scholarly journals Inducible mechanisms of disease tolerance provide an alternative strategy of acquired immunity to malaria

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Wiebke Nahrendorf ◽  
Alasdair Ivens ◽  
Philip J Spence
Keyword(s):  
Bone Marrow ◽  
Defense Mechanisms ◽  
Severe Disease ◽  
Malaria Episode ◽  
Acquired Immunity ◽  
Plasmodium Chabaudi ◽  
Pathogen Load ◽  
Pathogen Control ◽  
Inflammatory Macrophages ◽  
Pathogen Clearance

Immunity to malaria is often considered slow to develop but this only applies to defense mechanisms that function to eliminate parasites (resistance). In contrast, immunity to severe disease can be acquired quickly and without the need for improved pathogen control (tolerance). Using Plasmodium chabaudi, we show that a single malaria episode is sufficient to induce host adaptations that can minimise inflammation, prevent tissue damage and avert endothelium activation, a hallmark of severe disease. Importantly, monocytes are functionally reprogrammed to prevent their differentiation into inflammatory macrophages and instead promote mechanisms of stress tolerance to protect their niche. This alternative fate is not underpinned by epigenetic reprogramming of bone marrow progenitors but appears to be imprinted within the remodelled spleen. Crucially, all of these adaptations operate independently of pathogen load and limit the damage caused by malaria parasites in subsequent infections. Acquired immunity to malaria therefore prioritises host fitness over pathogen clearance.

scholarly journals Inducible mechanisms of disease tolerance provide an alternative strategy of acquired immunity to malaria

2020 ◽  
Author(s):  
Wiebke Nahrendorf ◽  
Alasdair Ivens ◽  
Philip J. Spence
Keyword(s):  
Bone Marrow ◽  
Defense Mechanisms ◽  
Severe Disease ◽  
Alternative Strategy ◽  
Malaria Episode ◽  
Acquired Immunity ◽  
Disease Tolerance ◽  
Pathogen Load ◽  
Pathogen Control ◽  
Inflammatory Macrophages

SummaryImmunity to malaria is often considered slow to develop but this only applies to defense mechanisms that function to eliminate parasites (resistance). In contrast, immunity to severe disease can be acquired quickly and without the need for improved pathogen control (tolerance). We show that a single malaria episode is sufficient to induce host adaptations that can minimise inflammation, prevent tissue damage and avert endothelium activation, a hallmark of severe disease. Furthermore, monocytes are functionally reprogrammed in tolerised hosts to prevent their differentiation into inflammatory macrophages and instead promote mechanisms of stress tolerance to protect their niche. This alternative fate is not underpinned by epigenetic reprogramming of bone marrow progenitors but is imprinted within the remodelled spleen. Crucially, all of these adaptations operate independently of pathogen load and limit the damage caused by malaria parasites in subsequent infections. Inducible mechanisms of disease tolerance therefore provide an alternative strategy of acquired immunity.

Evaluation of Congenital Neutropenic Disorders by in Vitro Bone Marrow Culture

PEDIATRICS ◽  
1977 ◽  
Vol 59 (5) ◽  
pp. 739-748
Author(s):  
Peter M. Falk ◽  
Kenneth Rich ◽  
Stephen Feig ◽  
E. Richard Stiehm ◽  
David W. Golde ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Severe Disease ◽  
Stem Cell Differentiation ◽  
Peripheral Blood Cell ◽  
Clinical Expression ◽  
Essentially Normal ◽  
Cell Counts

