Key message
New models for integration of major gene MAS with modern breeding approaches stand to greatly enhance the reliability and efficiency of breeding, facilitating the leveraging of ...traditional genetic diversity.
Genetic diversity is well recognised as contributing essential variation to crop breeding processes, and marker-assisted selection is cited as the primary tool to bring this diversity into breeding programs without the associated genetic drag from otherwise poor-quality genomes of donor varieties. However, implementation of marker-assisted selection techniques remains a challenge in many breeding programs worldwide. Many factors contribute to this lack of adoption, such as uncertainty in how to integrate MAS with traditional breeding processes, lack of confidence in MAS as a tool, and the expense of the process. However, developments in genomics tools, locus validation techniques, and new models for how to utilise QTLs in breeding programs stand to address these issues. Marker-assisted forward breeding needs to be enabled through the identification of robust QTLs, the design of reliable marker systems to select for these QTLs, and the delivery of these QTLs into elite genomic backgrounds to enable their use without associated genetic drag. To enhance the adoption and effectiveness of MAS, rice is used as an example of how to integrate new developments and processes into a coherent, efficient strategy for utilising genetic variation. When processes are instituted to address these issues, new genes can be rolled out into a breeding program rapidly and completely with a minimum of expense.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The kidney is an organ particularly susceptible to damage caused by infections and autoimmune conditions. Renal inflammation confers protection against microbial infections. However, if unchecked, ...unresolved inflammation may lead to kidney damage. Although proinflammatory cytokine IL-17 is required for immunity against extracellular pathogens, dysregulated IL-17 response is also linked to autoimmunity. In this review, we will discuss the current knowledge of IL-17 activity in the kidney in context to renal immunity and autoimmunity and raise the intriguing question to what extent neutralization of IL-17 is beneficial or harmful to renal inflammation.
The invasive fungal infections (IFIs) are a major cause of mortality due to infectious disease worldwide. Majority of the IFIs are caused by opportunistic fungi including
,
and
species. Lack of ...approved antifungal vaccines and the emergence of antifungal drug-resistant strains pose major constraints in controlling IFIs. A comprehensive understanding of the host immune response is required to develop novel fungal vaccines to prevent death from IFIs. In this review, we have discussed the challenges associated with the development of antifungal vaccines. We mentioned how host-pathogen interactions shape immunological memory and development of long-term protective immunity to IFIs. Furthermore, we underscored the contribution of long-lived innate and adaptive memory cells in protection against IFIs and summarized the current vaccine strategies.
The kidneys are life-sustaining organs that are vital to removing waste from our bodies. Because of their anatomic position and high blood flow, the kidneys are vulnerable to damage due to infections ...and autoinflammatory conditions. Even now, our knowledge of immune responses in the kidney is surprisingly rudimentary. Studying kidney-specific immune events is challenging because of the poor regenerative capacity of the nephrons, accumulation of uremic toxins, and hypoxia- and arterial blood pressure–mediated changes, all of which have unexpected positive or negative impacts on the immune response in the kidney. Kidney-specific defense confers protection against pathogens. On the other hand, unresolved inflammation leads to kidney damage and fibrosis. Interleukin-17 is a proinflammatory cytokine that has been linked to immunity against pathogens and pathogenesis of autoinflammatory diseases. In this review, we discuss current knowledge of IL-17 activities in the kidney in the context of infections, autoinflammatory diseases, and renal fibrosis.
•IL-17 is implicated in many organ-specific and systemic autoinflammatory diseases.•IL-17 exhibits both profibrotic and antifibrotic function in an organ and disease-specific manner.•Defining IL-17 ...signaling may identify novel drug targets in treating organ fibrosis.
