive and negative bacteria employ a number of adherence molecules like fnbps associated on their cell surface, which often exhibits binding to Fn and initiate colonization [3]. For instance Staphylococcus aureus (Staphylococcus aureus) bacteria have evolved a wide range of adhesion proteins known as adhesin i.e. Fnbps, which binds to selected host molecules and facilitate internalization [16,17]. Moreover, evidence is emerging in signaling events for Fn and its proteolytic breakdown product, which are raising the possibilities that bacterial Fnbps have action other than adhesion [16].

In TB pathogenesis, the genomics study of Staphylococcus aureus exploring unique and multi-gene family of adhesion molecules, which are highly related to adhesion proteins that are still unknown in their function. In this aspect, the mycobacterium hold a large number of genes expressing proteins whose N-terminal contains characteristics motifs pro-glu (PE) or pro-pro-glu (PPE) (A subgroup of the PE proteins contain polymorphic GC- repetitive sequence PGRS). The PE_PGRS family proteins expressed in Staphylococcus aureus exhibit multiple Fnbps, which have specific sequence in motifs possessing binding property [18]. Similarly, in other study, PE_PGRS proteins were also analyzed by western blotting in similar mycobacterial species for their existence like in M. bovis BCG, M. smegmatis, M. marinum and M. gordonae [19]. Simultaneously, it was also imparted that immune-fluorescent labeling of mycobacterium species signifies some PE_PGRS proteins are localized and associated with the cell surface of BCG and Staphylococcus aureus during infection [20].

On this subject, our recent investigation proposed that Staphylococcus aureus PE_PGRS60 family protein fnbp possessed a novel adhering property with Fn receptor molecules [21]. It was established that, Fn is occurred in insoluble or and in soluble form in host cell as well in body fluids and multi-functional molecules were reported as an adherence factor that play important role during pathogenesis of Staphylococcus aureus [7,22]. This complex and multifunctional property of this protein classify its binding ability with other molecules and these were also noted as wound healing [23].

Adhesion proteins and Staphylococcus aureus infection

Pathogenesis of TB begins with the interaction between pathogen and mononuclear phagocytic cell. Here the bacteria are engulfed by alveolar macrophage, which presumably equipped with multiple microbicidal mechanism including respiratory burst, phagolysosome fusion etc. of infecting microorganism leads to establish infection successfully [24]. Mycobacterium infected alveolar macrophage stimulates local chemokine signals that further attract other macrophages from local lymphatic tissue. T-cells also migrate into these tissues and release interferon-gamma (IFN- γ) resulting in macrophage activation. In short, in other studies it was established that, Staphylococcus aureus contains divergent adhesion proteins for instance CD44, an adhesion molecule in hematopoietic cells and which is connected to the cytoskeletal constituent such as hyaluronic acid, , fibronectin, and collagen etc. further involved in inflammatory responses. Likewise, CD44 shows prominent role in macrophage recruitment leads to delayed type hypersensitivity and exhibits binding ability in Staphylococcus aureus infection [25]. Despite in mycobacterium, Fnbp proteins also significantly increased the phagocytic activity in macrophage against Staphylococcus aureus, via alpha-5 (α-5) and beta-1 (β-1) chains which were associated with the cytoskeleton [26,27]. Integrins are α-β heterodimer, family of transmembrane receptors. There are 18 α and 8 β varieties of heterodimer which involved in several signaling pathways. Alpha-5 (α-5) and beta-1 (β-1) chains of integrin is major fn receptor present on most of the cells [28].

In short, integrin are crucial for cell invasion and migration not only for physically tethering cell to the matrix but also for sending and receiving chemical signals [29]. In Staphylococcus aureus infection, these subunits of the integrin act as receptor for extra cellular proteins which attaches cells to ECM and mediates cell-cell adhesion events. The binding activity of integrin to the extracellular matrix is synchronized via intracellular environment of the cell by abruption in signaling events. Thus, it was reported that adhesions mediates signaling that further influences several critical cellular process including cell cycle, programmed cell death and continual gene expression [30,31]. Only limited information is available belonging to fnbps with Fn, while many of integrin signals covers some cell cycle regulation event that further involved in to the cell cycle and differentiation [32]. However, in earlier studies it has been reported that, Fn and integrin play a crucial roles in a variety of morphogenetic process includes adhesion, migration and signal transduction.

