Noble rot is used to produce highly valued sweet dessert wines, such as Sauternes, Tokaji Aszu, and Amarone. The positive effects of noble rot are not only due to the concentration of sugar and aroma components through B. cinerea-induced water loss of the berry, but also from an enhanced synthesis of aromatic metabolites and their precursors, such as odorous lactones (γ and δ lactones) and their precursors (Miklósy and Kerényi, 2004; Tosi et al., 2012; Stamatopoulos et al., 2014; Lopez Pinar et al., 2017a,b; Stamatopoulos et al., 2018). In particular, this has been shown for S-conjugates of glutathione and cysteine, the precursors of varietal thiols reminiscent of citrus, grapefruit/passionfruit, or boxwood aroma. Their concentration can increase more than 100-fold upon B. cinerea infection (Sarrazin et al., 2007; Bailly et al., 2009; Thibon et al., 2009, 2011). The concomitant presence of S-conjugates of glutathione and cysteine in musts from infected berries as well as in botrytized berries highlights an activation of the glutathione biosynthetic pathways, a known strategy of plants as a general response to biotic (pathogenic attack) or abiotic stresses (injury, oxidative stress etc.; Hasanuzzaman et al., 2017). This has also been shown for grapevine leaves and berries exposed to cold and heat shock as well as UV irradiation (Kobayashi et al., 2011). Biosynthesis of S-conjugated amino acids and subsequent metabolites results from an increased release of reactive and toxic aldehydes, such as trans-2-hexenal reacting with glutathione to form glutathione S-conjugates, such as S-3-(hexan-1-ol)-glutathione, which in turn will be metabolized into S-conjugate cysteine and ultimately cleaved into sulfanylalcohols during fermentation by ß-lyase activity of Saccharomyces cerevisiae (Tominaga et al., 1998).

Other odorous volatile compounds, such as lactones (γ and δ lactones), furanone, methional, and phenylacetaldehyde, have been found in botrytized berries (Kikuchi et al., 1983; Miklósy and Kerényi, 2004; Tosi et al., 2012; Stamatopoulos et al., 2014; Lopez Pinar et al., 2017a,b; Stamatopoulos et al., 2018). These compounds can contribute in a desirable way to the flavor of sweet wines produced from noble rot-infected grapes (Schreier et al., 1976; Sarrazin et al., 2007; Tosi et al., 2012). Organic acids, such as tartaric and malic, are metabolized by the fungi and wines from botrytized berries have generally lower total acidity (Shimazu et al., 1984).

Gray mold can be very detrimental to fruit and wine quality due to the degradation of a number of grape berry components (Pallotta et al., 1998). In particular, phenolic compounds (anthocyanins, hydroxycinnamic acids, and flavanols) are oxidized by the polyphenol oxidase (laccase) activity of B. cinerea (Dubernet et al., 1977), which leads to quinones, that are highly reactive with glutathione and volatile odorous thiols. Ky et al. (2012) showed that all phenolic compounds (anthocyanins and proanthocyanidin monomers, dimers and trimers) decreased drastically in gray mold-infected grape skins as well as the mean degree of polymerization of the proanthocyanidin polymeric fraction.

Some aromatic components, like monoterpenes that play a major role in the aromas of Muscat grape cultivars and wines, are transformed into less odorous compounds (Boidron, 1978; Bock et al., 1986). Ethyl esters of fatty acids, which contribute to the fermentation aromas of wine, are hydrolyzed by the esterase activity of B. cinerea (Dubourdieu et al., 1983). Moreover, the development of gray mold, associated with abundant sporulation, as well as the presence of spores in the must, leads to the production of mushroom and earthy off-odors in the resulting wines (La Guerche et al., 2006; Lopez Pinar et al., 2017a,b). Compounds responsible for such off-odors have been identified as 1-octen-3-one, 1-octen-3-ol, 2-heptanol, and 2-octen-1-ol with mushroom notes, or 2-methylisoborneol with strong earthy notes. Sometimes, a certain proportion of botrytized grapes (< 1–5%) are co-contaminated with other saprophytic fungi belonging to the genus Penicillium spp., particularly P. expansum, as well as Mucor spp., Trichotecium spp., Cladosporium spp., Aureobasidium spp., Alternaria spp., etc., which may develop inside the grape clusters, resulting in secondary rot with yellow, green, or pink shades. Their presence is generally favored by their ability to grow at lower temperatures than B. cinerea (10–15°C). In this context, other off-odors may be detected in wines, associated with the formation of potent, malodorous compounds, particularly caused by the presence of Penicillium spp., in particular Penicillium expansum, and its production of (−)-geosmin (Darriet et al., 2000; La Guerche et al., 2006, 2007; Steel et al., 2013; Behr et al., 2014).

