Abstract
Infection and invasion are the prerequisites for developing the disease symptoms in a host. While the probable mechanism of host invasion and pathogenesis is known in many pathogens, very little information is available on Leptospira invasion/pathogenesis. For causing systemic infection Leptospira must transmigrate across epithelial barriers, which is the most critical and challenging step. Extracellular and membrane-bound proteases play a crucial role in the invasion process. An extensive search for the proteins experimentally proven to be involved in the invasion process through cell junction cleavage in other pathogens has resulted in identifying 26 proteins. The similarity searches on the Leptospira genome for counterparts of these 26 pathogenesis-related proteins identified at least 12 probable coding sequences. The proteins were either extracellular or membrane-bound with a proteolytic domain to cleave the cell junction proteins. This review will emphasize our current understanding of the pathogenic aspects of host cell junction-pathogenic protein interactions involved in the invasion process. Further, potential candidate proteins with cell junction cleavage properties that may be exploited in the diagnostic/therapeutic aspects of leptospirosis will also be discussed.
Key points
• The review focussed on the cell junction cleavage proteins in bacterial pathogenesis
• Cell junction disruptors from Leptospira genome are identified using bioinformatics
• The review provides insights into the therapeutic/diagnostic interventions possible
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Leptospirosis is an infectious zoonotic disease caused by bacteria belonging to the genus Leptospira. These Gram-negative aerobic organisms are either free-living non-pathogenic forms or pathogenic forms. The pathogenic forms are grouped into 17 species and represent > 250 serovars (Picardeau 2017). Leptospirosis mainly occurs in tropical and subtropical areas where heavy rainfall and poor sanitation facilities are common. The disease is significantly underreported due to inept diagnostic methods and the symptoms match with many other bacterial and viral infections. At the global level, 1.03 million new cases of leptospirosis are reported annually with a mortality rate of more than 58,900 (Costa et al. 2015). Findings also suggest that patients with leptospirosis are prone to coinfection with many other pathogens and may pose a serious threat to the treatment options and well-being of these patients (Suppiah et al. 2017).
Leptospira infects a spectrum of both wild and domestic mammals, and once infected, these animals act as reservoir hosts, contaminating the environment, particularly water through their excreta. The pathogens may remain viable for days to weeks in soil and water with a neutral pH and are easily transmitted from infected soil or water to their host organisms (Russell et al. 2018). These spiral-shaped, highly motile organisms can cross through skin abrasions, conjunctiva, or intact mucous membranes (Wunder et al. 2016). Once the pathogen enters the body, it comes into the bloodstream by damaging the endothelial linings of blood vessels and disseminating all over the tissues and organs. Humans are infected with Leptospira through occupational exposure and living in rodent-infested, flood-prone urban slums. The transmission cycle can be seen in Fig. 1.
Transmission cycle of leptospirosis. The diagram shows the transmission dynamics in leptospirosis between rodents, wild and domestic animal reservoirs, and the environment. Pathogens infect humans by contact with an infected host or by contaminated water or soil. Leptospira invades through skin lesions and/or mucous membranes (Levet, 2015). This picture is created by BioRender.com
Chronic leptospirosis affects multiple organs including the liver, brain, eyes, kidneys, and lungs, causing jaundice, kidney failure, pulmonary hemorrhage, meningitis, uveitis, and conjunctivitis (Levett 2001). To enter the host body, the pathogen must cross epithelial and endothelial barriers. During the invasion, pathogenic leptospires adhere to the extracellular matrix (ECM) and degrade it. Pathogenic leptospires express extracellular proteases, most likely metalloproteases for the degradation of host proteins and proteoglycans while those were not produced by non-pathogenic strains (Da Silva et al.2018). Proteases released by the pathogenic strains during the initial phases of infection may play a crucial role in the invasion process and also in defending and averting the immune reaction of the host (Fraga et al. 2014).
To date, very few studies have been conducted experimentally to identify and characterize Leptospiral proteases (Dhandapani et al. 2018; Thoduvayil et al. 2020; Amamura et al. 2017; Kumar et al. 2022; Anu et al. 2018; Sato and Coburn 2017; Martinez-Lopez et al. 2010). To understand Leptospiral pathogenesis, it is mandatory to identify and characterize proteins mediating interactions with host components. As the whole-genome sequence data of many pathogenic and non-pathogenic strains of Leptospira is available, it is easy to compare these sequences with bio-informatics tools to predict proteins with a role in pathogenesis.
The review explores the pathogenesis mechanism, especially the cleavage of cell junction proteins as a critical step in the invasion process by Leptospira. While reports are plenty on many intracellular pathogens and their invasion mechanism, very little is known about Leptospira. Even though the role of many proteins in the ECM component interaction as part of the invasion process is known (reviewed by Daroz et al. 2021; Vieira et al. 2014; Fernandes et al. 2016), studies on the latter stage, which involves the cleavage of cell junction proteins to gain entry to the circulatory system are not available. In this review, along with the compilation of cell junction proteins and their functional aspects reported from Leptospira, a comprehensive genome analysis to identify the orthologs of the pathogenesis-related proteins reported from common intracellular bacterial pathogens was also performed. The computational analysis identified more than 10 pathogenic proteins based on the sequence similarity between the pathogenesis-related proteins and it will pave the way to study their role in invasion and pathogenesis in leptospirosis.
Disrupters of epithelial junction during infection
Epithelial cells serve as the first barrier to prevent the entry of pathogens (excellently reviewed by Rogers et al. 2023; Backert et al. 2017; Zheng et al. 2021, and many more) such as Pseudomonas aeruginosa (Curran et al. 2018), Helicobacter pylori (Chmiela and Kupcinskas 2019), Enteropathogenic E. coli (Singh and Aijaz 2015), Clostridium difficile (Czepiel et al. 2019), and Clostridium perfringens (McClane 2001) into the circulatory system and internal organs. The epithelial cell layers on one side form a barrier between internal organs and external invading pathogens but on the other side, it also serves as an infectious foothold for the pathogens as an entry port to disseminate into deeper tissues (Ashida et al. 2011). They not only serve as a physical barrier rather they also serve as a physiological barrier by secreting some chemicals such as lysozymes in saliva and tears, hydrochloric acid in the stomach, and many antimicrobial peptides (reviewed by Johnstone and Herzberg 2022; Brzoza et al. 2021; Kim et al. 2023; Wang et al. 2019) to prevent the entry of pathogens. Infection can happen when these barriers have been disrupted as in wounds and burns. In the absence of wounding and disruption, pathogens cross epithelial barriers by establishing a link through adhesion or colonization on these surfaces (Bonsor and Sundberg 2019; Ansari and Yamaoka 2019). The epithelial cell layers also serve as barriers to the free passage of foreign molecules (Zheng et al. 2021).
The epithelium is a highly organized structure maintained by cell junctions. Cell junctions are complex multi-protein structures that provide contact among and between cells and ECM in animals. Thus, cell junctions help in holding animal cells together, maintain the paracellular barrier of epithelial cells, and control paracellular permeability (Garcia et al. 2018). There are mainly three types of cell junctions: adherens or anchoring junctions, tight or occluding junctions, and gap or communicating junctions. Different types of proteins are involved to form cell junctions such as cadherins, integrins, connexions, occludins, and claudins. Epithelial cell junctions show selective permeability and thus maintain polarity across the epithelium (Horowitz et al. 2023; Adil et al. 2021). Disruption of this barrier leads to the paracellular movement of molecules along with bacteria, viruses, toxins, etc. into the systemic circulation. Bacterial pathogens produce proteins to disrupt epithelial cell junctions by targeting these junctional proteins to get access to blood circulation (Al-Obaidi and Desa 2018; Zheng et al. 2021). A general representation of cell junction disruption by the bacterium is shown in Fig. 2.
