Matrix metalloproteinases with gelatinolytic activity induced by <i>Paracoccidioides brasiliensis</i> infection

Nishikaku, Angela Satie; Ribeiro, Luciana Cristina; Molina, Raphael Fagnani Sanchez; Albe, Bernardo Paulo; Cunha, Cláudia da Silva; Burger, Eva

doi:10.1111/j.1365-2613.2009.00663.x

Cited by 24 publications

(21 citation statements)

References 27 publications

(64 reference statements)

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“…The metalloproteinases MMP-2 and MMP-9 in particular are especially important in DCs migration, since they cleave collagen IV, a major component of basement membranes (Ratzinger et al, 2002; Vermaelen et al, 2003; Chiyasu et al, 2004). Several pathogens have been reported to induce the production and activation of MMP-9 by host cells to open the way through tissue and thereby to facilitate dissemination within the host (Luplertlop et al, 2006; Ramu et al, 2008; Nishikaku et al, 2009; Marsac et al, 2011). Therefore, we next investigated whether S. pneumoniae might exploit the DC-derived proteolysis to enhance its dissemination from the lungs to the regional lymph nodes.…”

Section: Resultsmentioning

confidence: 99%

Lung dendritic cells facilitate extrapulmonary bacterial dissemination during pneumococcal pneumonia

Rosendahl¹,

Bergmann²,

Hammerschmidt³

et al. 2013

Front. Cell. Infect. Microbiol.

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Streptococcus pneumoniae is a leading cause of bacterial pneumonia worldwide. Given the critical role of dendritic cells (DCs) in regulating and modulating the immune response to pathogens, we investigated here the role of DCs in S. pneumoniae lung infections. Using a well-established transgenic mouse line which allows the conditional transient depletion of DCs, we showed that ablation of DCs resulted in enhanced resistance to intranasal challenge with S. pneumoniae. DCs-depleted mice exhibited delayed bacterial systemic dissemination, significantly reduced bacterial loads in the infected organs and lower levels of serum inflammatory mediators than non-depleted animals. The increased resistance of DCs-depleted mice to S. pneumoniae was associated with a better capacity to restrict pneumococci extrapulmonary dissemination. Furthermore, we demonstrated that S. pneumoniae disseminated from the lungs into the regional lymph nodes in a cell-independent manner and that this direct way of dissemination was much more efficient in the presence of DCs. We also provide evidence that S. pneumoniae induces expression and activation of matrix metalloproteinase-9 (MMP-9) in cultured bone marrow-derived DCs. MMP-9 is a protease involved in the breakdown of extracellular matrix proteins and is critical for DC trafficking across extracellular matrix and basement membranes during the migration from the periphery to the lymph nodes. MMP-9 was also significantly up-regulated in the lungs of mice after intranasal infection with S. pneumoniae. Notably, the expression levels of MMP-9 in the infected lungs were significantly decreased after depletion of DCs suggesting the involvement of DCs in MMP-9 production during pneumococcal pneumonia. Thus, we propose that S. pneumoniae can exploit the DC-derived proteolysis to open tissue barriers thereby facilitating its own dissemination from the local site of infection.

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Section: Resultsmentioning

confidence: 99%

Lung dendritic cells facilitate extrapulmonary bacterial dissemination during pneumococcal pneumonia

Rosendahl¹,

Bergmann²,

Hammerschmidt³

et al. 2013

Front. Cell. Infect. Microbiol.