The four most recent whole-genome transcriptomic studies on B. cinerea-infected berries used either Microarrays (Agudelo-Romero et al., 2015; Kelloniemi et al., 2015) or RNA-seq (Blanco-Ulate et al., 2015; Lovato et al., 2019a,b) to detect differentially expressed genes upon B. infection. Varieties, sampling- and infection protocols vary in all studies, making it difficult to draw general conclusions. Agudelo-Romero et al. (2015) and Blanco-Ulate et al. (2015) investigate gray mold infection on Semillon berries sampled at maturity (23.9°Brix; Blanco-Ulate et al., 2015) and Trincadeira at two different stages of berry development (green berries: EL 33 and at véraison: EL 35; Agudelo-Romero et al., 2015). Both studies draw samples directly in situ. Kelloniemi et al. (2015) and Lovato et al. (2019b) studied noble rot on post-harvest-infected berries from Marselan berries cut at version and maturity (Kelloniemi et al., 2015) and on Muller-Thurgau and Garganega (Lovato et al., 2019b). Furthermore, the latter authors carried out a meta-analysis of transcriptomic data from all aforementioned studies on B. cinerea-infected grapes. They could identify only 17 commonly upregulated transcripts in all varieties and stages that were specific to B. cinera infection. When looking only at either gray mold or noble rot and only after véraison, commonly upregulated genes were found to be higher: 129 and 173, which seems still relatively low in comparison with other biotic (Rienth et al., 2019a) and abiotic stress (Rienth et al., 2014b; Lecourieux et al., 2017) transcriptomic studies. Obviously, this relatively low number of commonly regulated genes can, to some degree, be explained by the fact that gray mold and noble rot infections were compared from different varieties. However, it is very likely that the different, not very precisely defined and characterized berry sampling stages prevent the detection of more commonly genes modulated specifically by B. cinerea. It has been shown that a unprecise definition of berry sampling stages can biases biotic and abiotic stress to a high extent, mainly when studies include the stage of véraison (which is considered when 50% of berries change color), where a large transcriptomic reprogramming occurs (Terrier et al., 2005; Rienth et al., 2014a) within 24h from green to soft (and colored) berries. Thus mixing green and colored berries from a cluster at véraison can introduce unquantifiable biases that could cover important transcriptomic regulations (Carbonell-Bejerano et al., 2016; Shahood et al., 2020).

Nevertheless when looking at different metabolic pathways one can summarize that in all studies, B. cinerea caused an induction of secondary metabolism. Notably, the phenylpropanoid pathway was generally highly activated, as indicated by the upregulation of R2R3-MYB, VviMYB5a/b transcription factors (TFs), known as key regulators of phenylpropanoids, and the downstream key genes involved in the production of flavonoids, such as chalcones, flavonols, and anthocyanins, procyanidins, lignin, and lignans (Blanco-Ulate et al., 2015; Lovato et al., 2019a,b).

In particular, the biosynthesis of stilbenes, major defense compounds (Gindro et al., 2012a), is highly activated upon B. cinerea infection, as highlighted by the induction of VvMYB14, VvSTSs and PAL expressions in samples of Lovato et al. (2019a,b) which was similar to that of berries sampled at the véraison stage by Kelloniemi et al. (2015). Interestingly, in the white cultivar Semillon, noble rot caused by B. cinerea induced the expression of transcriptional regulators normally expressed in the skins of red cultivars, including five R2R3-MYBs that regulate stilbene (VvMYB14,VvMYB15), proanthocyanidin (VvMYBPA1), and phenylpropanoid (VvMYBC2-L1, VvMYB4a) metabolism, as well as other potential regulators of ripening, such as VvNAC33, VviNAC60, a zinc-finger transcription factor, a MYB transcription factor, and an AP2/ERF transcription factor (Blanco-Ulate et al., 2015).

Transcriptomic data regarding volatile compounds biosynthesis highlight a cultivar-dependent response. For example, Blanco-Ulate et al. (2015) observed a general upregulation of several terpene synthases, VvTPS, in Sémillon botrytized berries, which was, however, not confirmed in Trincadeira (Agudelo-Romero et al., 2015) or Muller-Thurgau and Garganega (Lovato et al., 2019b), where terpene biosynthetic genes were generally downregulated by the infection. A further, more general physiological response of berry metabolism upon B. cinerea infection is the upregulation of oxidative stress-related transcripts, abscisic acid, ethylene, jasmonate, and salicylate pathways, and genes encoding resistance (PR-genes; Agudelo-Romero et al., 2015; Coelho et al., 2019; Lovato et al., 2019b). Coelho et al. (2019) compared the hormonal response in Botrytis-infected berries of susceptible (Trincadeira) and resistant (Syrah) varieties and showed that high basal levels of salicylic acid (SA) and indoleacetic acid (IAA) at an early stage of ripening, together with activated SA and IAA metabolism and signaling seem to be important in providing a fast defense response leading to grape tolerance against B. cinerea.