The congenital neutropenias are a heterogeneous group of diseases whose etiology and pathogenesis are largely unknown. We studied nine neutropenic patients from seven families. Evaluation included peripheral blood cell and differential cell counts, epinephrine and typhoid vaccine stimulation studies, Rebuck skin windows, and bone marrow aspirations for morphological assessment and for in vitro culture in liquid suspension and in agar plates. Parallel cultures were set up with and without colony-stimulating activity (CSA), and peripheral leukocytes were assayed for cellular production of CSA. Patients were initially classified on the basis of their clinical course: benign, mild, moderately severe, or severe disease. One patient in the moderately severe group had an immunoglobulin disorder. Morphologically normal mature granulocytes were seen in bone marrow aspirates of two patients, and maturational defects of varying degree were seen in the remaining seven. Colony formation in agar was markedly reduced below normal in three of seven, moderately reduced in two of seven, and greater than normal in two patients. Colonies in six of seven patients consisted exclusively of macrophages. Marrow from all but one of the nine patients demonstrated poor neutrophil development in suspension culture, and addition of CSA did not result in augmented granulocytic proliferation or maturation. A scheme of normal neutrophil maturation is proposed, and the nine patients were categorized according to this scheme. Four patterns of congenital neutropenia emerged: type 1 was the most benign form of disease with essentially normal clinical and in vitro parameters, and a defect considered to be due to a small committed stem cell pool, abnormal release, or excessive utilization peripherally; type 2 had mild disease with presumed defective committed stem cell differentiation along the granulocyte line; type 3 included benign to severe clinical expression with an apparent defect at the level of the committed granulocyte precursor more severe than in type 2; type 4 disease had varied clinical expression but evidence for a defect at the level of the pluripotent stem cell.

The Basics of Microbiology

2021 ◽  
Author(s):  
Werner Solbach
Keyword(s):  
Infectious Diseases ◽  
Defense Mechanisms ◽  
Wide Spectrum ◽  
Severe Disease ◽  
Laboratory Diagnosis ◽  
Asymptomatic Infection ◽  
The Body ◽  
Sufficient Evidence ◽  
Effective Measure ◽  
Hygiene Measures

Microorganisms constitute 70 percent of the biomass on Planet Earth. Comparatively few species are adapted to colonize human surfaces and form a complex Meta-Organism with manyfold mutual benefits. Occasionally, microorganisms may overcome the barriers of the skin and mucosal surfaces and may multiply locally or in multiple sites inside the body. This process is called infection. Infections can be caused by bacteria, viruses, parasites, helminths, and fungi. Immediately after infection, numerous defense mechanisms of the immune system are activated to combat replication of the microbes. There is a balance between microorganism and human defense mechanisms, which may lead to either asymptomatic infection or result in a wide spectrum of symptoms from mild to severe disease and even death. The most important factors in the diagnosis of infectious diseases are a careful history, physical examination and the appropriate collection of body fluids and tissues. Laboratory diagnosis requires between 2 and 72 hours. Wherever possible, antibiotics should only be used when sufficient evidence of efficacy is available. Then, however, they should be used as early as possible and in high doses. In addition to everyday hygiene measures, vaccination is the most effective measure to prevent infectious diseases.

scholarly journals In vivo tracking of transplanted macrophages with near infrared fluorescent dye reveals temporal distribution and specific homing in the liver that can be perturbed by clodronate liposomes

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0242488
Author(s):  
Satoshi Nishiwaki ◽  
Shigeki Saito ◽  
Kyosuke Takeshita ◽  
Hidefumi Kato ◽  
Ryuzo Ueda ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Normal State ◽  
Near Infrared ◽  
Temporal Distribution ◽  
Organ Damage ◽  
The Other ◽  
Acquired Immunity ◽  
Activated Macrophages ◽  
Clodronate Liposomes

Macrophages play an indispensable role in both innate and acquired immunity, while the persistence of activated macrophages can sometimes be harmful to the host, resulting in multi-organ damage. Macrophages develop from monocytes in the circulation. However, little is known about the organ affinity of macrophages in the normal state. Using in vivo imaging with XenoLight DiR®, we observed that macrophages showed strong affinity for the liver, spleen and lung, and weak affinity for the gut and bone marrow, but little or no affinity for the kidney and skin. We also found that administered macrophages were still alive 168 hours after injection. On the other hand, treatment with clodronate liposomes, which are readily taken up by macrophages via phagocytosis, strongly reduced the number of macrophages in the liver, spleen and lung.

scholarly journals Acquired Immunity to Malaria

2009 ◽  
Vol 22 (1) ◽  
pp. 13-36 ◽  
Author(s):  
Denise L. Doolan ◽  
Carlota Dobaño ◽  
J. Kevin Baird
Keyword(s):  
Plasmodium Falciparum ◽  
High Risk ◽  
Immune Status ◽  
Severe Disease ◽  
Sub Saharan Africa ◽  
Acquired Immunity ◽  
Sub Saharan ◽  
High Risk Infants ◽  
Induced Immunity ◽  
Infants And Young Children