This review concern particularly in the effect of signaling events regulate the activities of numerous kinases occurred in cytoplasm, growth factor receptors and ion channels that further control the intracellular organization of the cells. Moreover, in past studies, it was postulated that, the focal adhesion kinase (FAK), protein-tyrosine kinase (PTK) links to the transmembrane integrin receptors involved in intracellular signaling pathway [33]. The triggering of FAK followed up nascent focal adhesion stimulation that further interact on activation either directly or via the talin and/or paxillin (cytoskeletal proteins) with the cytoplasmic tails of integrin β- subunit [32] (Figure 1).

Figure 1: Representation of adhesion protein fibronectin binding protein (Fnbp) expressed in Staphylococcus aureus and involved in cell adhesion: In host-pathogen interaction Fnbp i.e. a PE_PGRS family protein has binding property, which provide a bridge to link up with the host’s Fibronectin (Fn) receptor molecules [43] and brings stimulation of the Integrin receptor’s α-subunit and β-subunit, which may further serve up a docking site for several kinases, like Focal Adhesion Kinase (FAK)/ Pyk2, Src, talins etc. Resulting, activation of kinases follows up effective binding with cytoskeletal proteins tails, and paxillin with the cytoplasmic tails of integrin’s β- subunit. Thus, the ligand and receptor molecule interaction stimulates FAK tyrosin kinase phosphorylation that further promotes Phosphor-inositol 3- Kinase (PI3-Kinase) and phospholipase C-γ (PLC-γ) activities that may directly participate in catalytic metabolism and cell adhesion.

In addition to FAK, some other PTK, adversely called proline-rich tyrosine kinase-2 (PYK-2) and proposed a connection between integrin receptors and paxillin. Moreover, another function comment to Fn-stimulated FAK and PYK2 lead to promote signal stimulation to other kinase extracellular regulated kinase (ERK2), followed up triggering of PTKS activity (belongs to non-receptor SRC family kinase) [34]. Thus, adherence to cell surface is to be essential for the activation and delivery of certain virulence factor and in Staphylococcus aureus expression Fnbps make up a diverse group of surface adhesin that binds to receptor protein Fn leads to promotes cell adhesion [27].

Macrophage’s Response toward Staphylococcus aureus infection

In general, macrophage activation plays a significant role, not only in the activation of the inflammatory response but also in the resolution on this response. Potentially, Staphylococcus aureus has ability to manipulate host’s intra-cellular pathways which further influence bactericidal action during infection. The intracellular parasites Staphylococcus aureus promote their survival rate within the host via inhibiting phagolysosome fusion thus further avoids exposure to the lysosomal hydrolases [35-36]. Thus, observation postulated that, Staphylococcus aureus could successfully parasitize macrophages by disrupting the phago-lysosome maturation and provide it an intracellular compartment with endosomal rather than lysosomal uniqueness [37]. After a certain extension of Staphylococcus aureus survival, its replication reaches to threshold and secretes a number of proteins like ESAT-6, which mediate the host cell necrotic cell death. Furthermore, additional inflammatory cells activation resulting in production of cytokine such as TGF-β by infected macrophage. These cytokines further add the resolution of inflammation and to the initiation of wound healing via ECM induction components [38]. Moreover, in the course of Staphylococcus aureus internalization, the bacillus are also opsonized via specific antibody, its ingestion brings in term via macrophage Fc-gamma receptors (Fc-γRS) [39]. It was also proposed that fn also involved in opsonization process by phagocytosis as non-antibody and noncomplement opsonin. The binding of fn to bacteria, collagen, fibrin and actin are important for the roles of circulatory fn as an opsonin protein [40,41].

Host immune regulation in response to Staphylococcus aureus

In TB, cellular immunity is considered to be more important for the suppression of infection, but also for damage of host tissue [42]. It was reported that, in TB cell-mediated immunity (CMI) is responsible for the eradication of mycobacterium. The major effectors’ mechanism of CMI is through the activation of infected macrophage by activation of T-helper type-1 (TH-1) produced cytokines, particularly IFN-γ. However, the balance between TH-1 type and TH-2 type cytokines responses in TB infection may influence mycobacterial growth as well as immune-pathological effect of host cells [43-44]. A major breakthrough has come, when a subset of CD4+ T-cells constantly expressing the IL-2 receptor α-chain/CD25 (a high affinity, type-I trans-membrane protein present on activated T-cells) found to be increase in immunosuppressive activity during Staphylococcus aureus infection [45].

