Immunostimulation in the era of the metagenome

Proal, Amy D.; Albert, Paul; Blaney, Greg P.; Lindseth, Inge; Benediktsson, Chris; Marshall, Trevor G

doi:10.1038/cmi.2010.77

Cited by 24 publications

(14 citation statements)

References 132 publications

(141 reference statements)

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“…Furthermore, the same mice prophylactically treated with the ODN resisted MRSA infection. Treatments aimed at restoring the host's immune function have been shown to be effective for preventing the onset of infections in immunocompromised hosts; 24 , 25 , 26 , 27 , 28 , 29 however, the control of MRSA infection using immunologically acting substances remains limited. In our studies, the growth of MRSA was shown to be minimal in the blood and other organs of 25% TBSA burn mice therapeutically treated with the ODN.…”

Section: Discussionmentioning

confidence: 99%

Macrophage polarization and MRSA infection in burned mice

et al. 2016

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Mortality associated with Staphylococcus aureus infection remains high during the sub-acute phase of burn injury. In this study, we aimed to improve antibacterial resistance of sub-acutely burned mice through macrophage polarization. Sepsis did not develop in mice at the sub-acute phase of 5% total body surface area (TBSA) burn after being infected with methicillin-resistant S. aureus (MRSA), and M1 macrophages (interleukin (IL)-10IL-12 inducible nitric oxide synthase Mφ) were isolated from these mice. In contrast, predominantly M2b macrophages (C-C motif chemokine ligand 1 (CCL1)IL-10IL-12 Mφ) were isolated from mice with >15% TBSA burn, and all of these mice died after the same MRSA infection. Comparing NOD scid gamma mice inoculated with Mφ with 25% TBSA burns, all mice treated with CCL1 antisense oligodeoxynucleotide (ODN) survived after MRSA infection, whereas all untreated mice given the same infection died within 4 days. CCL1 antisense ODN has been characterized as a specific polarizer of M2bMφ. M1Mφ were isolated from MRSA-infected mice with 25% TBSA burn after treatment with CCL1 antisense ODN, and these mice were shown to be resistant against a lethal dose of MRSA infection. M1Mφ were also isolated from 25% TBSA-burned mice infected with MRSA when the ODN was administered therapeutically, and subsequent sepsis was effectively controlled in these mice. These results indicate that the M2bMφ polarizer is beneficial for controlling MRSA infection in mice at the sub-acute phase of severe burn injury.

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Section: Discussionmentioning

confidence: 99%

Macrophage polarization and MRSA infection in burned mice

et al. 2016

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“…(299–309)]; they may also be detected ultramicroscopically [e.g., Ref. (139–141, 190, 267, 300, 310)] or by flow cytometry (311), and dormant blood and tissue microbes probably underpin a great many chronic, inflammatory diseases normally considered to lack a microbial component (139–141, 144–147, 190, 267, 268, 302, 312–321). Multiple arguments serve to exclude “contaminants” as the source of the bacterial DNA (141): (1) there are significant differences between the blood microbiomes of individuals harboring disease states and nominally healthy controls, despite the fact that samples are treated identically; (2) the morphological type of organism (e.g., coccus vs. bacillus) seems to be characteristic of particular diseases; (3) in many cases, relevant organisms lurk intracellularly, which is hard to explain by contamination; (4) there are just too many diseases where bacteria have been found to play a role in the pathogenesis, that all of them may be caused by contamination; (5) the actual numbers of cells involved seem far too great to be explicable by contamination; given that blood contains ~5 × 10 9 erythrocytes mL −1 , if there was just one bacterial cell per 50,000 erythrocytes this will equate to 10 5 bacteria mL −1 .…”

Section: Prevalence Of Dormant Persistent or Latent Bacteria In Infmentioning

confidence: 99%

A Dormant Microbial Component in the Development of Preeclampsia

Kell

Kenny

2016

Front. Med.

