The Vi Capsular Polysaccharide Enables Salmonella enterica Serovar Typhi to Evade Microbe-Guided Neutrophil Chemotaxis

Wangdi, Tamding; Lee, Cheng Yuk; Spees, Alanna M.; Yu, Chenzhou; Kingsbury, Dawn D.; Winter, Sebastian; Hastey, Christine J.; Wilson, Ronald P.; Heinrich, Volkmar; Bäumler, Andreas J.

doi:10.1371/journal.ppat.1004306

Cited by 64 publications

(72 citation statements)

References 54 publications

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“…A local stimulus acting at the cell surface leads to reorganization of the adjacent cytoskeleton, which in turn creates a pushing force that displaces a membrane patch outward. This basic mechanism is consistent with the cell morphology observed during pure (i.e., cell-substrate-adhesion-free) chemotaxis (9)(10)(11)33). But it also implies that immediately after cell-target contact, a phagocyte should always form a protrusive pseudopod directly underneath the region of contact (where the phagocytosis-triggering stimulus is strongest).…”

Section: ) the Previous Argumentsupporting

confidence: 81%

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Controlled One-on-One Encounters between Immune Cells and Microbes Reveal Mechanisms of Phagocytosis

Heinrich

2015

Biophysical Journal

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Among many challenges facing the battle against infectious disease, one quandary stands out. On the one hand, it is often unclear how well animal models and cell lines mimic human immune behavior. On the other hand, many core methods of cell and molecular biology cannot be applied to human subjects. For example, the profound susceptibility of neutropenic patients to infection marks neutrophils (the most abundant white blood cells in humans) as vital immune defenders. Yet because these cells cannot be cultured or genetically manipulated, there are gaps in our understanding of the behavior of human neutrophils. Here, we discuss an alternative, interdisciplinary strategy to dissect fundamental mechanisms of immune-cell interactions with bacteria and fungi. We show how biophysical analyses of single-live-cell/single-target encounters are revealing universal principles of immune-cell phagocytosis, while also dispelling misconceptions about the minimum required mechanistic determinants of this process.

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Section: ) the Previous Argumentsupporting

confidence: 81%

“…1 B), and have already revealed insight into cellular behavior that had been inaccessible to traditional techniques. (For movies of representative single-live-cell experiments see https://www.youtube.com/user/HeinrichLab or the supplemental videos of (7,(9)(10)(11)(12)). …”

Section: Tight Control Over One-on-one Encounters Between Immune Cellmentioning

confidence: 99%

Controlled One-on-One Encounters between Immune Cells and Microbes Reveal Mechanisms of Phagocytosis

Heinrich

2015

Biophysical Journal

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“…For example, the typical time lag from placing a zymosan particle near a neutrophil to the first sign of a newly forming chemotactic pseudopod was found to be on the order of~60 s (9). Similar results were obtained for bacterial and fungal pathogens (6,8). On the other hand, for the typical cell-target distances (Dr z 5 mm) and target sizes (R z 2.5 mm) used in those experiments, Eq.…”

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confidence: 73%

“…Recent single-cell experiments have validated human neutrophils as uniquely capable biodetectors of minuscule amounts of complement-derived anaphylatoxins in the proximity of microbial and model pathogens ( Fig. 1) (6)(7)(8). But the question just how sensitive these immune cells are was not addressed by earlier studies.…”

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Quantifying the Sensitivity of Human Immune Cells to Chemoattractant

Francis

Heinrich

2017

Biophysical Journal

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The efficient recruitment of immune cells is a vital cornerstone of our defense against infections and a key challenge of immunotherapeutic applications. It relies on the ability of chemotaxing cells to prioritize their responses to different stimuli. For example, immune cells are known to abandon gradients of host-cell-produced cytokines in favor of complement-derived anaphylatoxins, which then guide the cells toward nearby pathogen surfaces. The aptitude to triage stimuli depends on the cells' specific sensitivities to different chemoattractants. We here use human neutrophils as uniquely capable biodetectors to map out the anaphylatoxic cloud that surrounds microbes in the presence of host serum. We quantify the neutrophil sensitivity in terms of the ratio between the chemoattractant concentration c and the production rate j 0 of the chemoattractant at the source surface. An integrative experimental/theoretical approach allows us to estimate the c/j 0 -threshold at which human neutrophils first detect nearby b-glucan surfaces as c/j 0 z 0.0044 s/mm.How does an immune cell cope with situations in which it faces multiple chemotactic stimuli? How does the cell decide on a particular response? Such questions touch on the core of our mechanistic understanding of immune-cell behavior, and have inspired the paradigm that immunotaxis comprises an intricate spatiotemporal hierarchy of distinct chemotactic processes (1-6). The systematic dissection of this hierarchy is an enormous interdisciplinary challenge that requires, among others, quantitative analyses of the stimulus-specific sensitivity of the responding cells.Complement-mediated chemotaxis has emerged as a universal, short-range homing mechanism by which chemotaxing immune cells can implement a last-minute course correction toward pathogenic bacteria and fungi. Recent single-cell experiments have validated human neutrophils as uniquely capable biodetectors of minuscule amounts of complement-derived anaphylatoxins in the proximity of microbial and model pathogens (Fig. 1) (6-8). But the question just how sensitive these immune cells are was not addressed by earlier studies.We here use an integrative theoretical/experimental strategy to tackle this difficult question. A recently found closed-form solution of the appropriate reaction-diffusion problem (V.H., E.A.F., and W.D. Simpson, unpublished data) predicts the spatiotemporal distribution of anaphylatoxins as a function of the time t and the radial distance from the source, Dr ¼ r À R (Fig. 1 B; Supporting Material). In the considered scenario, the source of chemoattractant is a sphere of radius R that, at time t ¼ 0, starts releasing anaphylatoxins at a constant rate given by the boundary flux j 0 . The chemoattractant is redistributed in the surrounding infinite space by diffusion. A realistic estimate gives a diffusion coefficient of D z 130 mm 2 /s for the dominant anaphylatoxin C5a (V.H., E.A.F., and W.D. Simpson, unpublished data). We further model the deactivation of chemoattractant by carboxype...