Schematic representation of the disruption of epithelial cell junctions by Leptospira. The barrier is composed of tight junctions, adherens junctions, desmosomes, and gap junctions. The infection affects the cell junction protein in two ways. Changes in the expression and location of these proteins (lead to changes in the epithelial barrier function) and the direct action of secreted and membrane-bound proteases disrupt the cell junction structures. Pathogens like Leptospira, using proteases target these cell junction proteins to cross themselves from the apical to basal side thus disrupting epithelial barrier function
The pathogens developed various mechanisms to circumvent the epithelial cell barrier by expressing several kinds of virulence factors, toxins, proteases, etc. during the course of invasion. Enteric Pathogens like enterohaemorrhagic E. coli, Shigella species, and enteropathogenic Yersinia employ the secretion systems type 3, 4 and 5 (type 3/4/5 secretion system—T3SS/T4SS/T5SS) to inject toxic proteins into the host cells, leading to the disarray of the host cell cytoskeleton, facilitating the invasion of the pathogen (reviewed by Whelan et al.2020; Viana et al. 2021). Pseudomonas aeruginosa uses a biofilm-like matrix for the transmigration process and uses multiple approaches to gain entry into the host cells, such as T2SS, quorum sensing, T3SS, and chemicals like N-(3-oxododecanoyl) L-homoserine lactone. The combined use of toxin and protease hamper the cell junction integrity allowing pathogen entry into the host cells (reviewed by Golovkine et al.2018; Qin et al.2022; Pont et al.2022). To cross the host blood barrier, Neisseria meningitides disrupt the endothelial permeability and it was proposed that N. meningitides recruit proteins involved in the formation and stabilization of adherens and tight junction into the cortical plaques, which is a molecular complex formed under the bacterial colonies, leading to the opening of intercellular cell junction (Coureuil et al. 2012). Helicobacter pylori use a complex virulence mechanism that supports the attachment, colonization, evasion, and modulation of the host immune system, activation of many virulence pathways, and disruption of the cell junctions to gain entry into the host cells (Baj et al. 2020). Downregulation of the expression of cell junction proteins is one of the effects of intracellular pathogen infection. Spontaneous bacterial peritonitis (SBP) is a severe condition of liver cirrhosis caused by E. coli and Proteus mirabilis (P. mirabilis). Haderer and co-workers found that the mucus layer of the intestine was thin in patients suffering from SBP. It is because, in SBP, E-cadherin and occludin proteins are downregulated in adherens and tight junctions respectively and for this reduction, bacterial-host direct interaction is required (Haderer et al. 2022).
Extracellular and membrane-bound proteases of pathogenic bacteria play a crucial role in the invasion process (Linz et al. 2023; Singh and Phukan 2019). One of the widely studied serine proteases, HtrA are expressed by several pathogenic bacteria such as C. jejuni, Salmonella enterica, EPEC, Proteus mirabilis, and Yersinia enterocolitica target E-cadherin during infection (Hoy et al. 2010; Backert et al. 2018; Song et al. 2021). Almost every bacterium causing infectious disease expresses at least one homolog of the HtrA family (Rawlings et al. 2008). In the case of E. coli, DegP, DegQ, and DegS show structural similarity with HtrA proteins of other Gram-negative bacteria (Waller and Sauer 1996). Other than E-cadherins, tight junction proteins such as claudins also act as a target for HtrA in C. jejuni (Sharafutdinov et al. 2020). In the animal models, knocking out of E-cadherin from the host or deletion of the HtrA gene from the pathogen prevented the pathogen’s entry into the host (Cao et al. 2021) evidencing that HtrA or HtrA homologs alone can control the pathogenesis in intracellular pathogens. A trypsin-like serine protease domain containing Ssp1 protease from Aeromonas hydrophila is responsible for the downregulation of a tight junction protein occludin (Feng et al.2022). InlA secreted by Listeria monocytogenes (Nikitas et al. 2011) is used by the pathogen to cross the intestinal barrier by interacting with E-cadherin. Some pathogens also activate the host’s protease that disrupts the epithelial barrier as in the case of periodontitis. In periodontitis, neutrophils of the host’s immune system get activated and these neutrophils start producing neutrophil elastase (NE) which further damages the E-cadherin, occludins, and desmoglein-1 of the oral epithelial tissue (Hiyoshi et al. 2022). Pseudomonas aeruginosa and Serratia marcescens secrete toxins ExlA (Exolysin) and ShlA (Serratia hemolysin A) respectively. These pore-forming toxins bind with host cell receptors and cause an increase in cytosolic Ca2+ that further triggers a host cell transmembrane metalloprotease ADAM10 activation leading to E-cadherin and VE-cadherin cleavage (Reboud et al. 2017). Bacterial proteases target cell junction proteins for the adhesion and invasion process are listed in Table 1.
Leptospira and cell junction proteins
Cell junction proteins act as targets for proteases expressed by pathogenic Leptospira for their attachment and invasion. It was reported that the pathogenic form of L. interrogans infected cells loosens its adherens junction proteins, VE-cadherin (vasculo-endothelial-cadherin), p120-, alpha and beta-catenins, and tight junction proteins, actin, and ZO-1 from the original site at intercellular junctions (Sato and Coburn 2017). De Brito and co-workers observed a loss of expression of E-cadherin protein on the membrane of hepatocytes in the case of human leptospirosis. Also, the expression of E-cadherin in liver cells was absent in areas of the lobule; thus, a stable intercellular adhesion was missing (De Brito et al. 2006). According to the study of Martinez-Lopez and co-workers, the binding changes membrane permeability and allowed the free passage of molecules and the pathogen itself across the endothelial cell layers. Pathogenic strains dislocate the endothelial cell layers by targeting cell junction proteins and creating gaps in between to increase vascular permeability leading to swelling in lung alveoli and hemorrhage (Martinez-Lopez et al. 2010). Evangelista et al. (2014a, b) found that pathogenic Leptospira binds with VE-cadherin of endothelial cells through adhesin proteins and lipoproteins.
The tripeptide RGD (Arg-Gly-Asp) motif present on many proteins binds to integrins and is the most common peptide motif responsible for cell adhesion to the ECM (Makowski et al. 2021). RGD motif is present in several other pathogenic microorganisms like Helicobacter pylori (Bub et al.2019), B. pertussis (Leininger et al.1991), and Mycobacterium tuberculosis (Dubey et al.2021). Cavenague and co-workers characterized an RGD motif-containing protein LIC12254 expressed by pathogenic species of Leptospira but not by intermediate or saprotrophic species through in silico analysis. They showed that recombinant LIC12254 interacts with human αVβ8 integrin and the α8 integrin chain via the RGD motif, while in the recombinant protein lacking RGD motif, binding was abolished (Cavenague et al. 2023). These results suggest that LIC12254 is an outer membrane protein that shows adhesion with human integrins via the RGD domain and has a role in leptospirosis. Recombinant LIC10831 (LRR containing protein) and recombinant dermal human microvascular endothelial cell line (HMEC-1) were generated by Eshghi et al. (2019) and using techniques like SPR (surface plasmon resonance) and ELISA (enzyme-linked immunosorbent assay); it was shown that rLIC10831 bind with endothelial cells. The binding was enhanced by Zn2+.
