Integrins are membrane glycoproteins composed of α and β subunits that form a heterodimer. Both subunits consist of well-defined domains: a large extracellular domain (ectodomain) and a relatively short transmembrane domain with ~60 amino acids (aa). The exception is the β4 integrin ^[1][132] with ~1000 aa and cytoplasmic domain ^[2][20]. The integrin cytoplasmic domain modulates crucial cell processes by interacting with various skeletal proteins and intracellular signaling molecules ^[3][9]. Two subunits in integrin complexes are held together by non-covalent bonds and form a ligand-binding site on the top of the two subunits. The ectodomain of α-chain is larger than that of β-chain: ~ 940𠀓1120 aa vs. ~700 aa. An α subunit ectodomain consists of two calf domains, a tight, and a seven-bladed β-propeller. The β subunit consists of a β-tail domain, four epidermal growth factor (EGF) modules, a hybrid domain with the inserted βI domain, and a plexin-semaphorin-integrin (PSI) domain.

There are 18 different found α subunits (α1–α11, αv, αIIb, αD, αL, αM, αX, and αE) and eight found β subunits (β1–β8). Nine of eighteen α subunits, namely α1, α2, α10, α11, αD, αL, αM, αX, and αE, have inserted the αI domain between the second and third blade of the β-propeller, which is crucial for the formation of a ligand binding region. This region also contains a Metal Ion-Dependent Adhesion Site (MIDAS) containing divalent cations such as Mg²⁺, Ca²⁺, or Mn²⁺. In the other nine α subunits (α3–α9, αv, and αIIb), the αI domain is missing, and a βI domain from an α-propeller domain in the α subunit headpiece and the MIDAS in the β subunit are responsible for forming the ligand binding region. In this case, other metal ion sites were also found similar to βI MIDAS; of the two ADMIDAS (Adjacent to MIDAS) sites, one of them is called a synergistic metal ion-binding site (SYMBS). Twenty-four integrins were identified in humans and can be classified according to their ligand-binding properties  (Figure 2b) or tissue expression ^[4][5][8,15].

Glycan structures added to integrins by post-translational modifications contribute to their structural and functional diversity ^{[6][7][8][9][10][11][12]}[133,134,135,136,137,138,139]. The glycosylation of proteins is a step-wise process carried out by glycosyltransferases. Glycosyltransferases (GTs) catalyze the transfer of glycosyl residue from a donor to an acceptor molecule ^[13][48]. The N- and O-glycosylations are the most frequent types of glycosylation. There are sufficient data linking aberrant glycosylation with pathological conditions, including chronic inflammation, immune diseases, cancer progression, and metastasis ^{[13][14][15][16][17]}[48,140,141,142,143]. N-glycans presence is crucial for the association of both subunits into heterodimers, their stability, conformation, and interactions with ligands. For example, α5β1 and α3β1 integrins contain 14 and 12 N-glycosylation sites on α and β subunits, respectively. Their presence is crucial for interactions with fibronectin and laminin, mediating cell adhesion, migration, differentiation, and apoptosis ^[7][134]. However, from multiple N-glycosylation sites, only those located on specific motifs have these roles ^[18][19][144,145]. Integrins also contain O-glycans associated with the adhesion and migration of tumor cells, but their functions are less investigated due to difficulties in their isolation. 

1.2. 3D structures of Integrins

X-ray crystallography, NMR spectroscopy, cryogenic electron microscopy, and molecular modeling methods solved the integrin structures and contributed to understanding their behavior. The first 3D structure of an integrin was the crystal structure of the integrin ectodomain for αvβ3 ^[20][146]. Up to now, there are more than 100 solved structures concerning various integrins’ parts, usually in complex with different ligands. The solved integrin-ligand complexes revealed the structures of binding sites and crucial interactions between inhibitor and ligand ^[2][20]. It is beyond the scope of this rpapesearchr to discuss all X-ray structures. Readers can find relevant information in reviews on this subject ^{[2][21][22][23][24][25]}[7,13,20,147,148,149]. In this section, rwesearchers will discuss some solved structures of integrins, as well predicted 3D structures by homology modeling.