Fibrosis affects all vital organs accounting for a staggering 45% of deaths worldwide and no effective therapies are currently available. Unresolved inflammation triggers downstream signaling events that lead to organ fibrosis. In recent years, proinflammatory cytokine Interleukin-17 (IL-17) has been implicated in several chronic inflammatory diseases that often culminate in organ damage followed by impaired wound healing and fibrosis. In this review, we outline the contribution of the IL-17 in mediating fibrotic diseases in various organs. A comprehensive understanding of the inflammatory events, and particularly the details of IL-17 signaling in vivo, could be beneficial in designing new therapeutic or preventive approaches to treat fibrosis. Additionally, understanding organ-specific differences in IL-17 activity could lead to targeted therapies and help spare other organs from unwanted side effects.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Key message
The integration of new technologies into public plant breeding programs can make a powerful step change in agricultural productivity when aligned with principles of quantitative and ...Mendelian genetics.
The breeder’s equation is the foundational application of quantitative genetics to crop improvement. Guided by the variables that describe response to selection, emerging breeding technologies can make a powerful step change in the effectiveness of public breeding programs. The most promising innovations for increasing the rate of genetic gain without greatly increasing program size appear to be related to reducing breeding cycle time, which is likely to require the implementation of parent selection on non-inbred progeny, rapid generation advance, and genomic selection. These are complex processes and will require breeding organizations to adopt a culture of continuous optimization and improvement. To enable this, research managers will need to consider and proactively manage the, accountability, strategy, and resource allocations of breeding teams. This must be combined with thoughtful management of elite genetic variation and a clear separation between the parental selection process and product development and advancement process. With an abundance of new technologies available, breeding teams need to evaluate carefully the impact of any new technology on selection intensity, selection accuracy, and breeding cycle length relative to its cost of deployment. Finally breeding data management systems need to be well designed to support selection decisions and novel approaches to accelerate breeding cycles need to be routinely evaluated and deployed.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Interleukin-17 (IL-17) induces pathology in autoimmunity and infections; therefore, constraint of this pathway is an essential component of its regulation. We demonstrate that the signaling ...intermediate MCPIP1 (also termed Regnase-1, encoded by Zc3h12a) is a feedback inhibitor of IL-17 receptor signal transduction. MCPIP1 knockdown enhanced IL-17-mediated signaling, requiring MCPIP1’s endoribonuclease but not deubiquitinase domain. MCPIP1 haploinsufficient mice showed enhanced resistance to disseminated Candida albicans infection, which was reversed in an Il17ra−/− background. Conversely, IL-17-dependent pathology in Zc3h12a+/− mice was exacerbated in both EAE and pulmonary inflammation. MCPIP1 degraded Il6 mRNA directly but only modestly downregulated the IL-6 promoter. However, MCPIP1 strongly inhibited the Lcn2 promoter by regulating the mRNA stability of Nfkbiz, encoding the IκBζ transcription factor. Unexpectedly, MCPIP1 degraded Il17ra and Il17rc mRNA, independently of the 3′ UTR. The cumulative impact of MCPIP1 on IL-6, IκBζ, and possibly IL-17R subunits results in a biologically relevant inhibition of IL-17 signaling.
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•MCPIP1 (Regnase-1) is a feedback inhibitor of IL-17 signal transduction•MCPIP1 deficiency enhances immunity to fungi but exacerbates pathology in EAE•MCPIP1 impairs activation of certain IL-17 target promoters by degrading IκBζ mRNA•MCPIP1 degrades transcripts encoding IL-17R subunits independently of the 3′ UTR
Interleukin-17 (IL-17) induces pathology in autoimmunity and infections and therefore its activity must be tightly regulated. Gaffen and colleagues report that the endoribonuclease MCPIP1 degrades IL-17-induced transcripts, including Il6 and Nfkbiz (Iκβζ), to negatively regulate IL-17 receptor signaling both in fungal immunity and experimental autoimmune encephalomyelitis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•During disseminated candidiasis C. albicans invade and damage kidney.•No approved antifungal vaccines to prevent renal damage in disseminated candidiasis.•Kidney-resident and infiltrating immune ...cells control fungal burden in the kidney.•IL-17 play a renal tissue protective role in disseminated candidiasis.
