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GH18 family glycoside hydrolase Chitinase A of Salmonella enhances virulence by facilitating invasion and modulating host immune responses [1]

['Kasturi Chandra', 'Department Of Microbiology', 'Cell Biology', 'Indian Institute Of Science', 'Bangalore', 'Atish Roy Chowdhury', 'Ritika Chatterjee', 'Dipshikha Chakravortty', 'Centre For Biosystems Science', 'Engineering']

Date: 2022-07

Salmonella is a facultative intracellular pathogen that has co-evolved with its host and has also developed various strategies to evade the host immune responses. Salmonella recruits an array of virulence factors to escape from host defense mechanisms. Previously chitinase A (chiA) was found to be upregulated in intracellular Salmonella. Although studies show that several structurally similar chitinases and chitin-binding proteins (CBP) of many human pathogens have a profound role in various aspects of pathogenesis, like adhesion, virulence, and immune evasion, the role of chitinase in the intravacuolar pathogen Salmonella has not yet been elucidated. Therefore, we made chromosomal deletions of the chitinase encoding gene (chiA) to study the role of chitinase of Salmonella enterica in the pathogenesis of the serovars, Typhimurium, and Typhi using in vitro cell culture model and two different in vivo hosts. Our data indicate that ChiA removes the terminal sialic acid moiety from the host cell surface, and facilitates the invasion of the pathogen into the epithelial cells. Interestingly we found that the mutant bacteria also quit the Salmonella-containing vacuole and hyper-proliferate in the cytoplasm of the epithelial cells. Further, we found that ChiA aids in reactive nitrogen species (RNS) and reactive oxygen species (ROS) production in the phagocytes, leading to MHCII downregulation followed by suppression of antigen presentation and antibacterial responses. Notably, in the murine host, the mutant shows compromised virulence, leading to immune activation and pathogen clearance. In continuation of the study in C. elegans, Salmonella Typhi ChiA was found to facilitate bacterial attachment to the intestinal epithelium, intestinal colonization, and persistence by downregulating antimicrobial peptides. This study provides new insights on chitinase as an important and novel virulence determinant that helps in immune evasion and increased pathogenesis of Salmonella.

Salmonella is one of the major foodborne pathogens that cause enteric diseases in humans and other mammals. Although Salmonella-mediated enteric illnesses can be treated, the high occurrences of drug-resistant strains challenge pathogen eradication. The human gastrointestinal tract is covered with two distinct types of glycan layers- mucin and complex oligosaccharides (glycocalyx) that protect the enterocytes from the environment [ 1 ]. An enteric pathogen, like Salmonella, should be able to cleave the mucinous layer to gain access to the enterocytes. In various human pathogens, glycoside hydrolases such as sialidases, muraminidases, glucosaminidases, pullulanases, N-acetylgalactosaminidases (GalNAcases), etc. are known to facilitate the bacterial attachment to the host cells [ 2 ]. GH18 family protein chitinases and chitin-binding proteins were also found to be involved in the pathogenesis of several human enteric (Vibrio cholerae, Listeria monocytogenes, Serratia marcescens) [ 3 – 7 ] and non-enteric pathogens (Pseudomonas aeruginosa, Legionella pneumophila) [ 8 – 10 ]. During the infections caused by these pathogens, the commonality of a mucin-rich host-pathogen interface hinted towards a potentially significant role of chitinases and chitin-binding proteins in breaching the mucosal barrier. Furthermore STM0018 encoded chitinase from Salmonella Typhimurium strain SL1344 has been implicated in cleaving β1–6 linked LacdiNAc molecules (prevalent on mammalian glycome and invertebrate glycans) along with other chitin-like chains containing β1–4 linkages [ 11 , 12 ]. However, chitinase from Salmonella Typhimurium str. LT2 did not have any effect on pathogenesis [ 13 ]. Salmonella causes infection in the gut mucosal region, which also has a protective mucinous layer. A BLAST search revealed that Salmonella Typhimurium exochitinase ChiA (encoded by STM14_0022) showed 20–40% identity with the abovementioned pathogenic proteins. Further, Salmonella Typhi chitinase (ChiA; STY0018) is 98% similar to the S. Typhimurium SL1344 chiA (STM0018) that was reported to be upregulated in the infected macrophages and epithelial cells [ 14 – 16 ].