Integrins play an essential role in the immune system by mediating leukocyte adhesion and their transmigration from blood to tissue during leucocyte adhesion ^[26][150]. Therefore, it is unsurprising that integrins involved in immunological functions were studied more intensively than others. The αXβ2 integrin was the first solved structure of the ectodomain containing the αI domain ^[27][151]. The integrins αvβ3 and αIIbβ3 belong to the most investigated. These integrins are present on platelets and are associated with platelet functions in hemostasis and thrombosis, and they also participate in cancer progression ^[28][152]. The crystal structures of the complete integrin αvβ3 ectodomain plus α/β transmembrane fragment ^[29][153] and the intact integrin αIIbβ3 in a nanodisc lipid bilayer were solved recently ^[30][154]. Both integrins adopted a similar bent conformation, in which the ligand binding site is near the membrane surface.

The solved crystal structures of integrin ectodomains and I domains ^{[2][21][25][31][32]}[7,20,21,149,155] revealed that integrins exist during activation in the dynamic equilibrium of at least three major conformers: bent-closed (BC), open-closed (OC), and open-extended (OE)] ^[21][33][34][7,156,157]. Three conformers are schematically shown in Figure 1. Interactions of integrins with extracellular and cytosolic ligands (activators) trigger a large conformational movement that changes conformational equilibrium. In the absence of a ligand, a salt bridge interaction between helices of the cytoplasmic tails of α and β subunits hold the resting integrin in a low-affinity conformation ^[35][158]. Interactions of some protein activators, e.g., talin, with CT of β-subunits and membrane break this salt bridge, separate the α- and β-subunits, and the integrins switch to an extended conformation ^[36][159] of the α and β ectodomains that retains its low ligand affinity. Then, integrins interacting with extracellular ligands change to an open-extended, high-activity conformation ^[37][160]. It was observed ^[38][161] that after activation, integrins form ~100 nm clusters of ~50 integrins assisted in an early adhesion of cells.

Recently, the conformational equilibriums of three conformers of the α5β1 integrin have been investigated by kinetics measurements using three different ligands ^[33][156]. The determined values of the free energy ΔG for the bent-closed (BC) and the extended-closed (EC) conformer are in the range from −1.2 kcal/mol to −1.8 kcal/mol and −0.7 kcal/mol to −1.2 kcal/mol, respectively, compared to the extended-open (EO) conformer (ΔG^EO = 0.0 kcal/mol). For the cyclic RGD peptide (cRGD) as the ligand, the values are ΔG^BC = −1.5 kcal/mol, ΔG^EC = −1.1 kcal/mol, and ΔG^EO = 0.0 kcal/mol corresponding to the population of x(BC):x(OC):x(OE) = 64.3%:31.3%:4.6%. Interestingly, the authors also found that variation in the N-glycosylation site number modulates conformational equilibria. The results revealed that bent-closed and extended-closed conformations are stabilized by a lower number of N-glycosylation sites on integrin α5β1 ^[33][156].

The αI domain is the ligand-binding site in the integrins containing this domain. Structural studies of the αI domains (α2, αM, and αL) complexed with a ligand and without a ligand revealed three distinct conformations: closed, intermediate, and open ^{[39][40][41][42]}[162,163,164,165]; it was suggested that the closed conformation that lacks a ligand is the most stable ^[21][7]. The αI domain possesses a Rossmann fold, and at the C-terminal end of the central β-sheet is a MIDAS binding motif that coordinates a divalent-metal binding site. The crystal structure of αLβ2 also revealed the presence of a ligand-induced allosteric site ^[43][166]. In contrast, integrins lacking the αI domain bind ligands in a binding site of the βI domain that is homologous to the αI domain. Readers can find a detailed discussion of the conformational changes of integrins in recent papers ^{[2][21][22][25]}[7,13,20,149].

Simultaneously with an effort to describe the 3D structure and conformational dynamic of integrins using experimental methods, molecular modeling methods were applied to provide additional information and aimed to fill the gaps in missing experimental data. The first homology model of an integrin was constructed in 1992 for the α-integrin EF hand-like sequence using the calmodulin sequence as a template ^[44][167]. A computational approach was used to design mutations that stabilized the αI domain of the αMβ2 integrin in either the open or closed conformation ^[45][168]. The analysis of the predicted mutants revealed that the conformational change in αI domain mediates ligand binding and that computationally proposed ligands are more active than previously suggested ligands.