Disseminated candidiasis is a hospital-acquired infection that results in high degree of mortality despite antifungal treatment. Autopsy studies revealed that kidneys are the major target organs in disseminated candidiasis and death due to kidney damage is a frequent outcome in these patients. Thus, the need for effective therapeutic strategies to mitigate kidney damage in disseminated candidiasis is compelling. Recent studies have highlighted the essential contribution of kidney-specific immune response in host defense against systemic infection. Crosstalk between kidney-resident and infiltrating immune cells aid in the clearance of fungi and prevent tissue damage in disseminated candidiasis. In this review, we provide our recent understanding on antifungal immunity in the kidney with an emphasis on IL-17-mediated renal defense in disseminated candidiasis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Deregulated production of IL-17 and IL-21 plays a key pathogenic role in many autoimmune disorders. A delineation of the mechanisms that underlie the inappropriate synthesis of IL-17 and IL-21 in ...autoimmune diseases can thus provide important insights into potential therapies for these disorders. Here we have shown that the serine-threonine kinase Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) becomes activated in mouse T cells under Th17 skewing conditions and phosphorylates interferon regulatory factor 4 (IRF4), a transcription factor that is absolutely required for the production of IL-17 and IL-21. We furthermore demonstrated that ROCK2-mediated phosphorylation of IRF4 regulated the synthesis of IL-17 and IL-21 and the differentiation of Th17 cells. Whereas CD4+ T cells from WT mice activated ROCK2 physiologically under Th17 conditions, CD4+ T cells from 2 different mouse models of spontaneous autoimmunity aberrantly activated ROCK2 under neutral conditions. Moreover, administration of ROCK inhibitors ameliorated the deregulated production of IL-17 and IL-21 and the inflammatory and autoantibody responses observed in these autoimmune mice. Our findings thus uncover a crucial link among ROCK2, IRF4, and the production of IL-17 and IL-21 and support the idea that selective inhibition of ROCK2 could represent an important therapeutic regimen for the treatment of autoimmune disorders.
Oropharyngeal candidiasis (OPC), caused by the commensal fungus Candida albicans, is an opportunistic infection associated with infancy, AIDS, and IL-17-related primary immunodeficiencies. The ...Th17-associated cytokines IL-23 and IL-17 are crucial for immunity to OPC, but the mechanisms by which they mediate immunity are poorly defined. IL-17RA-deficient humans and mice are strongly susceptible to OPC, with reduced levels of CXC chemokines and concomitantly impaired neutrophil recruitment to the oral mucosa. Paradoxically, humans with isolated neutropenia are typically not susceptible to candidiasis. To determine whether immunity to OPC is mediated via neutrophil recruitment, mice lacking CXCR2 were subjected to OPC and were found to be highly susceptible, although there was no dissemination of fungi to peripheral organs. To assess whether the entire neutrophil response is IL-17 dependent, IL-17RA(-/-) and IL-23(-/-) mice were administered neutrophil-depleting Abs and subjected to OPC. These mice displayed increased oral fungal burdens compared with IL-17RA(-/-) or IL-23(-/-) mice alone, indicating that additional IL-17-independent signals contribute to the neutrophil response. WT mice treated with anti-Gr-1 Abs exhibited a robust infiltrate of CD11b(+)Ly-6G(low)F4/80(-) cells to the oral mucosa but were nonetheless highly susceptible to OPC, indicating that this monocytic influx is insufficient for host defense. Surprisingly, Ly-6G Ab treatment did not induce the same strong susceptibility to OPC in WT mice. Thus, CXCR2(+) and Gr-1(+) neutrophils play a vital role in host defense against OPC. Moreover, defects in the IL-23/17 axis cause a potent but incomplete deficiency in the neutrophil response to oral candidiasis.
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