Interestingly, a group of sugar transporter (SWEETs) seems to play an important role during B. cinerea infections as shown for the first time by Chong et al. (2014), who demonstrated an involvement of the grapevine SWEET transporter 4 (VvSWEET4). Moreover, they further showed that VvSWEET4 is a glucose transporter localized in the plasma membrane, which is upregulated by inducers of reactive oxygen species and virulence factors from necrotizing pathogens. This led authors to the hypothesis that stimulation of expression of a developmentally regulated glucose uniporter by reactive oxygen species production and extensive cell death after necrotrophic fungal infection could facilitate sugar acquisition from plant cells by the pathogen. Later, Breia et al. (2020b) highlighted the role of several other VvSWEETs in grapevine berries upon pathogen infections. Notably the mono- and disaccharide transporter VvSWEET7 was strongly upregulated during B. cinerea infection of grape berries. This induction may be caused by the pathogen itself to promote leakage of sugars into the apoplastic space for nutrition, or, as a defense-related process to improve sugar remobilization which can trigger signaling cascades that activate plant defense mechanisms. The same authors showed as well that grapevine’s sucrose transporter Early-Response to Dehydration six-like 13 (VvERD6l13) was strongly upregulated in response to B. cinerea but as well by E. necator infection (Breia et al., 2020a).

As mentioned above, several studies report increased thiols, which correlate with the detoxification pathway and increased lactone content in wines and musts produced from B. cinerea-infected grapes. Together with the upregulation of the phenylpropanoid, anthocyanin, stilbene, and terpene pathways, and with the induction of defense phytohormones pathway, this highlights a deep metabolic reprogramming as a plant defense mechanism against B. cinerea infection. However, transcriptomic studies are unambiguous regarding volatile synthesis. More studies including more varieties and precise definitions of berry sampling and infection protocols are required in the future to better characterize stage and variety dependent responses to B. cinerea which could also give more insight on genotypic plasticity of tolerance to infection of some varieties.

Grapevine leafroll disease is considered the most widespread and devastating virus-associated disease. So far, nine serologically distinct virus types from the Closteroviridae family were associated with GLRD, named grapevine leafroll associated virus (GLRaV) types 1–9, with the most widespread ones being GLRaV-1 and GLRaV-3 (Maree et al., 2013; Velasco et al., 2014). GLRD causes important reductions in yield, vigor, and longevity of vines. It also delays fruit ripening, reduces sugar accumulation, and impairs fruit pigmentation (Guidoni et al., 1997; Maree et al., 2013; Naidu et al., 2014, 2015; Alabi et al., 2016). Decreases in anthocyanin and total flavonoid concentrations due to GLRD infections were related to the downregulation of anthocyanin-related transcripts, such as VvUFGT, VvMYABA1, and other phenylpropanoid genes, such as VvCHS, VvFLS1, and VvMYAPA1 (Vega et al., 2011; Vondras et al., 2021). Vega et al. (2011) also observed a viral repression of sugar transporters, which translated to lower sugar concentration in grapes. Interestingly, a study using a different berry sampling approach, which accounts for potential phenological shifts and intracluster berry heterogeneity, has demonstrated that the downregulation of genes belonging to primary and secondary metabolite pathways was mainly due to the berry phenological delay induced by GLRD infection and not to a direct effect of the viral infection (Rienth et al., 2019b; Ghaffari et al., 2020). In a very comprehensive study on Carbernet Franc over 2years on different rootstocks, Vondras et al. (2021) observed a rootstock specific transcriptomic response of berries from GLRaV-infected vines. Latter authors observed the modulation of genes related to pathogen detection, for example NBS-LRR genes that confer resistance to powdery and downy mildew (DM) in grapevine (Riaz et al., 2011; Zini et al., 2019), as well as abscisic acid (ABA) signaling, phenylpropanoid biosynthesis, and cytoskeleton remodeling similar to previous studies of Vega et al. (2011) and Ghaffari et al. (2020). Interestingly the increase of ABA abundance in GLRD-infected berries (Vondras et al., 2021) was different than that observed for red blotch virus-infected berries, in which ABA abundance and NCED expression decrease in infected berries after véraison (Blanco-Ulate et al., 2017).