So, Staphylococcus aureus persists inside macrophage despite vigorous immune responses that is still obscure. Recently it is shown that Fnbp (major antigenic complex), which is a mycobacterial membrane’s associated binding protein have immunomodulatory effect further follow up modulation in antigen presentation via MHC-II to CD4+ T-cells [46]. In addition to this, the inhibitory action of IFN-γ in infected host cell also reported because of Fnbps proteins expression in Staphylococcus aureus [47]. Continual studies in immunopathology of TB, It has also been reported that, the host’s immune system containing other ckemokines and chemokines like receptors like CCL3, CCL4, CCL5 and CXCLB which were equally contributed in macrophage proliferation as well as infection progression.

In support of this, the emerging literatures shown that, the inflammatory responses have generated after interacting with mycobacterium and macrophage/dendritic cells (DCs) in the lung mucosa and before their migration out of the inflamed tissues, they produced CCL3 and CCL5 further follow up to recruit immature DC to the site of infection [48]. Although we are having abundant knowledge of adhesion molecules in others bacterial species, but in mycobacterium infection it is still not well understood in terms of their effects in antigen presentation mechanism. Moreover, previous observation suggested that, during Staphylococcus aureus infection it expressed few of Intracellular Adhesion Molecule-I (ICAM-I) and macrophage adhesion ligand-1(MAC-I) marker on murine peritoneal macrophages, and reported that these adhesions possessing binding property with host cells [49,50]. In addition to enhance expression of ICAM-1 in response to Staphylococcus aureus was mediated in a paracrine or autocrine manner predominant via TNF-α that subsequently involves in the orchestrated production of chemokines and cytokines, further followed up granuloma formation (Figure 2). Thus, one hypothesis for the importance of the granuloma was postulated that the granuloma provides a wall of macrophage and lymphocytes surrounding infected cells that further help mycobacterium in survival [51,52].

Figure 1: Schematic representations of the immune invasion of the host cell during Staphylococcus aureus infection: In Staphylococcus aureus infection, initially the bacilli internalized within macrophage via adhesions proteins (Fnbps) result in early phagosome formation. Emergence in virulence factors further follows up antigen presentation via MHC-II class protein pathway. The interaction of the processed antigen’s peptide allocated to the T-helper cell 1 (Th1) via T-cell receptor (TCR), thus, interaction facilitate Th1 cell stimulation and macrophage induction secretes interleukin-2 (IL-2).
The essential cytokines production like IFN-γ may be inhibited through Fnbps expressed by Staphylococcus aureus. The defensive mechanism of the bacilli how it escape wisely from these bactericidal action and Fnbps act as a defensive molecules to inhibit IFN-γ stimulation with decline in MHC-II class protein expression remains elusive and up regulates the expression of Intracellular Adhesion Molecule-I (ICAM-I) and Macrophage adhesion ligand-1(MAC-I) marker proteins, Chemokines like Chemokine like ligand-3 (CCL-3), Chemokine like ligand- 4 (CCL-4) and Chemokine like ligand-5 (CCL-5). The secretion of certain chemokines through Staphylococcus aureus infection attracts on their respective receptors/moieties present on Natural Killer (N.K) cells contain CCR1, B-cells and T-cell (LFA) of the host and result in homotypic cellular adhesion may leads to granuloma formation.

Summary

The intimate connection between the infected cells and Staphylococcus aureus still not well understood. However it is well established that the mycobacterium have employed wide range of adherence molecules involved in evading host’s immune mechanisms for its persistence and survival. The host-pathogen interaction via adhesion molecules and their adhering abilities specifically to ligands, receptors that relatively contribute in signaling events involved in phagocytosis mechanism during this bacilli infection, which is still remains to be fully understood. The ligands and receptor molecules interaction, specifically Fn binding to integrins receptor molecule of the host’s cell via fnbp adhesion proteins that may offer a key possibilities in understanding the TB infection strategically caused by Staphylococcus aureus. So, targeting of these specific adhesion proteins could help us for development of novel drug that may further valuable in to reducing TB prevalence world widely.

We thank Dr. Rajesh S. Gokhale for making this work possible. The authors acknowledge financial support from OLP1121 and GAP0092 of the Department of Science and Technology and Council of Scientific & Industrial Research.