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Preeclampsia (PE) is a complex, multisystem disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany PE and are widely considered to contribute to its severity. These are abnormal trophoblast invasion of the placenta, anti-angiogenic responses, oxidative stress, and inflammation. What is lacking, however, is an explanation of how these themselves are caused. We here develop the unifying idea, and the considerable evidence for it, that the originating cause of PE (and of the four classes of dysregulation) is, in fact, microbial infection, that most such microbes are dormant and hence resist detection by conventional (replication-dependent) microbiology, and that by occasional resuscitation and growth it is they that are responsible for all the observable sequelae, including the continuing, chronic inflammation. In particular, bacterial products such as lipopolysaccharide (LPS), also known as endotoxin, are well known as highly inflammagenic and stimulate an innate (and possibly trained) immune response that exacerbates the inflammation further. The known need of microbes for free iron can explain the iron dysregulation that accompanies PE. We describe the main routes of infection (gut, oral, and urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of “preeclampsia” that we assessed has, in fact, also been shown to be raised in response to infection. An infectious component to PE fulfills the Bradford Hill criteria for ascribing a disease to an environmental cause and suggests a number of treatments, some of which have, in fact, been shown to be successful. PE was classically referred to as endotoxemia or toxemia of pregnancy, and it is ironic that it seems that LPS and other microbial endotoxins really are involved. Overall, the recognition of an infectious component in the etiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one.

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“…[291–301]); they may also be detected ultramicroscopically (e.g. [132–134; 183; 259; 292; 302]) or by flow cytometry [303], and dormant blood and tissue microbes probably underpin a great many chronic, inflammatory diseases normally considered to lack a microbial component [132–134; 137–140; 183; 259; 260; 294; 304–313]. Multiple arguments serve to exclude ‘contaminants’ as the source of the bacterial DNA [134]: 1.…”

Section: Introductionmentioning

confidence: 99%

A Dormant Microbial Component in the Development of Pre-Eclampsia¹

Kell

Kenny

2016

Preprint

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Pre-eclampsia (PE) is a complex, multi-system disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany PE, and are widely considered to contribute to its severity. These are abnormal trophoblast invasion of the placenta, anti-angiogenic responses, oxidative stress, and inflammation. What is lacking, however, is an explanation of how these themselves are caused.We here develop the unifying idea, and the considerable evidence for it, that the originating cause of PE (and of the four classes of dysregulation) is in fact microbial infection, that most such microbes are dormant and hence resist detection by conventional (replication-dependent) microbiology, and that by occasional resuscitation and growth it is they that are responsible for all the observable sequelae, including the continuing, chronic inflammation. In particular, bacterial products such as lipopolysaccharide (LPS), also known as endotoxin, are well known as highly inflammagenic and stimulate an innate (and possibly trained) immune response that exacerbates the inflammation further. The known need of microbes for free iron can explain the iron dysregulation that accompanies PE. We describe the main routes of infection (gut, oral, urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of “pre-eclampsia” that we assessed has in fact also been shown to be raised in response to infection. An infectious component to PE fulfils the Bradford Hill criteria for ascribing a disease to an environmental cause, and suggests a number of treatments, some of which have in fact been shown to be successful.PE was classically referred to as endotoxaemia or toxaemia of pregnancy, and it is ironic that it seems that LPS and other microbial endotoxins really are involved. Overall, the recognition of an infectious component in the aetiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one.Insight, innovation, integrationMany descriptors of pre-eclampsia are widely accepted (e.g. abnormal trophoblast invasion, oxidative stress, inflammation and altered immune response, and anti-angiogenic responses). However, without knowing what causes them, they do not explain the syndrome. The Biological Insight of this manuscript is that there is considerable evidence to the effect that each of these phenomena (hence PE) are caused by the resuscitation of dormant bacteria that shed (known and potent) inflammagens such as LPS, often as a consequence of iron availability. PE is thus seen as a milder form of sepsis. The Technological Innovations come from the use of molecular markers (of microbes and omics more generally, as well as novel markers of coagulopathies) to measure this. The Benefit of Integration comes from bringing together a huge number of disparate observations into a unifying theme.

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Immunostimulation in the era of the metagenome

Cited by 24 publications

References 132 publications

Macrophage polarization and MRSA infection in burned mice

Macrophage polarization and MRSA infection in burned mice

A Dormant Microbial Component in the Development of Preeclampsia

A Dormant Microbial Component in the Development of Pre-Eclampsia¹

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Immunostimulation in the era of the metagenome

Cited by 24 publications

References 132 publications

Macrophage polarization and MRSA infection in burned mice

Macrophage polarization and MRSA infection in burned mice

A Dormant Microbial Component in the Development of Preeclampsia

A Dormant Microbial Component in the Development of Pre-Eclampsia1

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A Dormant Microbial Component in the Development of Pre-Eclampsia¹