Kochi and co-workers cloned, expressed, and purified two novel putative surface-exposed hypothetical lipoproteins LIC11711 and LIC12587. Both proteins are conserved among pathogenic strains of Leptospira interrogans. Both recombinant proteins show binding affinity to E-cadherin and laminin, so provide initial adhesion to host epithelial cells and both interact with E-cadherin in a dose-dependent manner (Kochi et al. 2019). Pinne et al. (2010) identified OmpL37 (LIC12263) to determine the binding affinity of protein to host tissue by ELISA. OmpL37 is shown to bind with aortic as well as human skin elastin protein. It also binds with other ECM proteins like laminin, fibrinogen, and fibronectin. The binding of human skin elastin to recombinant OmpL37 as well as Leptospira interrogans indicates that OmpL37 helps pathogenic Leptospira to bind with host tissues via elastin. Moreover, it has been shown that OmpL37 is present only in pathogenic sp. of Leptospira but not in saprotrophic ones. Pereira et al. (2017) identified two surface protein-encoding genes Lsa25.6 (LIC13059) and Lsa16 (LIC10879), cloned them, and expressed them in the E. coli system and reported that both the recombinant proteins were adhesins, interacting with laminin in a dose-dependent manner. But when it comes to binding with epithelial cells, only Lsa16 shows binding with E-cadherin. Leptospira genome contain many genes showing sequence similarity with pathogenic proteases (Table 2).
Cell junction disrupter orthologs in Leptospira genome
During the last decade, research work targeting the pathogenesis mechanism of leptospirosis has seen an upsurge in the identification of components involved in the adhesion, colonization, immune evasion, and establishment of pathogens in the host system. Even though the complete genome is available for many pathogenic and non-pathogenic strains (Ramli et al. 2021; Vincent et al. 2019; Thibeaux et al. 2018) and many studies comparing the genomes are published, a clear picture of the pathogenesis mechanism is not available. In Leptospira, as per the current data, nearly 10 proteins were found to act on the cell junction proteins of the host system and play a role in the invasion/colonization process (Evangelista et al. 2014a, b; Eshghi et al. 2019; Pinne et al. 2010 and many more). Many of these reports were established using the recombinant proteins (Table 3), and few of them were using the protein purified from the culture medium.
The similarities that exist in the invasion and pathogenesis machinery among different pathogenic, intracellular bacteria prompted us to look for the presence of some of the most widely reported and critical components of the pathogenesis machinery in the Leptospira genome. The pathogen-related gene sequences mainly involved in cell junction cleavage obtained from other pathogens were used as bait to look for similar sequences in the Leptospira genome. In some cases, instead of nucleotide sequence, the amino acid sequence was used for the search due to very low similarity results with the nucleotides. To explore more about the pathogenicity-related genes in the genome of Leptospira, seven proteins, proven experimentally to be involved in the invasion process of different intracellular pathogens were selected. The sequences collected from different strains of Leptospira including the pathogenic, non-pathogenic, and intermediate forms were used to check for the presence of domains making them active proteases/peptidases. Localization onto the outer membrane or to the secretome was another criterion for the selection of sequences. Depending on the number of domains and sequence similarities the sequences were grouped into three major clades delimiting the strains as per their pathogenicity. Pathogenic strains showed the presence of pathogenic proteins reported from other species (more than 80% similarity indicated by red-colored blocks in the heatmap). Among the strains, L. interrogans showed the presence of 7 out of 9 proteins in the genome with high sequence similarity (Fig. 3). HtrA and FadA were present in the intermediate forms indicating that these two pathogenic proteins may have a widespread distribution among the genomes of pathogenic and intermediate forms of Leptospira. Two proteins PsaA and HAP were present only in the pathogenic strain L. borgpeterseni. The genome of two non-pathogenic strains (L. vantheilii and L. meyeri) selected for the study lacks any of the pathogenesis-related protein sequences used in the study.
Comparative amino acid sequence analysis of nine pathogenic proteins in different species of Leptospira. Nine proteins involved in the invasion/pathogenesis caused by different human pathogens were used to search for similar sequences in Leptospira. The heat map compares the percent identity of a particular protein sequence from 19 species of Leptospira (9 pathogenic, 4 intermediate, and 6 saprophytic). Sequence similarity is shown by red (80% and above), yellow with 40–60% similarity, and shades of blue from 30% to no similarity. Pathogenic species show more expression of proteins involved in pathogenesis over intermediate or non-pathogenic forms of Leptospira. Species of pathogenic, intermediate, and non-pathogenic forms of Leptospira are mentioned on the right side of the figure
Potential inhibitors of cell junction disrupters
Seven types of proteases are available on the MEROPS database, i.e., serine-, threonine, glutamate-, aspartate-, asparagine-, cysteine- and metalloprotease (Rawlings et al. 2018) which is the most common protease expressed by pathogenic bacteria. Protease inhibitors play a major role in the containment of many bacterial/viral diseases. So, it is a worthwhile practice to look for inhibitors and their applications in therapeutics. Out of 26 selected proteins from different pathogenic bacteria involved in invasion, nine were metalloproteases and five out of 12 selected proteases from Leptospira were also metalloproteases. The inhibitors of metalloproteases are mainly chenodeoxycholic acid, phosphinic acid-based pseudopeptide inhibitor, Raxibacumab, and phosphonamidate dipeptides (Sundar et al. 2023). The Zn2+ metalloprotease involved in the invasion/pathogenesis is represented by PsaA, LasB, BFT, and HA/P and can be inhibited by chenodeoxycholic acid, dithiothreitol, dithioerythreitol, and phosphinic acid-based pseudo peptides (Yang et al. 2011; Metz et al. 2019; Migone et al. 2009). UreB is a Ni2+-dependent protease found in many pathogenic bacteria. There are many natural and synthetic inhibitors of UreB reported in the literature (Loharch and Berlicki 2022).
HtrA is a serine protease expressed by a wide variety of pathogenic bacteria and contributes to pathogenesis directly (Zarzecka et al. 2019). It not only enables pathogens to survive in stressful conditions but also cleaves multiple host proteins such as E-cadherin and other extracellular matrix proteins (Wessler et al. 2017). Some of the HtrA inhibitors like camostat, gabexate, nafamostat mesylates (Amrutha et al. 2023), ecimicin (Choules et al. 2019), and rufomycin (Gao et al. 2015) have been developed against different pathogenic bacteria but show a harmful effect on human health. Hwang and co-workers (2021) designed and synthesized a peptide-based inhibitor JO146 using nanotechnology, which was not toxic to humans as well as other model organisms and effective only against Chlamydia (Hwang et al. 2021) and H. pylori (Hwang et al. 2022), but not effective against other pathogens like Staphylococcus sp., Pseudomonas sp., and pathogenic E. coli. Exploring the invasion mechanism in Leptospirosis further opens up new avenues for the identification and implementation of proteases against the disease.
Conclusion
Leptospirosis shows an increased occurrence worldwide in the last few decades, mainly due to changes in climatic conditions. This made the environment more conducive for the survival and multiplication of reservoir hosts and the zoonotic epidemics will be a serious threat to the healthcare system of developing countries in the coming years (Limaye 2021; Prillaman 2022). Unlike many intracellular pathogens, which makes their presence ubiquitous, Leptospires are common in tropical and subtropical regions, affecting mainly the population of developing countries. The complex interaction predicted with climate change and disease occurrence by several studies indicates the necessity of having a thorough understanding of zoonosis to prevent it efficiently. Mining the genome and proteome data to identify novel genes and proteins which play crucial roles in pathogenesis is important in this process. Even though in the last few years, there were many publications on Leptospiral protein interaction with ECM, epithelial cell junction, and the immune components of the host, many questions are still unanswered. The major queries about the components involved in the attachment, invasion, and colonization process are only partly answered. Further, a mechanism of transmigration to different organs and circulatory system needs to be identified. There were very few studies on the biological characterization of pathogenic proteins in the model pathogenic strains of Leptospira making it difficult to conclude anything with the information available at present. The new orthologous reported in this review may help us to fill some gaps.
