Antibacterial activity of human neutrophil peptide-1 against Mycobacterium tuberculosis H37Rv: in vitro and ex vivo study

Sharma, Sadhna; Verma, Indu; Khuller, G. K.

doi:10.1034/j.1399-3003.2000.16a20.x

Cited by 86 publications

(69 citation statements)

References 14 publications

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“…These data are consistent with reports from Peschel et al, indicating that M. tuberculosis contains a gene or genes related to the MprF gene of Staphylococcus aureus, which mediates resistance to HNP in that species (28). Two groups have reported that HNP-1 can kill M. tuberculosis in vitro (24,32). While we have used HNP from the same sources against the same strains of M. tuberculosis growing in the same medium as these groups, we have not observed mycobactericidal activity of HNP.…”

Section: Discussionsupporting

confidence: 82%

“…If the amount of HNP bound to M. tuberculosis varies with the amount of HNP in the medium, it should be possible to construct a standard curve relating the exposure to HNP to the amount of specific antibody staining. The MIC sufficient to prevent growth of M. tuberculosis has previously been reported to be 2.0 to 2.5 g/ml (32,33). Therefore, we incubated M. tuberculosis (Erdman strain) with HNP-1 at concentrations from 0.1 to 33 g/ml for 24 h at 37°C, after which the tubercle bacilli were quickly washed and fixed in formalin.…”

Section: Fig 3 Lack Of Effect Of Roi or Rni Inhibitors On Killing Bmentioning

confidence: 99%

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Tumor Necrosis Factor Alpha Stimulates Killing ofMycobacterium tuberculosisby Human Neutrophils

Kisich¹,

et al. 2002

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The ability of human neutrophils to aid in defense against pulmonary infection with Mycobacterium tuberculosis is controversial. In this study, we have shown that neutrophils respond to and phagocytose M. tuberculosis in human lesions. Neutrophils from healthy individuals were able to kill significant fractions of an inoculum of M. tuberculosis within 1 h of phagocytosis, and this ability was enhanced by tumor necrosis factor alpha but not by gamma interferon. The mycobactericidal mechanism was nonoxidative, as inhibitors of reactive oxygen or reactive nitrogen intermediates did not interfere with killing. However, the mycobactericidal mechanism was associated with increased exposure of intracellular M. tuberculosis to neutrophil defensins. In vitro, human neutrophil peptides 1 to 3 were not able to kill the bacilli even at much higher levels. These studies support the concept that human neutrophils are directly involved in defense against infection with M. tuberculosis.The observation that humans are not uniformly susceptible to infection by Mycobacterium tuberculosis may imply the existence of resistance mechanisms capable of sterilizing inhaled inoculae which operate independently of acquired immunity. Although studies with rodent models indicate that alveolar macrophages are important for containment of experimental aerogenic infections, it may be necessary to look to other effector cells to understand innate immune mechanisms which protect against human infections.There have been two reports that human neutrophils can kill virulent M. tuberculosis in vitro (5, 18). However, more-recent examinations of this issue have been unable to confirm these results (2, 10). Majeed et al. were able to demonstrate that cultured human neutrophils were able to kill an attenuated strain of M. tuberculosis, H37Ra, in a calcium-dependent manner (21). However, as H37Ra is not known to be virulent for humans, it remains important to resolve the issue of neutrophil capacity to kill virulent M. tuberculosis. Pedrosa et al. have suggested that murine neutrophils are protective against experimental infections of mice, although they found no evidence that the neutrophils phagocytosed the tubercle bacilli (27).The goal of these studies was to understand whether the neutrophil response characteristic of the earliest responses to tuberculosis (TB) infection could be effective in reducing or eliminating the inoculum. To this end, we established a model of in vitro infection of human neutrophils and characterized some of the effector mechanisms which come into play during the response of neutrophils both in vitro and during pulmonary infection of humans. We show that neutrophils in human pulmonary lesions contain intracellular M. tuberculosis, confirming a phagocytic role for neutrophils in human TB. We also show that human neutrophils can kill virulent intracellular M. tuberculosis in vitro, but with variability between individuals. Mycobactericidal activity could be stimulated by exposure of infected neutrophils to tumor necrosis facto...