SUMMARY Naturally acquired immunity to falciparum malaria protects millions of people routinely exposed to Plasmodium falciparum infection from severe disease and death. There is no clear concept about how this protection works. There is no general agreement about the rate of onset of acquired immunity or what constitutes the key determinants of protection; much less is there a consensus regarding the mechanism(s) of protection. This review summarizes what is understood about naturally acquired and experimentally induced immunity against malaria with the help of evolving insights provided by biotechnology and places these insights in the context of historical, clinical, and epidemiological observations. We advocate that naturally acquired immunity should be appreciated as being virtually 100% effective against severe disease and death among heavily exposed adults. Even the immunity that occurs in exposed infants may exceed 90% effectiveness. The induction of an adult-like immune status among high-risk infants in sub-Saharan Africa would greatly diminish disease and death caused by P. falciparum. The mechanism of naturally acquired immunity that occurs among adults living in areas of hyper- to holoendemicity should be understood with a view toward duplicating such protection in infants and young children in areas of endemicity.

scholarly journals THE INDUCTION OF GRAFT VERSUS HOST DISEASE IN MICE TREATED WITH CYCLOPHOSPHAMIDE

1968 ◽  
Vol 128 (2) ◽  
pp. 277-291 ◽  
Author(s):  
Albert H. Owens ◽  
George W. Santos
Keyword(s):  
Bone Marrow ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Severe Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Experimental Systems ◽  
Adult Mice ◽  
Competent Cells

In these studies adult mice treated with cyclophosphamide and foreign immunologically competent cells developed a graft versus host disease which outwardly resembled that encountered in other experimental systems. Progressively larger doses of cyclophosphamide produced an increasingly severe disease whereas comparable doses of mechlorethamine were ineffective. Increasingly larger cell inocula from parental, allogeneic, and xenogeneic donors resulted in a correspondingly more severe disease. Nucleated cells obtained from the peripheral blood were found to be the most potent inducers of this syndrome, while cells from the spleen, bone marrow, and thymus displayed lesser degrees of reactivity in that order. No such graft versus host disease occurred in mice given saline, lysed, or heat-killed cells in place of viable foreign cells. Neither did the disorder develop when comparable inocula of isogeneic cells were used.

scholarly journals Transcriptome analysis reveals ethylene-mediated defense responses to Fusarium oxysporum f. sp. cucumerinum infection in Cucumis sativus

2020 ◽  
Author(s):  
Jingping Dong ◽  
Yuean Wang ◽  
Qianqian Xian ◽  
Xuehao Chen ◽  
Jun Xu
Keyword(s):  
Fusarium Oxysporum ◽  
Cucumis Sativus ◽  
Fusarium Wilt ◽  
Defense Mechanisms ◽  
Molecular Mechanisms ◽  
Severe Disease ◽  
Defense Responses ◽  
Differentially Expressed ◽  
Pcr Analysis ◽  
Positive Role

Abstract Background: Fusarium wilt, caused by Fusarium oxysporum f. sp. cucumerinum (Foc), is a severe disease affecting cucumber (Cucumis sativus L.) production worldwide, but the molecular mechanisms underlying Fusarium wilt resistance in cucumber remain unknown. To gain an improved understanding of the defense mechanisms elicited in response to Foc inoculation, RNA sequencing-based transcriptomic profiling of responses of the Fusarium wilt-resistant cucumber line ‘Rijiecheng’ at 0, 24, 48, 96, and 192 h after Foc inoculation was performed.Results: We identified 4116 genes that were differentially expressed between 0 h and other time points after inoculation. All ethylene-related and pathogenesis-related genes from among the differentially expressed genes were filtered out. Real-time PCR analysis showed that ethylene-related genes were induced in response to Foc infection. Importantly, after Foc infection and exogenous application of ethephon, a donor of ethylene, these genes were highly expressed. In response to exogenous ethephon treatment in conjunction with Foc inoculation, the infection resistance of cucumber seedlings was enhanced and endogenous ethylene biosynthesis increased dramatically. Conclusion: Collectively, ethylene signaling pathways play a positive role in regulating the defense response of cucumber to Foc infection. The results provide insight into the cucumber Fusarium wilt defense mechanisms and provide valuable information for breeding new cucumber cultivars with enhanced Fusarium wilt tolerance.