Up to now, there are no crystal structures reported for the leukocyte integrin α4β1. The first step in generating a complete 3D structure of α4β1 was a homology model of β-subunits, including a bound Mg²⁺ ion ^[46][169]. The model was constructed using the I domain of integrin CD11B/CD18 containing Mg²⁺ ion as the template ^[47][170]. Then, several steps of restrained energy minimization and molecular dynamics, followed by a final minimization, were used to obtain the final homology model. The ligand-binding mechanism of the α4β1 integrin was studied by docking various molecules, including the vascular cell adhesion molecule (VCAM-1), into the active site of the model. The results shed light on the interactions of β4 with its ligands and explained the binding mechanism of α4β1 with the native ligand VCAM-1. Additionally, a qualitative explanation of the ligand binding selectivity between α4β1 and α4β7 was proposed.

The solved crystal structures of the complete unconstrained ectodomain plus short C-terminal transmembrane stretches of the &#;V and &#;3 subunits of the αvβ3 integrin ^[20][29][146,153] made it possible to construct a model for the ectodomain of the human αvβ5 integrin ^[48][171]. Homology modeling used the crystal coordinates of αvβ3 in its bound conformation as a template. The modeled receptor was refined using energy minimization and molecular dynamics simulations in explicit solvent. The resulting αvβ5 model was used to investigate a ligand binding selectivity toward αvβ3 and αvβ5 by docking various ligands into both integrins. Comparison of both structures and docking results explained the binding differences of both integrins by revealing that ligands with bulky substituents neighboring the carboxylate group are hampered by a “roof” presented on the top of the MIDAS region in αvβ5.

The homology of the platelet integrin αIIbβ3 has also been reported ^[49][172]. At the time of generating the homology model of the αIIb N-terminal portion of integrin αIIbβ3, the high-resolution structures of integrin αIIbβ3 were unavailable. The refined model was validated experimentally. The homology model revealed structural features responsible for the αIIbβ3 integrin function and proposed an interpretation of the role of naturally occurring mutations that produce Glanzmann thrombasthenia. However, more than 38 crystal structures related to integrin αIIbβ3 are now available that provide information on the mechanism of the αIIbβ3 integrin function ^[2][20]. The homology model of the extended full-length integrin αIIbβ3 was generated based on the crystal structures of the αvβ3 ectodomain ^[20][50][146,173] and on the β2 PSI/hybrid/I-EGF1-3 construct ^[51][174], including of computer models of the TM helices ^[52][175]. The model was complemented with N- and O-glycans, computer models of the TM helices, and NMR structures of the cytoplasmic domains ^[53][54][55][176,177,178]. The generated models were fit in the EM⁄ET maps, and their hydrodynamic parameters were then computed and compared with the experimental data. Later, the authors ^[56][179] refined this model (Figure 2a) using the new crystallographic structure of the integrin αIIbβ3 ectodomain ^[57][180] and the NMR structures of its transmembrane/cytoplasmic segments ^[58][181].

The recently developed deep-learning method AlphaFold ^[60][119] has been used to generate a homology model of the α4β1 integrin ^[59][182]. AlphaFold produced 25 partially optimized homology structures, including a pLDDT scoring function that evaluates the intra-domain confidence interval. Structures of all homology models were superposed using the USCF ChimeraX program. The analysis of overlapped 3D structures revealed only slight differences in non-structuralized loops. The selected homology model, based on pLDDT, was optimized, and its stability was evaluated with MD simulation using AMBER. The final 3D homology model of the α4β1 integrin is shown in Figure 2b, together with the homology structures of the α subunit (Figure 2c), and β subunit (Figure 2d).

