# A Smart and Sustainable Future for Viticulture Is Rooted in Soil: How to Face Cu Toxicity
## 2 Current Challenges
### Biotechnologies and Breeding for a More Resistant Plant Material  
Grapevine cultivation and wine production worldwide face challenges posed by the high pressure of fungal and fungal-like diseases, causing production losses [99]. The most common and severe problems in viticulture include those presented by downy mildew and powdery mildew infections, caused by _Plasmopara viticola_ and _Erisyphe necator_, respectively [100]. Both pathogens are commonly controlled by the application of fungicides in vineyards, mainly based on Cu [101]. However, the implementation of innovative strategies, such as the use of pathogen-resistant vine genotypes, is highly desirable with the aim of achieving a more sustainable viticulture. For this reason, breeding programs have been implemented in order to transfer the so-called resistance (\(R\)) genes from resistant _Vitis_ species to sensitive _V. vinifera_ varieties [102]. The production of resistant grapevine hybrids began in the 19 th Century, yet the first varieties, obtained from traditional breeding carried a high percentage of non-_V. vinifera_ genetic material and presented undesirable \"foxy\" flavors in the resulting wine, a distinctive feature of _V. labrusca_[101]. In the post-genomic era, new techniques, such as marker-assisted backcrossing, marker-assisted background selection and marker-assisted pyramidization, contributed to the development of breeding strategies allowing the precise introgression of wild alleles in susceptible genomes, while reducing the undesired residual genetic material [103]. At present, up to 27 Quantitative Trait Loci (QTL), known as _Rpv_ genes, are associated with the resistance to _P. viticola_, while up to 13 QTL (_Ren_ and _Run_ genes) are related to resistance against _E. necator_[102]. Following infections, _Rpv_ genes can induce different defense responses (e.g., hypersensitive response, the accumulation of phenolic compounds in the infected tissues, the accumulation of callose and lignin, the synthesis of phytoalexins, the induction of either cell necrosis or peroxidase activity; [104] and the references therein), while _Ren_ and _Run_ loci have been shown to encode small gene families of receptor-like proteins that are thought to directly or indirectly interact with pathogen-specific effectors. This interaction elicits a signaling cascade that leads to the transcriptional reprogramming of the host plant and the expression of plant defense genes [105]. Despite the potential economic and environmental benefits achievable, the diffusion of resistant hybrids is being prevented by the wine-making industry, which preferentially chooses traditional genotypes, despite their being susceptible, over resistant ones, mainly because of current regulations [102; 106]. A remarkable opportunity to overcome the issues related to traditional breeding might be offered by the genome editing approach, directed towards the susceptibility (\(S\)) genes encoded in the _V. vinifera_ genome [107]. The functionality of \(S\) genes is required for successful infections by both _E. necator_[108; 109] and _P. viticola_[106; 110]. Indeed, the targeted inactivation of \(S\) genes in _V. vinifera_ plants might potentially lead to the generation of resistant clones, while still preserving the genetic identity of the parental genotypes, which would be highly appreciated by the wine producing industry [106]. Interestingly, these new varieties can be defined as being tolerant to the pathogens; however, in cases of very high infection pressure, the endogenous plant responses might not be sufficient for counteracting disease, making the application of agrochemicals like Cu necessary for controlling and/or contrasting pathogen diffusion within the canopy (Figure 4). Indeed, despite not completely avoiding the application of fungicides, resistant varieties might contribute to strongly decreasing the use of agrochemicals in open fields.