1. Van PLA, Cassidy JP, Smedegaard BH, Agger PA (2000) Control of latent Mycobacterium Tuberculosis infection is dependent on CD8 T cells. Eur J Immunol 30: 3689-3698. Link: https://goo.gl/GPYBuX
2. Glickman MS, Cox JS, William RJ (2000) A noval Mycolic Acid Cyclopropane Synthetase is required for cording, persistence, and virulence of Mycobacterium Tuberculosis. J Mol cell Bio 5: 717-727. Link: https://goo.gl/ejRB2m
3. Monu, Meena P, Meena A, Meena LS (2015) Imperative role of fibronectin binding proteins in cell adhesion and invasion: An overview. J Biochem Biotechnol 2: 031-040. Link: https://goo.gl/r4DFys
4. Rawat R, Monu, Meena LS (2015) Adhesion molecules: A potent surface marker of mycobacterium play key role in host-pathogen interaction and pathogenesis. Adv Res J Biochem Biotech 2: 041-046. Link: https://goo.gl/bDQdSc
5. Desjardin LE, Kaufman TM, Potts B, Kutzbach B, Hong Yi, et al. (2002) Mycobacterium Tuberculosis-infected human macrophage exhibit enhanced cellular adhesion with increased expression of LFA-1 and ICAM- 1 and reduced expression and/or function of complement receptor, fc?RII and the mannose receptor. Microbiol 148: 3161-3171. Link: https://goo.gl/bgN3PS
6. Limper AH, Roman J (1992) Fibronectin: A versatile matrix protein with roles in thoracic development, repair and infection. Chest 101: 1663-1673. Link: https://goo.gl/s2G9eL
7. Abou-zeid C, Ratliff TL, Wiker HG, Harboe M, Bennedsen J, et al. (1988) Characterization of fibronectin-binding antigens released by Mycobacterium Tuberculosis and Mycobacterium bovis BCG. J Infect Immun 56: 3046-3051. Link: https://goo.gl/9QVQOt
8. Chuanyue W, Sarah Y, Keightley CLH, Radeva G, Coppolino M, et al. (1998) Integrin-linked protein kinase regulates fibronectin matrix assembly, E-Cadherin expression, and Tumorigenicity. J Bio Chem 273: 528-536. Link: https://goo.gl/bxIcmS
9. Wu YJ, David PLA, Wu J, Albert J, Yang BB (2005) The interaction of versican with its binding partners. Cell Res 15: 483-494. Link: https://goo.gl/80BR5o
10. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C (1998) Deciphering the biology of Mycobacterium Tuberculosis from the complete genome sequence. Nat 393: 537-544. Link: https://goo.gl/2Fwh5G
11. Ratliff TL, McCarthy R, Telle WB, Brown EJ (1993) Purification of a Mycobacterial adhesin for fibronectin. Infect Immun 61: 1889-1894. Link: https://goo.gl/zO3Txn
12. Wiker HG, Harboe M (1992) The antigen 85 complex: A major secretion product of Mycobacterium Tuberculosis. Microbiol Rev 56: 648-661. Link: https://goo.gl/hafLVY
13. Balcewicz-Sablinska MK, Keane J, Kornfeld H, Remold HG (1998) Pathogenic Mycobacterium Tuberculosis evades apoptosis of host macrophages by release of TNF-R2, resulting in inactivation of TNF-alpha. J Immunol 161: 2636-2641. Link:
14. Engele M, Stobel E, Castiglione K, Schwerdtner N, Wagner M, et al. (2002) Induction of TNF in human alveolar macrophages as a potential evasion mechanism of virulent Mycobacterium Tuberculosis. J Immunol 168: 1328-1337. Link:
15. Joh D, Elisabeth R, Wann BK, Speziale P, Hook M (1999) Role of fibronectin-binding MSCRAMMs in bacterial adherence and entry into mammalian cells. Matrix boil 18: 211-223. Link: https://goo.gl/jRckI3
16. Henderson B, Nair S, Pallas J, Williams MA (2011) Fibronectin: a multidomain host adhesin targeted by bacterial fibronectin-binding proteins. J FEMs 35: 147-200. Link: https://goo.gl/xgo0V4
17. Vanessa V, Xiaowen L, Horndhal JK, Ganesh VK, Emanuel S et al. (2011) Fibrinogen is a ligand for the Staphylococcus aureus microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) bone sialoprotein-binding Protein (Bbp). J. Bio Chem 286: 29797-29805. Link: https://goo.gl/c9KbX2