References
Adil MS, Narayanan SP, Somanath PR (2021) Cell-cell junctions: structure and regulation in physiology and pathology. Tissue Barriers 9(1):1848212. https://doi.org/10.1080/21688370.2020.1848212
Al-Obaidi MMJ, Desa MNM (2018) Mechanisms of blood brain barrier disruption by different types of bacteria, and bacterial-host interactions facilitate the bacterial pathogen invading the brain. Cell Mol Neurobiol 38(7):1349–1368. https://doi.org/10.1007/s10571-018-0609-2
Amamura TA, Fraga TR, Vasconcellos SA, Barbosa AS, Isaac L (2017) Pathogenic Leptospira secreted proteases target the membrane attack complex: a potential role for thermolysin in complement inhibition. Front Microbiol 8:958. https://doi.org/10.3389/fmicb.2017.00958
Amatsu S, Matsumura T, Zuka M, Fujinaga Y (2023) Molecular engineering of a minimal E-cadherin inhibitor protein derived from Clostridium botulinum hemagglutinin. J Biol Chem 299(3):102944. https://doi.org/10.1016/j.jbc.2023.102944
Amrutha MC, Wessler S, Ponnuraj K (2023) Inhibition of listeria monocytogenes HtrA protease with camostat, gabexate and nafamostat mesylates and the binding mode of the inhibitors. Protein J 42(4):343-354
Anderton JM, Rajam G, Romero-Steiner S, Summer S, Kowalczyk AP, Carlone GM, Sampson JS, Ades EW (2007) E-cadherin is a receptor for the common protein pneumococcal surface adhesin A (PsaA) of Streptococcus pneumoniae. Microb Pathog 42(5–6):225–236. https://doi.org/10.1016/j.micpath.2007.02.003
Ansari S, Yamaoka Y (2019) Helicobacter pylori virulence factors exploiting gastric colonization and its pathogenicity. Toxins (Basel) 11(11):677. https://doi.org/10.3390/toxins11110677
Anu PV, Madanan MG, Nair AJ, Nair GA, Nair GPM, Sudhakaran PR, Satheeshkumar PK (2018) Heterologous expression, purification and characterization of an oligopeptidase A from the pathogen Leptospira interrogans. Mol Biotechnol 60(4):302–309. https://doi.org/10.1007/s12033-018-0073-8
Ashida H, Ogawa M, Kim M, Mimuro H, Sasakawa C (2011) Bacteria and host interactions in the gut epithelial barrier. Nat Chem Biol 8(1):36–45. https://doi.org/10.1038/nchembio.741
Backert S, Schmidt TP, Harrer A, Wessler S (2017) Exploiting the gastric epithelial barrier: Helicobacter pylori’s attack on tight and adherens junctions. Curr Top Microbiol Immunol 400:195–226. https://doi.org/10.1007/978-3-319-50520-6_9
Backert S, Bernegger S, Skórko-Glonek J, Wessler S (2018) Extracellular HtrA serine proteases: an emerging new strategy in bacterial pathogenesis. Cell Microbiol 20(6):e12845. https://doi.org/10.1111/cmi.12845
Baj J, Forma A, Sitarz M, Portincasa P, Garruti G, Krasowska D, Maciejewski R (2020) Helicobacter pylori virulence factors-mechanisms of bacterial pathogenicity in the gastric microenvironment. Cells 10(1):27. https://doi.org/10.3390/cells10010027
Bonsor DA, Sundberg EJ (2019) Roles of adhesion to epithelial cells in gastric colonization by Helicobacter pylori. Adv Exp Med Biol 1149:57–75. https://doi.org/10.1007/5584_2019_359
Brzoza P, Godlewska U, Borek A, Morytko A, Zegar A, Kwiecinska P, Zabel BA, Osyczka A, Kwitniewski M, Cichy J (2021) Redox active antimicrobial peptides in controlling growth of microorganisms at body barriers. Antioxidants (Basel) 10(3):446. https://doi.org/10.3390/antiox10030446
Bub M, Tegtmeyer N, Schnieder J, Dong X, Li J, Springer TA, Backert S, Niemann HH (2019) Specific high affinity interaction of Helicobacter pylori CagL with integrin αVβ6 promotes type IV secretion of CagA into human cells. FEBS J 286(20):3980–3997. https://doi.org/10.1111/febs.14962
Bücker R, Krug SM, Rosenthal R, Günzel D, Fromm A, Zeitz M, Chakraborty T, Fromm M, Epple HJ, Schulzke JD (2011) Aerolysin from Aeromonas hydrophila perturbs tight junction integrity and cell lesion repair in intestinal epithelial HT-29/B6 cells. J Infect Dis 204(8):1283–1292. https://doi.org/10.1093/infdis/jir504
Burkholder KM, Bhunia AK (2010) Listeria monocytogenes uses Listeria adhesion protein (LAP) to promote bacterial transepithelial translocation and induces expression of LAP receptor Hsp60. Infect Immun 78(12):5062–5073. https://doi.org/10.1128/IAI.00516-10
Cao Q, Wei W, Wang H, Wang Z, Lv Y, Dai M, Tan C, Chen H, Wang X (2021) Cleavage of E-cadherin by porcine respiratory bacterial pathogens facilitates airway epithelial barrier disruption and bacterial paracellular transmigration. Virulence 12(1):2296–2313. https://doi.org/10.1080/21505594.2021.1966996
Cavenague MF, Teixeira AF, Fernandes LGV, Nascimento ALTO (2023) LIC12254 is a Leptospiral protein that interacts with integrins via the RGD motif. Trop Med Infect Dis 8(5):249. https://doi.org/10.3390/tropicalmed8050249
Chmiela M, Kupcinskas J (2019) Review: pathogenesis of Helicobacter pylori infection. Helicobacter 24(Suppl 1):e12638. https://doi.org/10.1111/hel.12638
Choules MP, Wolf NM, Lee H, Anderson JR, Grzelak EM, Wang Y, Ma R, Gao W, McAlpine JB, Jin YY, Cheng J, Lee H, Suh JW, Duc NM, Paik S, Choe JH, Jo EK, Chang CL, Lee JS, Jaki BU,…..Cho S (2019) Rufomycin targets ClpC1 proteolysis in Mycobacterium tuberculosis and M. abscessus. Antimicrobial Agents Chemother 63(3):e02204-e2218
Cosate MR, Siqueira GH, de Souza GO, Vasconcellos SA, Nascimento AL (2016) Mammalian cell entry (Mce) protein of Leptospira interrogans binds extracellular matrix components, plasminogen and β2 integrin. Microbiol Immunol 60(9):586–598. https://doi.org/10.1111/1348-0421.12406
Costa F, Hagan JE, Calcagno J, Kane M, Torgerson P, Martinez-Silveira MS, Stein C, Abela-Ridder B, Ko AI (2015) Global morbidity and mortality of leptospirosis: a systematic review. PLoS Negl Trop Dis 9(9):e0003898. https://doi.org/10.1371/journal.pntd.0003898
Coureuil M, Join-Lambert O, Lécuyer H, Bourdoulous S, Marullo S, Nassif X (2012) Mechanism of meningeal invasion by Neisseria meningitidis. Virulence 3(2):164–172. https://doi.org/10.4161/viru.18639
Curran CS, Bolig T, Torabi-Parizi P (2018) Mechanisms and targeted therapies for pseudomonas aeruginosa lung infection. Am J Respir Crit Care Med 197(6):708–727. https://doi.org/10.1164/rccm.201705-1043SO
Czepiel J, Dróżdż M, Pituch H, Kuijper EJ, Perucki W, Mielimonka A, Goldman S, Wultańska D, Garlicki A, Biesiada G (2019) Clostridium difficile infection: review. Eur J Clin Microbiol Infect Dis 38(7):1211–1221. https://doi.org/10.1007/s10096-019-03539-6
da Silva LB, Menezes MC, Kitano ES, Oliveira AK, Abreu AG, Souza GO, Heinemann MB, Isaac L, Fraga TR, Serrano SMT, Barbosa AS (2018) Leptospira interrogans secreted proteases degrade extracellular matrix and plasma proteins from the host. Front Cell Infect Microbiol 8:92. https://doi.org/10.3389/fcimb.2018.00092
Daroz BB, Fernandes LGV, Cavenague MF, Kochi LT, Passalia FJ, Takahashi MB, Nascimento Filho EG, Teixeira AF, Nascimento ALTO (2021) A review on host-Leptospira interactions: what we know and future expectations. Front Cell Infect Microbiol 11:777709. https://doi.org/10.3389/fcimb.2021.777709
