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Cyclic‐di‐GMP regulation of virulence in bacterial pathogens

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Signaling pathways allow bacteria to adapt to changing environments. For pathogenic bacteria, signaling pathways allow for timely expression of virulence factors and the repression of antivirulence factors within the mammalian host. As the bacteria exit the mammalian host, signaling pathways enable the expression of factors promoting survival in the environment and/or nonmammalian hosts. One such signaling pathway uses the dinucleotide cyclic‐di‐GMP (c‐di‐GMP), and many bacterial genomes encode numerous proteins that are responsible for synthesizing and degrading c‐di‐GMP. Once made, c‐di‐GMP binds to individual protein and RNA receptors to allosterically alter the macromolecule function to drive phenotypic changes. Each bacterial genome encodes unique sets of genes for c‐di‐GMP signaling and virulence factors so the regulation by c‐di‐GMP is organism specific. Recent works have pointed to evidence that c‐di‐GMP regulates virulence in different bacterial pathogens of mammalian hosts. In this review, we discuss the criteria for determining the contribution of signaling nucleotides to pathogenesis using a well‐characterized signaling nucleotide, cyclic AMP (cAMP), in Pseudomonas aeruginosa. Using these criteria, we review the roles of c‐di‐GMP in mediating virulence and highlight common themes that exist among eight diverse pathogens that cause different diseases through different routes of infection and transmission.

C‐di‐GMP signaling in vector‐borne pathogens. Repression of c‐di‐GMP‐regulated extracellular matrix components in the mammalian host prevents host immune recognition and clearance, thus allowing disseminating systemic infection. Activation of c‐di‐GMP‐regulated extracellular matrix components in the insect vector allows bacteria to survive the insect and infect additional mammalian hosts.
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C‐di‐GMP signaling in gastrointestinal pathogens. Repression of c‐di‐GMP‐regulated extracellular matrix components in the mammalian host prevents host recognition and immune clearance. Activation of c‐di‐GMP‐regulated extracellular matrix components outside the mammalian host allows bacteria to survive environmental stresses and reentry through the low pH of the stomach. Once inside the mammalian intestine, bacteria reduce c‐di‐GMP levels in order to establish a successful infection. *S. Typhimurium does not encode the pga genes encoding for the biosynthetic genes for producing the PNAG polysaccharide. Heterologous expression of pga genes attenuates virulence of S. Typhimurium.
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