Since we observed that Salmonella uses chitinase to colonize chitin-rich organs ( Fig 6D ), such as the terminal bulb, the essential structure that breaks down bacterial cells to provide nutrition to the worms, we next looked into the nutritional state of the worms by counting the number of pharyngeal pumps per min. We found a gradual yet profound reduction in the number of pharyngeal pumps/min after 72 hours of STY WT and STY ΔchiA:chiA infection, beginning as early as 24hpi, while STY ΔchiA infected worms did not show pumping defect until 72hpi ( Fig 7B ). In vivo oxidative stress due to pathogen infection was quantified using CL2166 worms, that possess oxidative stress-inducible GFP. STY WT and STY ΔchiA:chiA infected worms showed significantly higher oxidative stress and ‘bag of worms’ phenotype ( S4C and S4D Fig ). Furthermore, we observed significantly less fat storage in worms infected with STY WT and STY ΔchiA:chiA in comparison to STY ΔchiA strain ( Figs 7C and S4E ). It has been reported that oxidative stress (high ROS), nutritional stress, and pathogen attack can induce the MAPK pathway in the worms, leading to apoptosis [ 35 , 36 ]. Therefore, we checked the level of phosphor-p38 and the RNA expression of several effector genes that are downstream of the MAPK pathway. Although phosphor-p38 MAPK (PMK-1) was upregulated in all three STY strains infected worms, equal transcriptional downregulation of pmk1 and mek1 was observed ( S4F and S4G Fig ) and PMK-1 regulated antimicrobial peptides were differentially expressed. While the expression of MAPK regulated antimicrobial peptide genes clec85, lys7, ilys2 was downregulated in STY WT, STY ΔchiA and STY ΔchiA:chiA infected worms, their expression was partially rescued in the worms infected with STY ΔchiA bacteria ( Fig 7D ). Interestingly, STY ΔchiA infection completely rescued spp1 expression and significantly upregulated abf2 expression ( Fig 7E ), indicating an important function of chitinase in restricting the antimicrobial responses of the host.

Although Salmonella Typhi is an obligatory human pathogen that does not cause a significant infection in mice because of the presence of TLR11, however use of Tlr11 -/- mouse model has been reported to be largely inconsistent [ 30 , 31 ]. Long before the Tlr11 -/- mice model came into existence, Labrousse et al. suggested Caenorhabditis elegans could be used as an alternative host to study S. Typhi pathogenesis [ 32 ]. Given that C. elegans pharyngeal lumen is rich in chitin and chitinase substrate molecules, it served as a suitable host to study the role of chitinase in bacterial pathogenesis [ 33 ]. We checked the bacterial CFU in the infected worms after 24 hours (24hpi) and 48 hours (48hpi) of continuous feeding and found that the STY ΔchiA and STY ΔchiA:pQE60 strains showed a higher bacterial burden at 24hpi ( S3H Fig ), but the fold proliferation (CFU at 48hpi/CFU at 24hpi) of STY ΔchiA was lesser than that of the STY WT and STY ΔchiA:chiA strains ( Fig 6A ). Although these Salmonella Typhi strains were lethal to the nematodes, STY ΔchiA infected worms showed slower death (TD 50 330±8hrs) as compared to the STY WT (TD 50 190±10hrs) and STY ΔchiA:chiA (TD 50 270±12hrs) strains ( Fig 6B ). Together these data suggest that chitinase deletion reduces the virulence of Salmonella Typhi in C. elegans. We further checked bacterial colonization in the worm’s gut using the transgenic worm FT63 strain that expresses GFP in the epithelial cells. S. Typhi ΔchiA showed less colonization than STY WT at 24hpi, while the colonization was significantly reduced at 48hpi ( Fig 6C ). Several human pathogens such as Salmonella sp. and Pseudomonas aeruginosa have been reported to colonize the nematode gut lumen and cause gut distension [ 34 ]. Percent colonization as an indicator of gut distension was measured as the ratio of the diameter of the lumen occupied by the bacteria to the total diameter of the gut ( S3I Fig ). We next checked if S. Typhi utilizes chitinase to colonize the chitin-rich pharyngeal lumen by infecting N2 wildtype worms with different strains of Salmonella and stained the chitin-rich parts of the worms using eosin Y. Interestingly, after 24 hours of infection, luminal STY WT and STM ΔinvC bacteria, but not STY ΔchiA, colocalized with the chitin-rich regions of the pharyngeal wall and terminal bulb (grinder; Fig 6D ), indicating that Salmonella Typhi utilizes chitinase to colonize the chitin-rich pharynx and terminal bulb. Additionally, after 24 hours of feeding on STY ΔchiA followed by 24 hours feeding on E. coli OP50, the STY ΔchiA was unable to persist in the gut, whereas STY WT showed significantly higher colonization in the pharyngeal lumen ( S3J Fig ). Extended infection for 48 hours, followed by 24 hours of E. coli OP50 feeding revealed that STY WT could profoundly colonize the gut lumen, while STY ΔchiA colonization was diminished ( Fig 6E ). Interestingly, after 24 hours of continuous feeding, STY WT and STM ΔinvC were found attached to the luminal wall leading to extra-intestinal tissue invasion, but not STY ΔchiA. ( Figs 7A and S4A and S4B ), suggesting that chitinase might be required to invade extra-intestinal tissues of the worms. To the best of our knowledge, this study is the first report suggesting an extra-intestinal invasion/colonization by Salmonella Typhi in C. elegans.