De Brito T, Menezes LF, Lima DM, Lourenço S, Silva AM, Alves VA (2006) Immunohistochemical and in situ hybridization studies of the liver and kidney in human leptospirosis. Virchows Arch 448(5):576–583. https://doi.org/10.1007/s00428-006-0163-z
Deng W, Bai Y, Deng F, Pan Y, Mei S, Zheng Z, Min R, Wu Z, Li W, Miao R, Zhang Z, Kupper TS, Lieberman J, Liu X (2022) Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis. Nature 602(7897):496–502. https://doi.org/10.1038/s41586-021-04384-4
Deshpande NP, Wilkins MR, Castaño-Rodríguez N, Bainbridge E, Sodhi N, Riordan SM, Mitchell HM, Kaakoush NO (2016) Campylobacter concisus pathotypes induce distinct global responses in intestinal epithelial cells. Sci Rep 6:34288. https://doi.org/10.1038/srep34288
Dhandapani G, Sikha T, Pinto SM, Kiran Kumar M, Patel K, Kumar M, Kumar V, Tennyson J, Satheeshkumar PK, Gowda H, Keshava Prasad TS, Madanan MG (2018) Proteomic approach and expression analysis revealed the differential expression of predicted Leptospiral proteases capable of ECM degradation. Biochim Biophys Acta Proteins Proteom 1866(5-6):712–721. https://doi.org/10.1016/j.bbapap.2018.04.006
Diep DB, Nelson KL, Lawrence TS, Sellman BR, Tweten RK, Buckley JT (1999) Expression and properties of an aerolysin–Clostridium septicum alpha toxin hybrid protein. Mol Microbiol 31(3):785–794. https://doi.org/10.1046/j.1365-2958.1999.01217.x
Dubey N, Khan MZ, Kumar S, Sharma A, Das L, Bhaduri A, Singh Y, Nandicoori VK (2021) Mycobacterium tuberculosis peptidyl prolyl isomerase a interacts with host integrin receptor to exacerbate disease progression. J Infect Dis 224(8):1383–1393. https://doi.org/10.1093/infdis/jiab081
Eshghi A, Gaultney RA, England P, Brûlé S, Miras I, Sato H, Coburn J, Bellalou J, Moriarty TJ, Haouz A, Picardeau M (2019) An extracellular Leptospira interrogans leucine-rich repeat protein binds human E- and VE-cadherins. Cell Microbiol 21(2):e12949. https://doi.org/10.1111/cmi.12949
Evangelista K, Franco R, Schwab A, Coburn J (2014a) Leptospira interrogans binds to cadherins. PLoS Negl Trop Dis 8(1):e2672. https://doi.org/10.1371/journal.pntd.0002672
Evangelista KV, Hahn B, Wunder EA Jr, Ko AI, Haake DA, Coburn J (2014b) Identification of cell-binding adhesins of Leptospira interrogans. PLoS Negl Trop Dis 8(10):e3215. https://doi.org/10.1371/journal.pntd.0003215
Feng C, Liu X, Hu N, Tang Y, Feng M, Zhou Z (2022) Aeromonas hydrophila Ssp1: a secretory serine protease that disrupts tight junction integrity and is essential for host infection. Fish Shellfish Immunol 127:530–541. https://doi.org/10.1016/j.fsi.2022.06.068
Fernandes LG, Siqueira GH, Teixeira AR, Silva LP, Figueredo JM, Cosate MR, Vieira ML, Nascimento AL (2016) Leptospira spp.: novel insights into host-pathogen interactions. Vet Immunol Immunopathol 176:50–57. https://doi.org/10.1016/j.vetimm.2015.12.004
Fraga TR, DdosS C, Castiblanco-Valencia MM, Hirata IY, Vasconcellos SA, Juliano L, Barbosa AS, Isaac L (2014) Immune evasion by pathogenic Leptospira strains: the secretion of proteases that directly cleave complement proteins. J Infect Dis 209(6):876–886. https://doi.org/10.1093/infdis/jit569
Gao W, Kim JY, Anderson JR, Akopian T, Hong S, Jin YY, Kandror O, Kim JW, Lee IA, Lee SY, McAlpine JB, Mulugeta S, Sunoqrot S, Wang Y, Yang SH, Yoon TM, Goldberg AL, Pauli GF, Suh J W, Franzblau SG, … Cho S (2015) The cyclic peptide ecumicin targeting ClpC1 is active against Mycobacterium tuberculosis in vivo. Antimicrob Agents Chemother 59(2):880–889
Garcia MA, Nelson WJ, Chavez N (2018) Cell-cell junctions organize structural and signaling networks. Cold Spring Harb Perspect Biol 10(4):a029181. https://doi.org/10.1101/cshperspect.a029181
Golovkine G, Faudry E, Bouillot S, Voulhoux R, Attrée I, Huber P (2014) VE-cadherin cleavage by LasB protease from Pseudomonas aeruginosa facilitates type III secretion system toxicity in endothelial cells. PLoS Pathog 10(3):e1003939. https://doi.org/10.1371/journal.ppat.1003939
Golovkine G, Reboud E, Huber P (2018) Pseudomonas aeruginosa takes a multi target approach to achieve junction breach. Front Cell Infect Microbiol 7:532. https://doi.org/10.3389/fcimb.2017.00532
Haderer M, Neubert P, Rinner E, Scholtis A, Broncy L, Gschwendtner H, Kandulski A, Pavel V, Mehrl A, Brochhausen C, Schlosser S, Gülow K, Kunst C, Müller M (2022) Novel pathomechanism for spontaneous bacterial peritonitis: disruption of cell junctions by cellular and bacterial proteases. Gut 71(3):580–592. https://doi.org/10.1136/gutjnl-2020-321663
Hiyoshi T, Domon H, Maekawa T, Tamura H, Isono T, Hirayama S, Sasagawa K, Takizawa F, Tabeta K, Terao Y (2022) Neutrophil elastase aggravates periodontitis by disrupting gingival epithelial barrier via cleaving cell adhesion molecules. Sci Rep 12(1):8159. https://doi.org/10.1038/s41598-022-12358-3
Horowitz A, Chanez-Paredes SD, Haest X, Turner JR (2023) Paracellular permeability and tight junction regulation in gut health and disease. Nat Rev Gastroenterol Hepatol 20(7):417–432. https://doi.org/10.1038/s41575-023-00766-3
Hoy B, Löwer M, Weydig C, Carra G, Tegtmeyer N, Geppert T, Schröder P, Sewald N, Backert S, Schneider G, Wessler S (2010) Helicobacter pylori HtrA is a new secreted virulence factor that cleaves E-cadherin to disrupt intercellular adhesion. EMBO Rep 11(10):798–804
Hoy B, Geppert T, Boehm M, Reisen F, Plattner P, Gadermaier G, Sewald N, Ferreira F, Briza P, Schneider G, Backert S, Wessler S (2012) Distinct roles of secreted HtrA proteases from gram-negative pathogens in cleaving the junctional protein and tumor suppressor E-cadherin. J Biol Chem 287(13):10115–10120. https://doi.org/10.1074/jbc.C111.333419
Hu Y, Park N, Seo KS, Park JY, Somarathne RP, Olivier AK, Fitzkee NC, Thornton JA (2021) Pneumococcal surface adhesion A protein (PsaA) interacts with human Annexin A2 on airway epithelial cells. Virulence 12(1):1841–1854. https://doi.org/10.1080/21505594.2021.1947176
Hwang J, Strange N, Phillips MJ, Krause AL, Heywood A, Gamble AB, Huston WM, Tyndall JD (2021) Optimization of peptide-based inhibitors targeting the HtrA serine protease in Chlamydia: design, synthesis and biological evaluation of pyridone-based and N-Capping group-modified analogues. Eur J Med Chem 224:113692
Hwang J, Mros S, Gamble AB, Tyndall JDA, McDowell A (2022) Improving antibacterial activity of a HtrA protease inhibitor JO146 against Helicobacter pylori: a novel approach using microfluidics-engineered PLGA nanoparticles. Pharmaceutics 14(2):348
Inoshima I, Inoshima N, Wilke GA, Powers ME, Frank KM, Wang Y, Bubeck Wardenburg J (2011) A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice. Nat Med 17(10):1310–1314. https://doi.org/10.1038/nm.2451
Johnstone KF, Herzberg MC (2022) Antimicrobial peptides: defending the mucosal epithelial barrier. Front Oral Health 3:958480. https://doi.org/10.3389/froh.2022.958480