18. Bottai D, Brosch R (2009) Mycobacterial PE, PPE and ESX clusters: novel insights into the secretion of these most unusual protein families. J Mol Microbiol 73: 325-328. Link: https://goo.gl/jdC2dq
19. Banu S, Honore N, Saint-Joanis B, Philpott D, Marie-Christine P, et al.(2002) Are the PE-PGRS Proteins of Mycobacterium Tuberculosis variable surface antigens? J Mol Microbiol 44: 9-19. Link: https://goo.gl/d4U3ln
20. Brennan MJ, Delogu G, Chen Y, Bardarov S, Kriakov J, et al. (2001) Evidence that Mycobacterial PE-PGRS proteins are cell surface constituents that influence interaction with other cells. Infect Immunity 69: 7326-7333. Link: https://goo.gl/gdJi6v
21. Meena LS, Meena J (2015) Cloning and characterization of a novel PE-PGRS60 protein (Rv3652) of Mycobacterium Tuberculosis H37Rv exhibit fibronectin-binding property. J Biotechnol Appl Biochem 63: 525–531. Link: https://goo.gl/i9xnWG
22. Ruoslahti E, Engvall E, Hayman, EG (1981) Fibronectin: Current concepts of its structure and functions. Coll Relat Res 1: 95-128. Link: https://goo.gl/okGZoM
23. Richard A (1987) Fibronectin: A brief overview of its structure, function and physiology. Review of infectious disease. Rev infects dis 9: 317-321. Link: https://goo.gl/evBNJ6
24. McDonough KA, Kress Y, Bloom BR (1993) Pathogenesis of tuberculosis: interaction of Mycobacterium Tuberculosis with macrophages. Infect Immun 61: 2763-2773. Link: https://goo.gl/ZEmrGh
25. Jaklien C, Leemens SF, Heikens M, Pals ST, Van Der Neut R, et al. (2003) CD44 is a macrophage binding site for Mycobacterium Tuberculosis that mediates macrophage recruitment and protective immunity against tuberculosis. J Clin Invest 111: 681-689. Link: https://goo.gl/07Lliv
26. Dziewanowska K, Patti JM, Deobald CF, Bayles KW, Trumble WR, et al. (1999) Fibronectin Binding Protein and Host cell Tyrosine Kinase Are Required for internalization of Staphylococcus aureus by epithelial cells. J Infect Immun 67: 4673-4678. Link: https://goo.gl/tZ3n0w
27. Stones DH, Anne-marie K (2015) Fatal attraction: How bacterial adhesins affect host signaling and what we can learn from them. Int J Mol Sci 16: 2626-2640. Link: https://goo.gl/Yxigjt
28. Ulanova M, Gravelle S, Barnes R (2009) The role of epithelial integrin receptors in recognition of pulmonary pathogens. J Innate Immun 1(1): 4-17. Link: https://goo.gl/I2t8YY
29. Hood JD, Cheresh DA (2002) Role of integrins in cell invasion and migration. Nat Rev Cancer 2: 91-100. Link: https://goo.gl/OmBb2O
30. Hynes RO (1992) Integrins: Versatility, modulation and signaling in cell adhesion. J cell 69: 11-25. Link:
31. Miyamoto S, Kathz BZ, Lafrenie RM, Yamada KM (2006) Fibronectin and integrins in cell adhesion, signaling and morphogenesis. Anne NY Acad sci 857: 119-129. Link: https://goo.gl/VG1Ha4
32. Giancotti FG, Ruoslahti E (1999) Integrin Signaling. Sci 285: 1028-1033. Link: https://goo.gl/aGbqjg
33. Garcia AJ, Boettiger D (1999) Integrin-fibronectin interactions at the cell-material interface: initial integrin binding and signaling. Biomet 20: 2427-2433. Link: https://goo.gl/lPEZln
34. Sieg DJ, dusko-Ilic KCJ, Damsky CH, Hunter T, Schlaepfer DD (1998) PYK2 and Src-family Protein- Tyrosine Kinases Compensate for the loss of FAK in fibronectin-stimulated signaling events but Pyk2 does not fully function to enhance FAK-cell migration. J EMBO 17: 5933-5947. Link: https://goo.gl/3As9Xr
35. Goren MB, Arcy-Hart PD, Young MR, Armstong JA (1976) Prevention of phagosome-lysosome fusion in cultured macrophages by Sulfatides of Mycobacterium Tuberculosis. Proc Natl Acad sci USA 73: 2510-2514. Link: https://goo.gl/2AWY1W