To delineate the role of chitinase in Salmonella infection in vivo, we orally infected C57BL/6J mice with 10 8 CFU of bacterial strains and monitored animal survival. The STM ΔchiA infected animals showed enhanced survival than the STM WT infected cohort ( Fig 5A ). We also found that STM ΔchiA bacteria were shed in the feces prior to the STM WT and the ΔchiA mutant was defective in Peyer’s patches (PP) colonization at 2 hpi ( Fig 5B and 5C ). Further, we orally infected C57BL/6J mice with a sublethal dose of Salmonella strains (10 7 CFU/animal) and bacterial CFU from the liver, spleen, mesenteric lymph node (MLN), and PP were enumerated. We found that STM ΔchiA mutant infected animals showed less bacterial burden in each organ and bodyweight reduction than the STM WT infected animals ( Fig 5D–5H ). Additionally, STM ΔchiA infected mice showed a significantly reduced burden till 20 days post-infection (dpi; S3A and S3B Fig ). We also found significantly enlarged spleens in STM ΔchiA infected mice 20 dpi ( S3C and S3D Fig ). We previously showed that STM ΔchiA infected spleens harbored fewer bacteria ( Fig 5E ); therefore, we hypothesized that STM ΔchiA infection leads to T cell activation and enlargement of the spleens. To validate this hypothesis and our ex vivo data showing the correlation between reduced NO induction and higher T cell activation by ΔchiA mutant, we isolated total splenocytes from the spleens of the STM ΔchiA infected animals and quantified the CD4 + CD25 + T cell population by flow cytometry. Interestingly, we found that STM ΔchiA infection leads to a significant increase in the CD4 + and CD25 + T cells, as well as the double-positive CD4 + CD25 + T cell population ( Fig 5I ). Analysis of T cell-mediated cytokine response revealed a significant increase in the pro-inflammatory cytokines IL-2 and IFN-γ in the serum isolated from ΔchiA infected animals ( Fig 5J and 5K ), while no difference was observed in the anti-inflammatory cytokine levels ( S3E and S3F Fig ). Previous reports suggested that high IFN-γ can induce B cell proliferation and enhance IgG2a and IgG3 production [ 29 ]. Therefore, we quantified the anti-Salmonella IgG titer from infected mice serum. Interestingly, we found a significant increase in the anti-Salmonella IgG titer in the serum obtained from STM ΔchiA infected cohort ( Fig 5L ). We further used the polyclonal convalescent sera from STM ΔchiA infected mice to probe against STM WT-mCherry whole cell lysate to test the reactivity of the sera. Multiple dense bands against various Salmonella proteins were obtained after incubating the membrane with sera collected from STM ΔchiA mutant infected cohort ( S3G Fig ). Together these data suggest that Salmonella chitinase A is essential for restricting innate and humoral immune responses in vivo.