Katz J, Sambandam V, Wu JH, Michalek SM, Balkovetz DF (2000) Characterization of Porphyromonas gingivalis-induced degradation of epithelial cell junctional complexes. Infect Immun 68(3):1441–1449. https://doi.org/10.1128/IAI.68.3.1441-1449.2000
Kazemian H, Pourmand MR, Siadat SD, Mahdavi M, Yazdi MH, Avakh Majelan P, Afshar D, Yaseri M, Davari M, Ibrahim Getso M (2019) Molecular cloning and immunogenicity evaluation of PpiC, GelE, and VS87_01105 proteins of enterococcus faecalis as vaccine candidates. Iran Biomed J 23(5):344–353. https://doi.org/10.29252/.23.5.344
Kim J, Cho BH, Jang YS (2023) Understanding the roles of host defense peptides in immune modulation: from antimicrobial action to potential as adjuvants. J Microbiol Biotechnol 33(3):288–298. https://doi.org/10.4014/jmb.2301.01005
Kochi LT, Fernandes LGV, Souza GO, Vasconcellos SA, Heinemann MB, Romero EC, Kirchgatter K, Nascimento ALTO (2019) The interaction of two novel putative proteins of Leptospira interrogans with E-cadherin, plasminogen and complement components with potential role in bacterial infection. Virulence 10(1):734–753. https://doi.org/10.1080/21505594.2019.1650613
Koo OK, Amalaradjou MA, Bhunia AK (2012) Recombinant probiotic expressing Listeria adhesion protein attenuates Listeria monocytogenes virulence in vitro. PLoS ONE 7(1):e29277. https://doi.org/10.1371/journal.pone.0029277
Krueger S, Hundertmark T, Kuester D, Kalinski T, Peitz U, Roessner A (2007) Helicobacter pylori alters the distribution of ZO-1 and p120ctn in primary human gastric epithelial cells. Pathol Res Pract 203(6):433–444. https://doi.org/10.1016/j.prp.2007.04.003
Kumar P, Chang YF, Akif M (2022) Characterization of novel nuclease and protease activities among Leptospiral immunoglobulin-like proteins. Arch Biochem Biophys 727:109349. https://doi.org/10.1016/j.abb.2022.109349
Laforce-Nesbitt SS, Sullivan MA, Hoyer LL, Bliss JM (2008) Inhibition of Candida albicans adhesion by recombinant human antibody single-chain variable fragment specific for Als3p. FEMS Immunol Med Microbiol 54(2):195–202. https://doi.org/10.1111/j.1574-695X.2008.00465.x
Leininger E, Roberts M, Kenimer JG, Charles IG, Fairweather N, Novotny P, Brennan MJ (1991) Pertactin, an Arg-Gly-Asp-containing Bordetella pertussis surface protein that promotes adherence of mammalian cells. Proc Natl Acad Sci U S A 88(2):345–349. https://doi.org/10.1073/pnas.88.2.345
Levett PN (2001) Leptospirosis. Clin Microbiol Rev 14:296–326
Limaye VS (2021) Making the climate crisis personal through a focus on human health. Clim Change 166(3–4):43. https://doi.org/10.1007/s10584-021-03107-y
Linz B, Sharafutdinov I, Tegtmeyer N, Backert S (2023) Evolution and role of proteases in Campylobacter jejuni lifestyle and pathogenesis. Biomolecules 13(2):323. https://doi.org/10.3390/biom13020323
Loharch S, Berlicki Ł (2022) Rational development of bacterial ureases inhibitors. Chem Rec 22(8):e202200026
Mahendran V, Liu F, Riordan SM, Grimm MC, Tanaka MM, Zhang L (2016) Examination of the effects of Campylobacter concisus zonula occludens toxin on intestinal epithelial cells and macrophages. Gut Pathog 8:18. https://doi.org/10.1186/s13099-016-0101-9
Makowski L, Olson-Sidford W, W-Weisel J, (2021) Biological and clinical consequences of integrin binding via a rogue RGD motif in the SARS CoV-2 spike protein. Viruses 13(2):146. https://doi.org/10.3390/v13020146
Manich M, Knapp O, Gibert M, Maier E, Jolivet-Reynaud C, Geny B, Benz R, Popoff MR (2008) Clostridium perfringens delta toxin is sequence related to beta toxin, NetB, and Staphylococcus pore-forming toxins, but shows functional differences. PLoS ONE 3(11):e3764. https://doi.org/10.1371/journal.pone.0003764
Mao YF, Yan J (2004) Construction of prokaryotic expression system of ureB gene from a clinical Helicobacter pylori strain and identification of the recombinant protein immunity. World J Gastroenterol 10(7):977–984. https://doi.org/10.3748/wjg.v10.i7.977
Martinez-Lopez DG, Fahey M, Coburn J (2010) Responses of human endothelial cells to pathogenic and non-pathogenic Leptospira species. PLoS Negl Trop Dis 4(12):e918. https://doi.org/10.1371/journal.pntd.0000918
McClane BA (2001) The complex interactions between Clostridium perfringens enterotoxin and epithelial tight junctions. Toxicon 39(11):1781–1791. https://doi.org/10.1016/s0041-0101(01)00164-7
Metz P, Tjan MJH, Wu S, Pervaiz M, Hermans S, Shettigar A, Sears CL, Ritschel T, Dutilh BE, Boleij A (2019) Drug discovery and repurposing inhibits a major gut pathogen-derived oncogenic toxin. Front Cell Infect Microbiol 9:364
Migone TS, Subramanian GM, Zhong J, Healey LM, Corey A, Devalaraja M, Lo L, Ullrich S, Zimmerman J, Chen A, Lewis M, Meister G, Gillum K, Sanford D, Mott J, Bolmer SD (2009) Raxibacumab for the treatment of inhalational anthrax. N Engl J Med 361(2):135–144
Nikitas G, Deschamps C, Disson O, Niault T, Cossart P, Lecuit M (2011) Transcytosis of Listeria monocytogenes across the intestinal barrier upon specific targeting of goblet cell accessible E-cadherin. J Exp Med 208(11):2263–2277. https://doi.org/10.1084/jem.20110560
Nusrat A, von Eichel-Streiber C, Turner JR, Verkade P, Madara JL, Parkos CA (2001) Clostridium difficile toxins disrupt epithelial barrier function by altering membrane microdomain localization of tight junction proteins. Infect Immun 69(3):1329–1336. https://doi.org/10.1128/IAI.69.3.1329-1336.2001
Ortega FE, Rengarajan M, Chavez N, Radhakrishnan P, Gloerich M, Bianchini J, Siemers K, Luckett WS, Lauer P, Nelson WJ, Theriot JA (2017) Adhesion to the host cell surface is sufficient to mediate Listeria monocytogenes entry into epithelial cells. Mol Biol Cell 28(22):2945–2957. https://doi.org/10.1091/mbc.E16-12-0851
Pereira PRM, Fernandes LGV, de Souza GO, Vasconcellos SA, Heinemann MB, Romero EC, Nascimento ALTO (2017) Multifunctional and redundant roles of Leptospira interrogans proteins in bacterial-adhesion and fibrin clotting inhibition. Int J Med Microbiol 307(6):297–310. https://doi.org/10.1016/j.ijmm.2017.05.006
Phan QT, Myers CL, Fu Y, Sheppard DC, Yeaman MR, Welch WH, Ibrahim AS, Edwards JE Jr, Filler SG (2007) Als3 is a Candida albicans invasin that binds to cadherins and induces endocytosis by host cells. PLoS Biol 5(3):e64. https://doi.org/10.1371/journal.pbio.0050064
Picardeau M (2017) Virulence of the zoonotic agent of leptospirosis: still terra incognita? Nat Rev Microbiol 15(5):297–307. https://doi.org/10.1038/nrmicro.2017.5
Pinne M, Choy HA, Haake DA (2010) The OmpL37 surface-exposed protein is expressed by pathogenic Leptospira during infection and binds skin and vascular elastin. PLoS Negl Trop Dis 4(9):e815. https://doi.org/10.1371/journal.pntd.0000815
Pont S, Janet-Maitre M, Faudry E, Cretin F, Attrée I (2022) Molecular mechanisms involved in Pseudomonas aeruginosa Bacteremia. Adv Exp Med Biol 1386:325–345. https://doi.org/10.1007/978-3-031-08491-1_12
Prillaman M (2022) Climate change is making hundreds of diseases much worse. Nature. https://doi.org/10.1038/d41586-022-02167-z.