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“…These pathways involve S. Typhi-specific genes contained within SPI-7. The first mechanism requires the expression of the Vi polysaccharide capsule of S. Typhi, which prevents complement activation and neutrophil-mediated clearance of S. Typhi (43). Furthermore, the Vi antigen also was shown to shield S. Typhi LPS and reduces the TLR4-dependent immune response (12,44).…”

Section: Discussionmentioning

confidence: 99%

Differences in Host Cell Invasion and Salmonella Pathogenicity Island 1 Expression between Salmonella enterica Serovar Paratyphi A and Nontyphoidal S . Typhimurium

et al. 2016

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Active invasion into nonphagocytic host cells is central to Salmonella enterica pathogenicity and dependent on multiple genes within Salmonella pathogenicity island 1 (SPI-1). Here, we explored the invasion phenotype and the expression of SPI-1 in the typhoidal serovar S. Paratyphi A compared to that of the nontyphoidal serovar S. Typhimurium. We demonstrate that while S. Typhimurium is equally invasive under both aerobic and microaerobic conditions, S. Paratyphi A invades only following growth under microaerobic conditions. Transcriptome sequencing (RNA-Seq), reverse transcription-PCR (RT-PCR), Western blot, and secretome analyses established that S. Paratyphi A expresses much lower levels of SPI-1 genes and secretes lesser amounts of SPI-1 effector proteins than S. Typhimurium, especially under aerobic growth. Bypassing the native SPI-1 regulation by inducible expression of the SPI-1 activator, HilA, considerably elevated SPI-1 gene expression, host cell invasion, disruption of epithelial integrity, and induction of proinflammatory cytokine secretion by S. Paratyphi A but not by S. Typhimurium, suggesting that SPI-1 expression is naturally downregulated in S. Paratyphi A. Using streptomycin-treated mice, we were able to establish substantial intestinal colonization by S. Paratyphi A and showed moderately higher pathology and intestinal inflammation in mice infected with S. Paratyphi A overexpressing hilA. Collectively, our results reveal unexpected differences in SPI-1 expression between S. Paratyphi A and S. Typhimurium, indicate that S. Paratyphi A host cell invasion is suppressed under aerobic conditions, and suggest that lower invasion in aerobic sites and suppressed expression of immunogenic SPI-1 components contributes to the restrained inflammatory infection elicited by S. Paratyphi A. Salmonella enterica is a highly diverse and ubiquitous pathogen containing more than 2,600 different serovars classified by their antigenic presentation (1). Salmonella serovars differ by their host specificity and by the clinical syndromes they cause, ranging from asymptomatic carriage to invasive systemic disease. While many nontyphoidal Salmonella (NTS) serovars, such as Typhimurium and Enteritidis, are generalist pathogens with broad host specificity, a few S. enterica serovars, including Typhi, Sendai, and Paratyphi A, are highly adapted to humans. These specialist pathogens, collectively referred to as typhoidal Salmonella serovars, are the causative agents of enteric fever, posing an estimated global annual burden of over 27 million cases, resulting in more than 200,000 deaths (2). While NTS cause inflammatory gastroenteritis that is confined to the terminal ileum and colon in immunocompetent patients, typhoidal serovars do not induce a strong inflammatory response during the initial invasion of the intestinal mucosa (3-5). This noninflammatory phase associated with typhoidal infections is thought to facilitate its dissemination to systemic sites (6).Regardless of the clinical manifestation, both typhoidal and NTS ...

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The Vi Capsular Polysaccharide Enables Salmonella enterica Serovar Typhi to Evade Microbe-Guided Neutrophil Chemotaxis

Cited by 64 publications

References 54 publications

Controlled One-on-One Encounters between Immune Cells and Microbes Reveal Mechanisms of Phagocytosis

Controlled One-on-One Encounters between Immune Cells and Microbes Reveal Mechanisms of Phagocytosis

Quantifying the Sensitivity of Human Immune Cells to Chemoattractant

Differences in Host Cell Invasion and Salmonella Pathogenicity Island 1 Expression between Salmonella enterica Serovar Paratyphi A and Nontyphoidal S . Typhimurium

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