After establishing a successful niche in the epithelial cells, Salmonella transcytoses to the lamina propria (LP) and infects the LP-resident macrophages and dendritic cells [ 28 ]. To understand the role of chitinase in phagocytic cell infection, we infected U937 monocytes and bone-marrow derived dendritic cells (BMDCs). Although the ΔchiA mutants were phagocyted less by U937 monocytes, they showed enhanced survival compared to the WT strains ( Fig 4A–4D and S2A and S2B ). While STM WT and STM ΔchiA were phagocytosed equally, STY ΔchiA showed increased phagocytosis and better survival in BMDCs than STY WT ( Figs 4E–4H and S2C and S2D ). We detected significantly less nitric oxide (NO) in the spent media from the ΔchiA mutant infected BMDCs ( Fig 4I ). Interestingly, both WT and ΔchiA mutant bacteria survived equally in NOS2 -/- BMDCs ( Fig 4J and 4K ). Furthermore, ΔchiA infected peritoneal macrophages (PM) showed significantly less ROS level than the WT bacteria-infected cells ( Fig 4L ), indicating that chitinase might be regulating RNI and ROS levels in the infected cells. To check the effect of NO on antigen presentation and T cell expansion, we quantified CD8 + T cell proliferation using OT1 transgenic mouse (C57BL/6-Tg(TcraTcrb) 1100Mjb/J). The TCR of this transgenic mouse recognizes OVA 257-264 when presented by MHC-I molecules. This TCR recognition of MHC-I bound cognate peptide results in CD8 + T cell proliferation that can be measured by incorporation of 3 H thymidine in the DNA of the proliferating population. We found that ΔchiA mutant infected BMDCs significantly expanded CD8 + T cells in response to the antigen stimulation ( Fig 4M ). Since macrophages and DCs possess MHC-I and MHC-II on the cell surface to induce CD8 + and CD4 + T cells population, respectively, we detected the surface MHC-II molecules on activated PMs. We found a significant reduction in the surface MHC-II level with WT infection, but not in ΔchiA infection ( Figs 4N and 4O and S2E and S2F ), indicating that Salmonella ChiA facilitates pathogen survival by dampening host antimicrobial responses.

Since several reports suggested that disruption of Salmonella-containing vacuoles (SCVs) leads to bacterial hyperproliferation in the cytoplasm of the epithelial cells [ 24 ], we checked the intracellular niche of the bacteria in the infected Caco-2 cells. Early SCVs contain early endosomal markers, such as EEA1, Rab4, Rab5, and transferrin receptors, etc., while the late maturation phase is marked by late endosomal markers LAMP1/2, Rab7, Rab11, and vATPases [ 25 ]. Interestingly, ΔchiA mutant bacteria did not colocalize with the late-endosomal marker LAMP1 at 16 hpi ( Figs 3A and S1G and S1H ), suggesting disruption of SCVs in the ΔchiA mutant bacteria-infected cells. Upon counting the number of SCV-bound and cytoplasmic bacterial population, we found that 81.6±0.03% of STM ΔchiA and 87.2±0.05% of STY ΔchiA quit the vacuolar niche compared to the WT bacteria (STM WT 12.2±0.04%, STY WT 8.2±0.03%; Fig 3B and 3C ). We also found that EEA1, an early endosomal marker, remained associated with the SCVs in WT and ΔchiA mutant infected Caco-2 cells at 15–120 mpi, while LAMP1 did not colocalize with the bacteria at early time points (15–30 mpi; Figs 3D and S1I ). It is known that the cytoplasmic bacteria that escape xenophagy, can hyper-replicate in the cytosol of the epithelial cells [ 26 ]. Therefore, we enumerated the cytosolic population by chloroquine (CHQ) resistance assay. Upon transportation into the SCVs by proton pumps present on the SCV membrane, CHQ increases the vacuolar pH and kills the vacuolar Salmonella, while the cytosolic bacteria remain viable [ 27 ]. Notably, we found a significantly higher number of cytosolic mutant bacteria at 16 hpi ( Fig 3E and 3F ), suggesting that chitinase deletion leads to SCV disruption in epithelial cells and hyper-proliferation in the cytoplasm.