Integrins, as transmembrane glycoproteins located on the surfaces of the cells, recognize many physiological ligands ^[61][229]. They bind through their ectodomains with numerous ligands and, thus, are involved in cell–cell and cell–ECM interactions influencing cell migration and ECM assembly and remodeling. Among the most relevant ligands belong ICAM-1 (Intercellular Adhesion Molecule 1; also known as CD54), VCAM-1 (Vascular Cell Adhesion Molecule 1; CD106), MAdCAM-1 (Mucosal Addressin Cell Adhesion Molecule 1), E-cadherin, PECAM-1 (Platelet Endothelial Cell Adhesion Molecule 1; CD31), EPCR (Endothelial Cell Protein C Receptor), thrombomodulin, fibronectin, collagen, and irisin ^[62][230]. The cytoplasmic domain of integrins also interacts with many cytoskeletal proteins and signaling molecules. These interactions mediate fundamental cell processes associated with diverse physiological and pathological pathways. Though integrin–ligand interactions play a pivotal role in maintaining the health conditions of various tissues, their aberrant activation is detrimental in multiple diseases, including development, immunity, hemostasis and thrombosis, inflammation, angiogenesis, tumor growth and metastasis, multiple sclerosis, inflammatory bowel disease, nephritis, osteoporosis, sickle cell disease, and fibrosis ^{[3][22][63][64][65]}[9,13,24,231,232]. Many papers exist regarding the role of aberrant integrin adhesion and signaling in the pathogenesis of many human diseases. It is beyond this rpapesearchr’s scope to discuss this complex area of research in detail. Therefore, the following sections only briefly discuss the importance of integrins in various diseases, and readers may find more detailed insight in available reviews.

Inflammation. Activated integrins are involved in leukocyte extravasation from blood to inflamed tissues. This process consists of multiple sequential molecular interactions called leukocyte adhesion cascade ^[26][66][150,233]. Circulating leukocytes interact during tethering and rolling with selectins on the activated endothelium. These contacts are identified by chemokines, which trigger inside-out activation (by binding effectors to the cytoplasmic tail of the β subunit) of leukocyte integrins (e.g., αLβ2, αMβ2, α4β1, and α4β7) that then bind to their counter-receptors on the endothelium, including ICAMs and VCAMs. Binding these adhesion ligands stabilizes the high-affinity integrin conformation and strengthens the binding of leukocytes to the endothelium. Firmly bound leukocytes crawl along the endothelium and finally migrate through the endothelium to inflamed sites ^[67][183].

Integrins are crucial components of the leukocyte adhesion cascade responsible for proper leukocyte homing in inflammatory responses. Their role is documented by patients with leukocyte adhesion deficiency (LAD) syndromes who suffer from recurrent infections and bleeding disorders. It was discovered that a mutation in β2 integrins is responsible for LAD affecting the interaction with kindlins-3, and as a result, leukocytes cannot get to the inflammation site ^[68][235]. A complete failure of platelet aggregation to form a clot caused by mutations of the αIIbβ3 integrin is characteristic of Glanzmann’s thrombasthenia ^[69][236]. Abnormal bleeding that can be life-threatening is a typical symptom of patients suffering from Glanzmann’s thrombasthenia. Another genetic disease is Epidermolysis bullosa, a connective tissue disorder that causes your skin to blister and tear easily, caused by a mutation of the α6β4 integrin ^[70][237]. Symptoms are often severe with life-threatening complications. Integrins are crucial in preventing chronic inflammation by removing apoptotic neutrophils by macrophages in acute inflammation, an efferocytosis process ^[71][238].

Inflammatory bowel diseases. Leukocyte integrins play a prominent role in inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC). Uncontrolled inflammation of the gastrointestinal tract is typical for IBDs ^[72][73][239,240]. The migration of activated T-lymphocytes to the intestinal vasculature is mediated by interactions of α4β1, α4β7, and αEβ7 integrins with their ligands VCAM-1, MAdCAM-1, and E-cadherin. In the inflamed gut of IBDs patients, an increased number of VCAM-1 and MAdCAM-1 ligands were observed that contributed to the increase of pro-inflammatory lymphocytes, which are retained through enhanced interactions between the αEβ7 integrin and E-cadherin. Thus, aberrant interactions of α4β1, α4β7, and αEβ7 integrins with their ligands VCAM-1, MAdCAM-1, and E-cadherin play critical roles in the pathogenesis of BDIs ^[72][239]. Therefore, the therapy based on inhibiting these interactions may be beneficial for treating patients suffering from BDIs.