scholarly journals Macrophages and Epithelial Cells Mutually Interact through NLRP3 to Clear Infection and Enhance the Gastrointestinal Barrier

Immuno ◽  
2021 ◽  
Vol 2 (1) ◽  
pp. 13-25
Author(s):  
Michael Bording-Jorgensen ◽  
Heather Armstrong ◽  
Madison Wickenberg ◽  
Paul LaPointe ◽  
Eytan Wine
Keyword(s):  
Epithelial Cells ◽  
Receptor Protein ◽  
Epithelial Barrier ◽  
Inflammasome Activation ◽  
Colonic Epithelial Cells ◽  
Epithelial Barrier Function ◽  
Barrier Integrity ◽  
Pathogen Control ◽  
Pathogen Clearance

Activation of the nod-like receptor protein 3 (NLRP3) leads to the release of the proinflammatory cytokine IL-1β, which then facilitates pathogen control by macrophages. The role of NLRPs in controlling infection of epithelial cells is not well understood. Our hypothesis was that activation of the NLRP3 inflammasome in colonic epithelial cells would promote macrophage-mediated epithelial recovery after infection with the pathogen Citrobacter rodentium. We devised a co-culture model using mouse colonic epithelial cells (CMT-93) and macrophages (J774A.1) during infection with C. rodentium. Inflammasome was activated using LPS and ATP and inhibited by YVAD. We assessed cytokine secretion (ELISA), macrophage recruitment and pathogen penetration (immunofluorescence), and epithelial barrier integrity (transepithelial electrical resistance). Macrophages were recruited to the apical membrane of epithelial cells, associated with tight junctions, promoted epithelial barrier recovery, and displaced C. rodentium. While NLRP3 was expressed in infected epithelial cells, IL-18 or IL-1β secretion remained unchanged. Supernatants from infected epithelial cells promoted infection clearance by macrophage; while this was inflammasome-independent, ATP significantly improved epithelial barrier recovery. The inflammasome appears to promote epithelial barrier function, independent of IL-18 and IL-1β secretion. Inflammasome activation in macrophages plays a dual role of promoting pathogen clearance and improving epithelial barrier integrity.

scholarly journals Transcriptome analysis reveals ethylene-mediated defense responses to Fusarium oxysporum f. sp. cucumerinum infection in Cucumis sativus L.

2020 ◽  
Author(s):  
Jingping Dong ◽  
Yuean Wang ◽  
Qianqian Xian ◽  
Xuehao Chen ◽  
Jun Xu
Keyword(s):  
Fusarium Oxysporum ◽  
Cucumis Sativus ◽  
Defense Mechanisms ◽  
Severe Disease ◽  
Defense Responses ◽  
Ethylene Biosynthesis ◽  
Differentially Expressed ◽  
Pcr Analysis ◽  
Positive Role ◽  
Cucumis Sativus L

Abstract Background: Fusarium wilt, caused by Fusarium oxysporum f. sp. cucumerinum (Foc), is a severe disease affecting cucumber (Cucumis sativus L.) production worldwide, but mechanisms underlying Fusarium wilt resistance in cucumber remain unknown. To better understand of the defense mechanisms elicited in response to Foc inoculation, RNA sequencing-based transcriptomic profiling of responses of the Fusarium wilt-resistant cucumber line ‘Rijiecheng’ at 0, 24, 48, 96, and 192 hours after Foc inoculation was performed.Results: We identified 4116 genes that were differentially expressed between 0 hour and other time points after inoculation. All ethylene-related and pathogenesis-related genes from the differentially expressed genes were filtered out. Real-time PCR analysis showed that ethylene-related genes were induced in response to Foc infection. Importantly, after Foc infection and exogenous application of ethephon, a donor of ethylene, the ethylene-related genes were highly expressed. In response to exogenous ethephon treatment in conjunction with Foc inoculation, the infection resistance of cucumber seedlings was enhanced and endogenous ethylene biosynthesis increased dramatically. Conclusion: Collectively, ethylene signaling pathways play a positive role in regulating the defense response of cucumber to Foc infection. The results provide insight into the cucumber Fusarium wilt defense mechanisms and provide valuable information for breeding new cucumber cultivars with enhanced Fusarium wilt tolerance.

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