Qin S, Xiao W, Zhou C, Pu Q, Deng X, Lan L, Liang H, Song X, Wu M (2022) Pseudomonas aeruginosa: pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics. Signal Transduct Target Ther 7(1):199. https://doi.org/10.1038/s41392-022-01056-1
Ramli SR, Bunk B, Spröer C, Geffers R, Jarek M, Bhuju S, Goris M, Mustakim S, Pessler F (2021) Complete genome sequencing of Leptospira interrogans isolates from Malaysia reveals massive genome rearrangement but high conservation of virulence-associated genes. Pathogens 10(9):1198. https://doi.org/10.3390/pathogens10091198
Rawlings ND, Barrett AJ, Thomas PD, Huang X, Bateman A, Finn RD (2018) The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database. Nucleic Acids Res 46(D1):D624–D632
Rawlings ND, Morton FR, Kok CY, Kong J, Barrett AJ (2008) MEROPS: the peptidase database. Nucleic Acids Res 36(Database issue):D320–D325. https://doi.org/10.1093/nar/gkm954
Reboud E, Bouillot S, Patot S, Béganton B, Attrée I, Huber P (2017) Pseudomonas aeruginosa ExlA and Serratia marcescens ShlA trigger cadherin cleavage by promoting calcium influx and ADAM10 activation. PLoS Pathog 13(8):e1006579. https://doi.org/10.1371/journal.ppat.100657
Rogers AP, Mileto SJ, Lyras D (2023) Impact of enteric bacterial infections at and beyond the epithelial barrier. Nat Rev Microbiol 21(4):260–274. https://doi.org/10.1038/s41579-022-00794-x
Rubinstein MR, Wang X, Liu W, Hao Y, Cai G, Han YW (2013) Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe 14(2):195–206. https://doi.org/10.1016/j.chom.2013.07.012
Russell CD, Jones ME, O’Shea DT, Simpson KJ, Mitchell A, Laurenson IF (2018) Challenges in the diagnosis of leptospirosis outwith endemic settings: a Scottish single centre experience. J R Coll Physicians Edinb 48(1):9–15. https://doi.org/10.4997/JRCPE.2018.102
Sato H, Coburn J (2017) Leptospira interrogans causes quantitative and morphological disturbances in adherens junctions and other biological groups of proteins in human endothelial cells. PLoS Negl Trop Dis 11(7):e0005830. https://doi.org/10.1371/journal.pntd.0005830
Seike S, Takehara M, Takagishi T, Miyamoto K, Kobayashi K, Nagahama M (2018) Delta-toxin from Clostridium perfringens perturbs intestinal epithelial barrier function in Caco-2 cell monolayers. Biochim Biophys Acta Biomembr 1860(2):428–433. https://doi.org/10.1016/j.bbamem.2017.10.003
Sharafutdinov I, Esmaeili DS, Harrer A, Tegtmeyer N, Sticht H, Backert S (2020) Campylobacter jejuni serine protease HtrA cleaves the tight junction component claudin-8. Front Cell Infect Microbiol 10:590186. https://doi.org/10.3389/fcimb.2020.590186
Singh AP, Aijaz S (2015) Enteropathogenic E. coli: breaking the intestinal tight junction barrier. F1000Research 4:231. https://doi.org/10.12688/f1000research.6778.2
Singh V, Phukan UJ (2019) Interaction of host and Staphylococcus aureus protease-system regulates virulence and pathogenicity. Med Microbiol Immunol 208(5):585–607. https://doi.org/10.1007/s00430-018-0573-y
Song Y, Ke Y, Kang M, Bao R (2021) Function, molecular mechanisms, and therapeutic potential of bacterial HtrA proteins: an evolving view. Comput Struct Biotechnol J 20:40–49. https://doi.org/10.1016/j.csbj.2021.12.004
Steck N, Hoffmann M, Sava IG, Kim SC, Hahne H, Tonkonogy SL, Mair K, Krueger D, Pruteanu M, Shanahan F, Vogelmann R, Schemann M, Kuster B, Sartor RB, Haller D (2011) Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation. Gastroenterology 141(3):959–971. https://doi.org/10.1053/j.gastro.2011.05.035
Sugawara Y, Matsumura T, Takegahara Y, Jin Y, Tsukasaki Y, Takeichi M, Fujinaga Y (2010) Botulinum hemagglutinin disrupts the intercellular epithelial barrier by directly binding E-cadherin. J Cell Biol 189(4):691–700. https://doi.org/10.1083/jcb.200910119
Sumitomo T, Nakata M, Higashino M, Terao Y, Kawabata S (2013) Group A streptococcal cysteine protease cleaves epithelial junctions and contributes to bacterial translocation. J Biol Chem 288(19):13317–13324. https://doi.org/10.1074/jbc.M113.459875
Sundar S, Piramanayagam S, Natarajan J (2023) A comprehensive review on human disease-causing bacterial proteases and their impeding agents. Arch Microbiol 6;205(8):276
Suppiah J, Chan SY, Ng MW, Khaw YS, Ching SM, Mat-Nor LA, Ahmad-Najimudin NA, Chee HY (2017) Clinical predictors of dengue fever co-infected with leptospirosis among patients admitted for dengue fever - a pilot study. J Biomed Sci 24(1):40. https://doi.org/10.1186/s12929-017-0344-x
Takahashi MB, Teixeira AF, Nascimento ALTO (2021) The Leptospiral LipL21 and LipL41 proteins exhibit a broad spectrum of interactions with host cell components. Virulence 12(1):2798–2813. https://doi.org/10.1080/21505594.2021.1993427
Tegtmeyer N, Wessler S, Necchi V, Rohde M, Harrer A, Rau TT, Asche CI, Boehm M, Loessner H, Figueiredo C, Naumann M, Palmisano R, Solcia E, Ricci V Backert S (2017) Helicobacter pylori employs a unique basolateral type IV secretion mechanism for CagA delivery. Cell Host Microbe 22(4):552–560.e5. https://doi.org/10.1016/j.chom.2017.09.005
Thibeaux R, Iraola G, Ferrés I, Bierque E, Girault D, Soupé-Gilbert ME, Picardeau M, Goarant C (2018) Deciphering the unexplored Leptospira diversity from soils uncovers genomic evolution to virulence. Microb Genom 4(1):e000144. https://doi.org/10.1099/mgen.0.000144
Thoduvayil S, Dhandapani G, Brahma R, Devasahayam Arokia Balaya R, Mangalaparthi KK, Patel K, Kumar M, Tennyson J, Satheeshkumar PK, Kulkarni MJ, Pinto SM, Prasad TSK, Madanan MG (2020) Triton X-114 fractionated subcellular proteome of Leptospira interrogans shows selective enrichment of pathogenic and outer membrane proteins in the detergent fraction. Proteomics 20(19–20):e2000170. https://doi.org/10.1002/pmic.202000170