Arthritis. Inflammation of the synovium tissue is characteristic of chronic inflammatory arthritides. Rheumatoid arthritis (RA) is the best-studied disease in this group ^[74][75][76][241,242,243]. In RA, enhanced pro-inflammatory cell levels cause overexpression integrin receptors and their ligands ^[77][244]. The analysis of integrin distribution in synovial tissue of RA revealed ^[76][243] an increased expression of collagen-, laminin-, and fibronectin-binding integrins, especially those containing α5, αv, and β1 subunits. Additionally, an upregulation of the αLβ2 (LFA-1) integrin that enhances the migration of immune cells into the synovial tissue was observed ^[76][243]. Enhanced levels of these integrins causes the overproduction of matrix-degrading enzymes and fibroblasts that degrade cartilage, and thus preserve RA. All these findings suggest integrins’ crucial role in RA disease that can be restrained with integrin inhibitors.

Fibrosis. Five integrins containing the αv subunit (αvβ1, αvβ3, αvβ5, αvβ6, and αvβ8) have been identified to play a relevant role in fibrotic diseases ^[78][245] in several organs, including the heart, blood vessels, lung, kidney, liver, and skin ^[79][246]. Typical for fibrosis is ECM stiffening with loss of elasticity and excessive tissue deposition with a debilitating condition ^[80][247]. Under chronic injury or inflammation, integrins activate pro-fibrotic transforming growth factor β (TGFβ). Induced fibroblasts upregulate ECM production, leading to fibrosis progression. It was found that αv integrins are upregulated in fibrotic diseases, and studies using knockout mice demonstrated that deletion of αv integrins might attenuate fibrosis progression ^[81][248].

Atherosclerosis. Integrin signaling plays a crucial role in atherosclerosis, a chronic inflammatory disease affecting large arteries ^[82][83][249,250]. The binding of the αIIbβ3 integrin with fibrinogen is involved in platelet aggregation, and β2 integrins (αM4β2 and αLβ2) control macrophage binding. An overexpression of integrins and their ligands was observed in atherosclerosis ^[82][249]. For example, an upregulation of the α4β7 integrin and its ligands VCAM-1 and MAdCAM-1 was found in atherosclerosis, and the atherosclerotic plaque area was significantly reduced in the α4β7 deficient mice ^[84][85][251,252]. In addition, attenuated atherosclerosis was observed upon deletion of other integrins, such as the leukocyte αXβ2 ^[86][253], αvβ3 ^[87][254], and α5β1 ^[88][255]. Therefore, the inhibition of these integrins has the potential to reduce the progression of atherosclerosis.

Eye diseases. Integrins play an essential role in normal development and the development of pathological processes in the eye ^[89][26]. For example, the αvβ6 integrin is a key player in corneal fibrosis ^[90][256]; integrins α1, α3, α4, αL, β1, β3, and β4 were upregulated in the heredity eye disease Fuchs’ corneal dystrophy ^[91][257]. The αL integrin plays a vital role in dry eye diseases, and its inhibition significantly improves ailments ^[92][258]. In glaucoma, the αvβ3 integrin was upregulated in retinal ganglion cells and the glial cells of the nerve head after nerve crush in mice ^[93][259]. The examples mentioned above documented some eye diseases associated with the deregulation of integrins.

Cancer. A multistep process of cancer development includes tumor initiation and sustainable chronic proliferation, local invasion and intravasation into blood, surviving circulation, adhesion to the endothelium, extravasation, initial seeding, and proliferation in the target tissue ^{[94][95][96][97]}[260,261,262,263]. Many studies have indicated that integrins mediate various aspects of these steps ^{[98][99][100][101][102][103][104]}[23,264,265,266,267,268,269], and below, rwesearchers present only a few selected examples. Biochemical and genetic studies have documented aberrant integrin activity in cancer cells associated with an altered expression of integrins, which is dependent on the cancer type and the stage of the disease ^[98][23]. A high abundance of various β1, β4, and αv integrins (α3β1, α4β1, α5β1, α6β4, αvβ3, αvβ5, αvβ6, and αvβ8) is associated with metastasis and frequently correlates with poor prognoses ^[98][102][23,267]. However, the role of integrins is not straightforward. For example, although β1 integrins play a crucial role in cancer development and the α3β1 integrin is vital for mammary cancer ^[105][270], the α2β1 integrin is a metastatic suppressor in breast cancer ^[106][271].