Discussion

Salmonella is a facultative intracellular human pathogen that has co-evolved with its host and has also developed various strategies to evade the host’s immune responses. Although Salmonella pathogenesis is governed by classical virulence factors such as adhesins, invasins, and toxins, emerging reports suggest that various unique metabolic proteins are important in various aspects of Salmonella pathogenesis. Several reports suggest that Salmonella can utilize a large pool of chemically diverse host nutrients, such as carbohydrates, lipids, amino acids, etc. [37]. Bacterial chitinases belong to GH18 and GH19, which are getting recognized as bacterial virulence factors along with several other structurally similar glycosidases such as sialidases, muraminidases, N-acetylgalactosaminidases, etc. [2]. Although Salmonella chiA was upregulated during infection, the role of this chitinase in Salmonella pathogenesis remains elusive. To answer this question, we generated isogenic ΔchiA mutant by the one-step gene inactivation method. Interestingly, we found that the mutant was invasion defective in epithelial cells. Salmonella injects several Salmonella pathogenicity island-1 (SPI1) effectors to induce bacterial entry into the epithelial cells [38]. Interestingly, the expression of two major SPI-1 encoded genes invF and hilA was significantly higher in the STM ΔchiA mutant strain, indicating that the bacteria overexpress these effectors to counter the lack of ChiA. Previous reports suggested that Salmonella remodels the host cell surface glycans to facilitate invasion in the epithelial cells [17–19]. Our observations from the lectin-binding assay indicate that chitinase aids in glycan remodeling by cleaving the terminal glycosyl molecules and making the mannose residues accessible to the bacteria for binding. We also found that ΔchiA mutants remain encased in SCVs as seen by EEA1-SCV colocalization at 15 mpi in Caco-2 cells until 10 hpi as seen by LAMP1-SCV colocalization, and after which the mutants escape the SCV and hyper-proliferate in the host cell cytoplasm. One conceivable explanation for this phenomenon could be limited nutrient availability. Salmonella utilizes an extended network of tubular vacuolar structures, known as Salmonella-induced filaments (SIFs), to acquire nutrients from the host cell cytoplasm [39]. SifA, a component of SIFs, interacts with SifA-Kinesin interacting protein (SKIP) to facilitate the recruitment of the motor protein kinesin-1 on the SCVs [40]. Interestingly, kinesin-1 and several other kinesin-like proteins (KIF18A, KIF17b, etc.) are heavily glycosylated, phosphorylated, and sumoylated post-translationally, and often the N-acetylglucosamine (GlcNAc) residues block the phosphorylation sites leading to disruption of the mobility of these motor proteins [41]. It is conceivable that chitinase being a glycoside hydrolase, could remove the GlcNAc residue to facilitate phosphorylation and mobility of the motor proteins. Therefore, in the strain lacking ChiA, this mobility is affected, leading to nutritional stress and quitting of the vacuoles. Additionally, the ΔchiA mutants were protected from phagocytes-mediated bacterial killing since the mutant bacteria-infected phagocytes showed reduced oxidative burst. NO is an important cell signaling molecule, produced against many human pathogens, such as Salmonella, Mycobacterium, Listeria, etc. [42]. Previous studies suggested that a low level of NO enhances T cell survival [43], while very high [NO] inhibit T cell proliferation [44]. Previous literature suggests that mammals also possess several GH18 family enzymes. Among these, chitotriosidase, acidic mammalian chitinase (true chitinases), and BRP-39/YKL-40 (CHI3L1; a chitinase-like protein or CLP) may have chitin-like targets and can modulate host immune responses during infections, allergy, tissue injury, inflammation, and tumor. Furthermore, BRP-39 was found to activate DCs and T cells and induce Th2 inflammatory responses [45]. Interestingly, CHI3L1 neutralization in vivo reduced Salmonella Typhimurium load in the peripheral organs, indicating a definitive role of this CLP in immune modulation during Salmonella pathogenesis [46]. Additionally, Ma et al. showed that CHI3L1 is a potent stimulator of lymphocyte activation gene 3 protein (LAG3), which in turn inhibits T cell activation [47]. Chitinase being a member of the same enzyme class, we can theorize that similar activities could be performed by chitinase as well. We also found that ChiA was important for downregulating the MHC-I molecules on the dendritic cells, leading to the inhibition of CD8+ T cell proliferation and subsequent antigen presentation. In coherence with the available literature [44], the enhanced T cell proliferation could be attributed to the absence of NO induction by the ΔchiA mutant strains. We further showed that the absence of chiA failed to downregulate the surface MHC-II molecules on the activated macrophages, which is a well-known phenomenon during Salmonella infection [48]. Existing literatures