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Section: Discussionsupporting

confidence: 82%

Section: Fig 3 Lack Of Effect Of Roi or Rni Inhibitors On Killing Bmentioning

confidence: 99%

Tumor Necrosis Factor Alpha Stimulates Killing ofMycobacterium tuberculosisby Human Neutrophils

Kisich¹,

et al. 2002

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“…Among the proteins known to exhibit bactericidal activity against mycobacteria, EPO seems to be the most potent. The other known mycobactericidal proteins, such as defensins (38,43,44), protregrins (35), NK lysins (2), and granulysin (19,48), exhibit significant mycobactericidal activity starting at a concentration of 10 M. After 4 to 5 h, a minimal effect was found, and at least 24 h was required before significant activity of these proteins was observed. Additionally, glutathione and S-nitrosoglutathione are able to kill mycobacteria, but in this case the activity is even weaker, on a molar basis, than the activities of the proteins mentioned above.…”

Section: Discussionmentioning

confidence: 99%

Human Eosinophil Peroxidase Induces Surface Alteration, Killing, and Lysis ofMycobacterium tuberculosis

Borelli¹,

Vita²,

Shankar

et al. 2003

Infect Immun

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The antimycobacterial role of eosinophil peroxidase (EPO), one of the most abundant granule proteins in human eosinophils, was investigated. Our data indicate that purified EPO shows significant inhibitory activity towards Mycobacterium tuberculosis H37Rv. On a molar basis, this activity was similar to that exhibited by neutrophil myeloperoxidase (MPO) and was both dose and time dependent. In contrast to the activity of MPO, which requires H 2 O 2 , EPO also exhibited anti-M. tuberculosis activity in the absence of exogenously added peroxide. Morphological evidence confirmed that the mechanism of action of EPO against mycobacteria differs from that of MPO. While MPO kills M. tuberculosis H37Rv exclusively in the presence of hydrogen peroxide, it does not induce morphological changes in the pathogen. In contrast, EPO-treated bacteria frequently had cell wall lesions and eventually underwent lysis, either in the presence or in the absence of H 2 O 2 .

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“…Other possible substrates of the MmpL proteins are the antimicrobial peptides produced by the host. Antimycobacterial activity has been found in several defensins, such as human and rabbit neutrophil peptide-1 or porcine protegrin (25,44,45). The MtrD protein of Neisseria gonorrhoeae, which is also a member of the RND family, modulates susceptibility to antibacterial peptides (43).…”

Section: Discussionmentioning

confidence: 99%

Contribution of theMycobacterium tuberculosisMmpL Protein Family to Virulence and Drug Resistance

2005

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The genome sequence of Mycobacterium tuberculosis revealed the presence of 12 membrane proteins proposed to have a function in the transport of lipids. Insertional inactivation of 11 of these has revealed that only 1 (MmpL3) is apparently essential for viability. Five of these proteins are conserved within the genome of Mycobacterium leprae. The drug susceptibilities of these 11 mutants to a broad spectrum of agents are unaltered, suggesting that unlike their function in other organisms, these proteins do not play a significant role in intrinsic drug resistance. Each of these mutants was assessed for growth kinetics and lethality in a murine low-dose aerosol model of tuberculosis, and four were found to be impaired in one or both measures of virulence. Two of these, with mutations of MmpL4 and the previously characterized MmpL7, which transports phthiocerol dimycocerosate, were found to have both impaired growth kinetics and impaired lethality. Mutants with inactivation of MmpL8, which transports a precursor of the sulfatides, or MmpL11, which transports an unknown substrate, were found to establish infection normally but to be significantly attenuated for lethality in time-to-death studies. These studies support the concept that MmpL-mediated lipid secretion both contributes to the innate ability of the pathogen to survive intracellularly and also contributes directly to the host-pathogen dialogue that determines the ultimate outcome of infection.

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Antibacterial activity of human neutrophil peptide-1 against Mycobacterium tuberculosis H37Rv: in vitro and ex vivo study

Cited by 86 publications

References 14 publications

Tumor Necrosis Factor Alpha Stimulates Killing ofMycobacterium tuberculosisby Human Neutrophils

Tumor Necrosis Factor Alpha Stimulates Killing ofMycobacterium tuberculosisby Human Neutrophils

Human Eosinophil Peroxidase Induces Surface Alteration, Killing, and Lysis ofMycobacterium tuberculosis

Contribution of theMycobacterium tuberculosisMmpL Protein Family to Virulence and Drug Resistance

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