Genetic studies have revealed that the β4 integrin is necessary for tumor initiation and progression in mammary and skin tumorigenesis ^[100][265]. Additionally, it was found ^[104][269] that an overexpression of the αvβ3 integrin plays a vital role in developing tumor-initiating cells in lung and pancreatic cancers. These cells are assumed to contribute to cancer relapse after the initial response to treatment. Furthermore, the αvβ3 integrin was found to mediate the resistance of tumor-initiating cells to tyrosine kinase inhibitors through the activation of NF-κB in a ligand-independent manner ^[107][272].

Cancer metastasis is a complex multi-step process, and from a vast number of primary tumors, only a tiny number of metastases develop. To form metastasis in nearby or distant organs, cancer cells have to accomplish all of several consecutive steps: detachment from the primary tumor, intravasation to the blood vessel, survival of circulation in blood and adhesion to the endothelium, extravasation from the blood into the target organ, and proliferation in the organ microenvironment ^[94][97][260,263]. Accumulating experimental evidence showed that during the circulation in the blood, cancer cells utilize a similar mechanism used by leukocytes in the inflammatory cascade ^[108][109][273,274]. Various adhesion molecules mediate the transendothelial migration of cancer cells, including activated integrins of cancer cells, such as α4β1 binding to endothelium ligand VCAM-1 and αLβ1 binding to LCAM-1.

However, the role of integrins is more complex, and some data suggest that laminin-binding integrins α3β1 and α6β4 might have an inhibitory effect on cancer metastasis ^[110][275]. The dual role of the α3β1 integrin was shown in breast cancer. The absence of integrin α3β1 reduced the survival of mice, and increased tumor growth was observed ^[111][276]. Similarly, the α3 subunit of the α3β1 integrin interacts with various ECM ligands, and its function depends on the cancer type. In patients with hepatocellular carcinoma (HCC), the expression of α3 negatively correlated with tumor growth and metastasis ^[112][277]. An opposite functioning of α9 was observed in breast cancer, where knocking out α9 significantly reduced tumor growth, angiogenesis, and metastasis ^[113][278].

Integrins are also involved in ECM remodeling to induce cancer cell invasion, with cancer-associated fibroblasts (CAFs) playing a vital role. It was found ^[114][279] that the αvβ3 integrin expressed by CAFs participates in CAFs’ assembling of fibronectin and metastasis. In addition, other integrins, such as the α5β1 integrin ^[115][280], αvβ6 integrin ^[116][117][281,282], and α9β1 integrin, promote the recruitment of CAFs. Angiogenesis supplies nutrition for tumor survival and supports tumor cell transfer into blood vessels for circulation. Three endothelial integrins, namely αvβ3, αvβ5, and α5β1 mediate tumor angiogenesis ^[118][283]. It has been shown that tumors use integrin-ECM interactions as one of the strategies to escape anti-tumor therapies ^[119][284]. To achieve this goal, tumors overexpress integrins, such as β1, and activate signaling pathways that block the effect of drugs ^[120][121][285,286].

Integrins as a route to invasion by viruses and bacteria. Various pathogens can exploit integrins as receptors to attach and enter the host cells; for review, see references ^{[122][123][124][125]}[287,288,289,290]. Over time, viruses have evolved multiple mechanisms to colonize host cells. The binding to the host is the first step of virus entry (internalization), and among different receptors, viruses utilize integrins.