suggest that SPI-2 effector SteD stimulates E3 ubiquitin ligase MARCH8 mediated ubiquitination of MHCII, leading to its degradation and suppression of T cell-mediated adaptive immune responses [49,50]. Interestingly, MHCs also have complex glycosylation marks that often end with a terminal sialic acid residue [51]. The glycosylation status of MHC-I can regulate its structure, activity, stability, trafficking and spacing. Glc1Man9GlcNAc2 glycosylation on the MHC-I molecules facilitates its interaction with calnexin and calreticulin and regulates its folding and assembly, whereas improper interactions lead to MHC-I retention in the endoplasmic reticulum [52]. Therefore, further investigation is required to understand whether the glycoside hydrolase activity of chitinase could also contribute to the inhibition of endosomal recycling and MHC replenishment on the cell membrane. In vivo infection in C57BL/6 mice suggested that STM ΔchiA mutant could not invade the PP, leading to an early fecal shedding, a lower bacterial burden in different organs, enhanced pathogen clearance and increased host survival. Additionally, the sustained innate activated IFNγ production could be attributed to iNOS-mediated signaling in ΔchiA mutant infected mice [53]. Bhat et al. suggested that enhanced IFNγ production by cytotoxic CD8+ T cells can facilitate T cell mobility, proliferation, and cytolytic function during viral infection and cancer [54]. Analysis of total splenic lymphocytes by flow cytometry suggested that the ΔchiA mutant infected mice had an increased activated T cell population (CD4+CD25+) in the spleens, suggesting an intensified immune response in these mice. However, this needs to be explored further since Salmonella is known to induce immune tolerance in the chicken intestine by upregulating CD4+CD25+ regulatory T cells [55]. Activation of the adaptive immune responses was corroborated by significant increment in the pro-inflammatory cytokines and anti-STM IgG antibody titer in the STM ΔchiA infected mice sera. Invertebrates also possess a chitinase substrate, LacdiNAc, as cell surface glycans [11,12]. By infecting C. elegans with STY strains, we further showed that chitinase aids in bacterial attachment to the pharyngeal lumen as well as colonization and persistence in the worms. In addition, our data suggest that Salmonella Typhi chitinase might be important for extra-intestinal tissue invasion in the worms. Although the nematodes lack phagocytes-like specialized immune cells, during pathogen infections, C. elegans produce ROS, often localized to the host-pathogen interface [56]. Oxidative stress caused by pathogen infection and nutrient starvation leads to the worm bagging, which is the internal egg hatching [57]. This phenomenon was described by Aballay et al. in the case of Salmonella Typhimurium infection [34]. Our data suggest that Salmonella infection induces oxidative stress, leading to “bag of worms” formation. The host also employs the ROS detox system which is transcriptionally regulated by SKN-1 and DAF-16. SKN-1 induction and its nuclear localization is regulated by the p38 MAPK signaling pathway, which is comprised of NSY-1 (MAPKKK; ASK-1 homolog), SEK-1 (MAPKK) and PMK-1 (MAPK; p38 homolog) [58,59]. Although phospho-p38 (PMK-1) was increased in STY infection, this further validates that ROS induction leads to p38 activation and apoptosis [36]. Furthermore, Salmonella was reported to induce programmed cell death in germline cells by the LPS-Tol1 axis [35]. p38 MAPK pathway and DAF-16 also regulate antimicrobial response in C. elegans as the major defense mechanism. Among these, lysozyme family (LYS), Ascaris suum antibacterial factor family (ABF), saposin-like proteins family (SPP), and C-type lectins family (CLEC) have been shown to play an important role in the induced immune responses to bacterial infection [60]. We found significantly higher expression of fat-responsive antimicrobial peptides genes spp1 and abf2 when the worms were infected with the STY ΔchiA strain. SPP1 and ABF2 are predominantly found in the intestine and on the grinder, respectively [61], both of which are the sites of Salmonella attachment as found in this study. Together these data indicate a potential role of chitinase in modulating the innate immune response in the worms.

In summary, our results reveal that the glycoside hydrolase ChiA plays a wide range of crucial, although not indispensable, functions during Salmonella pathogenesis. Although speculative at this stage, some of our findings can be attributed to the moonlighting activity of chitinase and require further investigation regarding the structural and biochemical properties of this protein. Collectively, we showed that Salmonella Chitinase regulates different aspects of pathogenesis, ranging from aiding in invasion in the epithelial cells, impairing the activity of professional antigen-presenting cells to as diverse as immune response regulation in various hosts (Fig 7F), and emerges as a novel virulence factor.

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