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“…NO deficiency was also associated with organized granulomas of i.p. infected mice [28], while exacerbated inflammatory reactions and cytokines production was described in i.v. infected mice [29].…”

Section: Introductionmentioning

confidence: 97%

TNF-α and CD8+ T Cells Mediate the Beneficial Effects of Nitric Oxide Synthase-2 Deficiency in Pulmonary Paracoccidioidomycosis

et al. 2013

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BackgroundNitric oxide (NO), a key antimicrobial molecule, was previously shown to exert a dual role in paracoccidioidomycosis, an endemic fungal infection in Latin America. In the intravenous and peritoneal models of infection, NO production was associated with efficient fungal clearance but also with non-organized granulomatous lesions. Because paracoccidioidomycosis is a pulmonary infection, we aimed to characterize the role of NO in a pulmonary model of infection.Methodology/Principal FindingsC57Bl/6 wild type (WT) and iNOS−/− mice were i.t. infected with 1×106 Paracoccidioides brasiliensis yeasts and studied at several post-infection periods. Unexpectedly, at week 2 of infection, iNOS−/− mice showed decreased pulmonary fungal burdens associated with an M2-like macrophage profile, which expressed high levels of TGF-β impaired ability of ingesting fungal cells. This early decreased fungal loads were concomitant with increased DTH reactions, enhanced TNF-α synthesis and intense migration of activated macrophages, CD4+ and CD8+ T cells into the lungs. By week 10, iNOS−/− mice showed increased fungal burdens circumscribed, however, by compact granulomas containing elevated numbers of activated CD4+ T cells. Importantly, the enhanced immunological reactivity of iNOS−/− mice resulted in decreased mortality rates. In both mouse strains, depletion of TNF-α led to non-organized lesions and excessive influx of inflammatory cells into the lungs, but only the iNOS−/− mice showed increased mortality rates. In addition, depletion of CD8+ cells abolished the increased migration of inflammatory cells and decreased the number of TNF-α and IFN-γ CD4+ and CD8+ T cells into the lungs of iNOS−/− mice.Conclusions/SignificanceOur study demonstrated that NO plays a deleterious role in pulmonary paracoccidioidomycosis due to its suppressive action on TNF-α production, T cell immunity and organization of lesions resulting in precocious mortality of mice. It was also revealed that uncontrolled fungal growth can be overcome by an efficient immune response.

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“…It is well known that the chronicity of wounds is related to elevated levels of MMPs. The role of MMPs, especially of MMP‐9 or MMP‐2, has been implicated in the pathogenesis of several infectious diseases . Several groups demonstrate that delayed healing is characterized by an increase in MMPs, a decrease in tissue inhibitors of MMPs, and a reduction in some growth factors.…”

Section: Resultsmentioning

confidence: 99%

Novel protease‐based diagnostic devices for detection of wound infection

Heinzle

Papen-Botterhuis²,

Schiffer

et al. 2013

Wound Repair Regeneration

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A gelatinase-based device for fast detection of wound infection was developed. Collective gelatinolytic activity in infected wounds was 23 times higher (p ≤ 0.001) than in noninfected wounds and blisters according to the clinical and microbiological description of the wounds. Enzyme activities of critical wounds showed 12-fold elevated enzyme activities compared with noninfected wounds and blisters. Upon incubation of gelatin-based devices with infected wound fluids, an incubation time of 30 minutes led to a clearly visible dye release. A 32-fold color increase was measured after 60 minutes. Both matrix metalloproteinases and elastases contributed to collective gelatinolytic enzyme activity as shown by zymography and inhibition experiments. The metalloproteinase inhibitor 1,10-phenanthroline (targeting matrix metalloproteinases) and the serine protease inhibitor phenylmethlysulfonyl fluoride (targeting human neutrophil elastase) inhibited gelatinolytic activity in infected wound fluid samples by 11-37% and 60-95%, respectively. Staphylococcus aureus and Pseudomonas aeruginosa, both known for gelatinase production, were isolated in infected wound samples.

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Matrix metalloproteinases with gelatinolytic activity induced by Paracoccidioides brasiliensis infection

Cited by 24 publications

References 27 publications

Lung dendritic cells facilitate extrapulmonary bacterial dissemination during pneumococcal pneumonia

Lung dendritic cells facilitate extrapulmonary bacterial dissemination during pneumococcal pneumonia

TNF-α and CD8+ T Cells Mediate the Beneficial Effects of Nitric Oxide Synthase-2 Deficiency in Pulmonary Paracoccidioidomycosis

Novel protease‐based diagnostic devices for detection of wound infection

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