| Summary: | <i>Xylella fastidiosa</i> is the causal agent of several plant diseases affecting fruit and nut crops. <i>Methylobacterium mesophilicum</i> strain SR1.6/6 was isolated from <i>Citrus sinensis</i> and shown to promote plant growth by producing phytohormones, providing nutrients, inhibiting <i>X. fastidiosa</i>, and preventing Citrus Variegated Chlorosis. However, the molecular mechanisms involved in the interaction among these microbes are still unclear. The present work aimed to analyze physiological and molecular aspects of <i>M. mesophilicum</i> SR1.6/6 and <i>X. fastidiosa</i> 9a5c in co-culture. The transcriptome and secretome analyses indicated that <i>X. fastidiosa</i> down-regulates cell division and transport genes and up-regulates stress via induction of chaperones and pathogenicity-related genes including, the lipase-esterase LesA, a protease, as well as an oligopeptidase in response to <i>M. mesophilicum</i> competition. On the other hand, <i>M. mesophilicum</i> also down-regulated transport genes, except for iron uptake, which was up-regulated. Secretome analysis identified four proteins in <i>M. mesophilicum</i> exclusively produced in co-culture with <i>X. fastidiosa</i>, among these, three are related to phosphorous uptake. These results suggest that <i>M. mesophilicum</i> inhibits <i>X. fastidiosa</i> growth mainly due to nutrient competition for iron and phosphorous, thus promoting <i>X. fastidiosa</i> starvation, besides producing enzymes that degrade <i>X. fastidiosa</i> cell wall, mainly hydrolases. The understanding of these interactions provides a direction for control and management of the phytopathogen <i>X. fastidiosa</i>, and consequently, helps to improve citrus growth and productivity.
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