Several viruses display on the viral surface proteins containing amino acid moiety RGD, which they use for binding with RGD-binding integrins ^[124][289] (αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, α8β1, and αIIbβ3). Among those, many adenoviruses interact with αv integrins as documented by the solved structure of the complex with the αvβ5 integrin by cryoelectron microscopy ^[126][291]. The binding starts virus internalization, and it was shown that inhibition of binding resulted in a significant decrease in viral infection ^[127][292]. Interestingly, adenovirus binding also induces the clustering of integrins that enhance infection. Similarly, several members of the Herpesviridae family, such as Kaposi’s sarcoma-associated herpes virus or human herpes virus 8, utilize the αvβ3 integrin ^[128][293]. The integrins αIIbβ3 and αvβ3 function as receptors for pathogenic strains of hantaviruses, while non-pathogenic strains of the Prospect Hill virus utilize the β1 integrin ^[129][130][294,295]. Coxsackievirus, a member of the enterovirus family, uses the αvβ6 integrin for cell entry ^[131][296]. Interactions of retrovirus human immunodeficiency virus 1 (HIV-1) with the α4β7, αvβ5, αvβ3, and α5β1 integrins are critical for cell entry ^{[132][133][134]}[297,298,299]. Among other RGD-binding viruses, deadly Ebola virus interactions with the α5β1 integrin are essential for fibroblast infection ^[135][300]. Other viruses using RGD moiety for engagements with host cells include Zika virus ^[136][301] (αvβ5), rotavirus ^[137][302] (αvβ3), and foot-and-mouth disease ^[138][303] (αvβ6). Recently, it was suggested that SARS-CoV-2 might also use RGD-binding integrins as cell receptors through interactions with spike protein ^[139][140][304,305].

Not all viruses recognize RGD moiety for their interactions with integrins. An alphavirus Ross River virus associated with polyarthritis utilizes the binding of integrins α1β1 and α2β1 for cell entry and infection ^[141][306]. The role of the α2β1 integrin is supported by blocking infection with function-antibodies against α2β1 ^[141][306]. Rotavirus spike protein uses different spike amino acids moieties to enter a cell: the YFL domain binds with the α4β1 and α4β7 integrins ^[142][307], and the GPR moiety interacts with the αXβ2 integrin ^[143][144][308,309]. Human echovirus, which is associated with meningoencephalitis, utilizes for successfully infecting cell clusters of the α2β1 integrin ^[145][310]. Interestingly, HIV-1, in addition to binding RGD-binding integrins, also uses interactions with the α4β7 integrin for efficient cell-to-cell spreading ^[133][298].

Integrin receptors are also vital for many bacterial infections, and in the following, only some examples will be presented. More details can be found in reviews ^[123][125][288,290]. Some bacteria use an adhesion, a protein expressed on their surface, to interact with integrins on host cells to initiate cell entry. For example, Yersinia bacteria cause pain and tenderness in the abdomen, nausea, and diarrhea, and use the protein invasin to interact with five β1 integrins, namely α3β1, α4β1, α5β1, α6β1, and αvβ1, for efficient host cell entry ^[146][311]. Helicobacter pylori is linked to various stomach diseases, and the host clustered β1 integrins attach bacteria through a type 4 secretion system to the cell membrane ^[147][312]. Borrelia burgdorferi bacteria is a source of Lyme disease, and a membrane protein P66 binding to β3 integrins has been identified as the mechanism of bacteria adhesion ^[148][313].

Some bacteria express proteins that bind to the protein fibronectin from ECM and through fibronectin to host cell integrins in the so-called sandwich model ^[149][314]. For example, Staphylococcus bacteria cause mucosal or septicemic infection and express two fibronectin-binding proteins, FnbpA and B. These proteins interact with the α5β1 integrin and can be inhibited by RGD peptides ^[150][315]. Streptococcus bacteria use a similar mechanism responsible for acute pharyngitis in humans ^[151][316] and by Porhyronomas bacteria that causes periodontitis ^[152][317]. A common bacterium, Pseudomonas aeruginosa, causes acute or chronic lung infections and employs interactions with α5β1 and αvβ5 integrins and their ligands fibronectin and vitronectin to invade host cells ^[153][318]. Neisseria bacteria cause sexually transmitted gonorrhea disease (N. gonorrhoeae) and meningitis (N. meningitidis). Infections by Neisseria commence with an attachment to host cell surfaces. Then, the host cell receptors trigger signaling, activating the α5β1 and αvβ3 integrins with the following cell entry ^[154][319]. The above-discussed example illustrates the crucial importance of integrins’ recognition in viral and bacterial infections. In many cases, they mediate attachment, internalization, and tissue. Thus, they represent potential targets for therapeutic intervention.