In leaves, some studies report a similar upregulation of defense-related genes and a concomitant accumulation of phenylpropanoids, such as resveratrol, which led to an enhanced resistance to downy mildew (Repetto et al., 2012). This highly interesting observation was somehow confirmed in a very elegant experiment, where authors transmitted GFLaV and grapevine rupestris stem pitting-associated virus (GRSPaV), by in vitro-grafting, to Nebbiolo and Chardonnay. Upon subsequent downy and powdery mildew infection, GFLV-infected plants showed a reduction in severity of the diseases caused by powdery and downy mildews in comparison to virus-free plants, which highlights a potential upregulation of plant innate immunity by GLRD infection (Gilardi et al., 2020).

Grapevine red blotch disease is caused by the Grapevine red blotch-associated virus (GRBaV) and was discovered in 2008 in California. GRBD has recently become a major economic problem for the wine industry in many growing regions (Sudarshana et al., 2015; Adiputra et al., 2018; Reynard et al., 2018). GRBaV infections result in the appearance of red patches on the leaf blades, veins, and petioles in red grape varieties, whereas in white grape varieties, they cause irregular chlorotic areas on the leaf blades. Detrimental effects of red blotch disease are similar to GLRD. GRBaV affects berry physiology, causing uneven ripening, higher titratable acidity, and lower anthocyanin and sugar content (Girardello et al., 2019, 2020; Rumbaugh et al., 2021) putatively due to an impairment of carbon import into the berry (Martínez-Lüscher et al., 2019). Rumbaugh et al. (2021) observed a general decrease of fruity aroma compounds in Cabernet Sauvignon, mostly linked to a reduction of monoterpenes, such as limonene, ß-myrcene, α-terpinene, geranial, and p-cymene. Higher titratable acidity has been attributed to lower acid respiration as shown by Pereira et al. (2021), who found 56% higher malic acid and lower tartaric acid and phenolic compounds, such as the flavan-3-ols, catechin, epicatechin and the flavonol quercetin-glucoside, in Cabernet Sauvignon infected with GRBaV.

Using RNA-seq for differential gene expression analysis, Blanco-Ulate et al. (2017) associated the GRBD-induced deterioration of grape quality with a downregulation of key genes of the phenylpropanoid pathway, which confirms aforementioned phenotypic observation. Furthermore, Blanco-Ulate et al. (2017) showed that GRBD disturbs berry development and induces stress responses by altering transcription factors (e.g., VviNACs, VviMYBs, and VviAP2-ERFs) and phytohormone networks causing an inhibition of the ripening process thus reducing color, flavor, and aroma compounds in berries.

Grapevine fanleaf disease is one of the oldest known viral diseases of grapevines and has been found in all wine-growing regions around the world (Raski et al., 1983; Silva et al., 2017). GFLD has been reported to cause significant economic losses by reducing grape yield due to reduction of both cluster weight and berry weight, shortening the longevity of vines, and affecting fruit quality by decreasing the sugar content and titratable acidity (Raski et al., 1983). More detailed studies focusing on berry physiology and quality are not very numerous and often ambiguous. It has been shown that GFLD can also affect the anthocyanin levels in a cultivar-dependent manner. In the variety Manto Negro, GFLD reduced the anthocyanin level (Cretazzo et al., 2010), while in Schioppettino, an increase in anthocyanin content is observed and the relative proportions between di- and tri-hydroxylated or -methylated derivatives of anthocyanins seem to be affected via the upregulation of VviF3H1 and VviF3’H5 and downregulation of VviF3H (Rupnik-Cigoj et al., 2018). Further studies on berries from GFLD-infected vines, including several developmental stages and cultivars, are utterly needed to better understand the effect on fruit quality of this widespread pathogen.

Recently, several emerging viruses have been described (Cieniewicz et al., 2020), with the Pinot Gris Virus (Giampetruzzi et al., 2012) being the most threatening one. It is present in most wine-growing regions from North (Al Rwahnih et al., 2016) and South America (Debat et al., 2020) to almost all the European countries, such as Italy (Gentili et al., 2017), Germany (Messmer et al., 2021), Spain (Ruiz-García and Olmos, 2017), and France (Renault-Spilmont et al., 2018). Although leaf symptoms are well-characterized, its impact on berry physiology has not yet been characterized in detail. The most important detrimental impact of Pinot Gris virus in viticulture is certainly the great reduction in yield, which can range between 66 and 85%, as shown for Glera and Pinot Noir; however, it causes no significant alteration of fruit quality (Bertazzon et al., 2017).