36. Meena LS, Rajni (2010) Survival mechanism of pathogenic Mycobacterium Tuberculosis H37Rv. FEBS J 277: 2416-2427. Link: https://goo.gl/CXbgx6
37. Malik ZA, Lyer SS, Kusner DJ (2001) Mycobacterium Tuberculosis phagosome exhibit altered Calmodulin-dependent signal transduction: contribution to inhibition of phagosome-lysosome fusion and intracellular survival in human macrophages. J Immunol 166: 3392-3401. Link: https://goo.gl/3rPNUW
38. Zhang X, Mosser DM (2008) Macrophage activation by endogenous danger signals. J Pathol 214: 161-178. Link: https://goo.gl/S0ZEhp
39. Malik ZA, Denning GM, Kusner DJ (2000) Inhibition of Ca2+ Signaling by Mycobacterium TuberculosisIs Associated with Reduced Phagosome–Lysosome Fusion and Increased Survival within Human Macrophages. J Exp Med 191: 287-302. Link: https://goo.gl/4ThjL8
40. Deitch EA, Gelder F, McDonald JC (1984) The role of plasma Fibronectin as a nonantibody, noncomplement opsonin for Staphylococcus aureus. J Trauma 24: 208-213. Link: https://goo.gl/J7n4Le
41. Vuento M, Korkolainen M, Stenman UH (1982) Fibronectin binds to charge-modified proteins. Adv Exp Med Biol 155: 623-628. Link: https://goo.gl/j5oUoB
42. Aderem A, Underhil DM (1999) Mechanisms of phagocytosis in macrophages. Annul Rev Immunol 17: 593-623. Link: https://goo.gl/5xudE7
43. Crevel RV, Karyadi E, Preyers F, Leenders M, Kulberg BJ, et al. (2000) Increased production of interleukin 4 by CD4+ and CD8+ T cells from patients with tuberculosis is related to the presence of pulmonary cavities. J Infect Dis 181: 1194-1197. Link: https://goo.gl/0f0xyP
44. Prescott SL, Macaubas C, Holt BJ, Troy B, Loh SR, et al. (1998) Transplacental priming of the human system to environmental allergens: Universal skewing of initial T cell responses toward to Th2 Cytokine profile. J Immunol 160: 4730-4737. Link: https://goo.gl/RbU8vi
45. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, et al. (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22: 329-341. Link: https://goo.gl/cBOJby
46. Meena PR, Monu, Meena LS (2015) Fibronectin binding protein and Ca2+ play and access key role to mediate pathogenesis in Mycobacterium Tuberculosis; An overview. Biotechnol Appl Biochem Link: https://goo.gl/bFTn0p
47. Gehring AJ, Dobos KM, Belisle JT, Harding CV, Boom WH (2004) Mycobacterium Tuberculosis LprG (Rv1411c): A novel TLR-2 Ligand that inhibits human macrophage class-II MHC antigen processing. J Immunol 173: 2660-2668. Link: https://goo.gl/ygga2E
48. Lande R, Giacomini E, Grassi T, Remoli ME, Lona E, et al. (2003) IFN-?? released by Mycobacterium Tuberculosis-infected human dendritic cells induces the expression of CXCL10: Selective recruitment of NK and activated T-Cells. J Immunol 70: 1174-1182. Link: https://goo.gl/qilmia
49. Ghosh S, Saxsena RK (2004) Early effect of Mycobacterium Tuberculosis infection on Mac-1 and ICAM-1 expression on mouse peritoneal macrophages. Exp Mol Med 36: 387-395. Link: https://goo.gl/9iOxXt
50. Ramirez GML, Rom WN, Ciotoli C, Talbot A, Martiniuk F, et al. (1994) Mycobacterium Tuberculosis alters expression of adhesion molecules on monocytic cells. Infect Immun 62: 2515-2520. Link: https://goo.gl/vT2n4i
51. Saunders BM, Cooper AM (2000) Restraining Mycobacteria: Role of Granulomas in mycobacterial infections. J Immunol Cell Bio 78: 334-341. Link: https://goo.gl/M6eKFr
52. Yoshida YO, Umemura M, Yahagi A, Brien RLO, Ikuta K, et al. (2010) Essential role of IL-17A in the formation of a mycobacterial infection-induced granuloma in the lung. J Immunol 184: 4414-4422. Link: https://goo.gl/EsVMNS