Viana F, Peringathara SS, Rizvi A, Schroeder GN (2021) Host manipulation by bacterial type III and type IV secretion system effector proteases. Cell Microbiol 23(11):e13384. https://doi.org/10.1111/cmi.13384
Vieira ML, Fernandes LG, Domingos RF, Oliveira R, Siqueira GH, Souza NM, Teixeira AR, Atzingen MV, Nascimento AL (2014) Leptospiral extracellular matrix adhesins as mediators of pathogen-host interactions. FEMS Microbiol Lett 352(2):129–139. https://doi.org/10.1111/1574-6968.12349
Villar CC, Kashleva H, Nobile CJ, Mitchell AP, Dongari-Bagtzoglou A (2007) Mucosal tissue invasion by Candida albicans is associated with E-cadherin degradation, mediated by transcription factor Rim101p and protease Sap5p. Infect Immun 75(5):2126–2135. https://doi.org/10.1128/IAI.00054-07
Vincent AT, Schiettekatte O, Goarant C, Neela VK, Bernet E, Thibeaux R, Ismail N, Mohd Khalid MKN, Amran F, Masuzawa T, Nakao R, Amara Korba A, Bourhy P, Veyrier FJ, Picardeau M (2019) Revisiting the taxonomy and evolution of pathogenicity of the genus Leptospira through the prism of genomics. PLoS Negl Trop Dis 13(5):e0007270. https://doi.org/10.1371/journal.pntd.0007270
Waller PR, Sauer RT (1996) Characterization of degQ and degS, Escherichia coli genes encoding homologs of the DegP protease. J Bacteriol 178(4):1146–1153. https://doi.org/10.1128/jb.178.4.1146-1153.1996
Wang J, Dou X, Song J, Lyu Y, Zhu X, Xu L, Li W, Shan A (2019) Antimicrobial peptides: promising alternatives in the post feeding antibiotic era. Med Res Rev 39(3):831–859. https://doi.org/10.1002/med.21542
Wessler S, Schneider G, Backert S (2017) Bacterial serine protease HtrA as a promising new target for antimicrobial therapy? Cell Commun Signal 15(1):1–5
Whelan R, McVicker G, Leo JC (2020) Staying out or going in? The interplay between type 3 and type 5 secretion systems in adhesion and invasion of enterobacterial pathogens. Int J Mol Sci 21(11):4102. https://doi.org/10.3390/ijms21114102
Wroblewski LE, Shen L, Ogden S, Romero-Gallo J, Lapierre LA, Israel DA, Turner JR, Peek RM Jr (2009) Helicobacter pylori dysregulation of gastric epithelial tight junctions by urease-mediated myosin II activation. Gastroenterology 136(1):236–246. https://doi.org/10.1053/j.gastro.2008.10.011
Wu S, Lim KC, Huang J, Saidi RF, Sears CL (1998) Bacteroides fragilis enterotoxin cleaves the zonula adherens protein, E-cadherin. Proc Natl Acad Sci U S A 95(25):14979–14984. https://doi.org/10.1073/pnas.95.25.14979
Wu Z, Nybom P, Magnusson KE (2000) Distinct effects of Vibrio cholerae haemagglutinin/protease on the structure and localization of the tight junction-associated proteins occludin and ZO-1. Cell Microbiol 2(1):11–17. https://doi.org/10.1046/j.1462-5822.2000.00025.x
Wu S, Rhee KJ, Zhang M, Franco A, Sears CL (2007) Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and gamma-secretase-dependent E-cadherin cleavage. J Cell Sci 120(Pt 11):1944–1952. https://doi.org/10.1242/jcs.03455
Wunder EA Jr, Figueira CP, Santos GR, Lourdault K, Matthias MA, Vinetz JM, Ramos E, Haake DA, Picardeau M, Dos Reis MG, Ko AI (2016) Real-time PCR reveals rapid dissemination of Leptospira interrogans after intraperitoneal and conjunctival inoculation of hamsters. Infect Immun 84(7):2105–2115. https://doi.org/10.1128/IAI.00094-16
Xu M, Yamada M, Li M, Liu H, Chen SG, Han YW (2007) FadA from Fusobacterium nucleatum utilizes both secreted and non-secreted forms for functional oligomerization for attachment and invasion of host cells. J Biol Chem 282(34):25000–25009. https://doi.org/10.1074/jbc.M611567200
Yang G, Zhou B, Wang J, He X, Sun X, Nie W, Tzipori S, Feng H (2008) Expression of recombinant Clostridium difficile toxin A and B in Bacillus megaterium. BMC Microbiol 8:192. https://doi.org/10.1186/1471-2180-8-192
Yang KW, Cheng X, Zhao C, Liu CC, Jia C, Feng L, Xiao JM, Zhou LS, Gao HZ, Yang X, Zhai L (2011) Synthesis and activity study of phosphonamidate dipeptides as potential inhibitors of VanX. Bioorg Med Chem Lett 21(23):7224–7227
Zarzecka U, Modrak-Wójcik A, Figaj D, Apanowicz M, Lesner A, Bzowska A, Lipinska B, Pawlik A, Backert S, Skorko-Glonek J (2019) Properties of the HtrA protease from bacterium Helicobacter pylori whose activity is indispensable for growth under stress conditions. Front Microbiol 10:961
Zheng M, Sun S, Zhou J, Liu M (2021) Virulence factors impair epithelial junctions during bacterial infection. J Clin Lab Anal 35(2):e23627. https://doi.org/10.1002/jcla.23627
Acknowledgements
The authors acknowledge the infrastructure facilities provided by CIL-Botany, ISLS, and CDS, BHU.
Funding
PKS acknowledges the project grant support from the Science and Engineering Research Board (SERB), Govt. of India, (Project No. EEQ/2018/000254), IoE grant of Banaras Hindu University, Varanasi (R/Dev/D/loE/incentive /2022-23/47678), and Centre of Advanced Studies, Department of Botany, BHU. PK acknowledges the financial support from the Council of Scientific and Industrial Research (CSIR), India.
Author information
Authors and Affiliations
Contributions
SPK and PK conceived the idea. PK, SY, and SS compiled and analyzed the data. PK and SY did the bioinformatics part of the work. SPK and PK wrote the manuscript. All the authors read the manuscript and agreed to the submission.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Ethical statement
This article does not contain any studies with human participants or animals performed by any of the authors.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Kumari, P., Yadav, S., Sarkar, S. et al. Cleavage of cell junction proteins as a host invasion strategy in leptospirosis. Appl Microbiol Biotechnol 108, 119 (2024). https://doi.org/10.1007/s00253-023-12945-y
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00253-023-12945-y