Rac2 is a major actor of Drosophila resistance to Pseudomonas aeruginosa acting in phagocytic cells

Abstract

Pathogen recognition and engulfment by phagocytic cells of the blood cell lineage constitute the first line of defense against invading pathogens. This cellular immune response is conserved throughout evolution and depends strictly on cytoskeletal changes regulated by the RhoGTPases family. Many pathogens have developed toxins modifying RhoGTPases activity to their own benefit. In particular, the Exoenzyme S (ExoS) toxin of the Gram-negative bacteria Pseudomonas aeruginosa is directly injected into the host cell cytoplasm and contains a GAP domain (ExoSGAP) targeting RhoGTPases. Searching for the contribution of each RhoGTPases, Rho1, Rac1, Rac2, Mtl (Mig2-like) and Cdc42 to fly resistance to P. aeruginosa infections, we found that Rac2 is required to resist to P. aeruginosa and to other Gram-negative or Gram-positive bacteria. The Rac2 immune-deficient phenotype is attributable to defective engulfment of pathogens since Rac2 -mutant macrophages exhibited strong reduction in the phagocytosis level of both Gram-negative and Gram-positive bacterial particles whereas systemic immune signaling pathways, including Toll, Immune deficiency and Jun kinases, were not affected. Co-expression of Rac2 and ExoSGAP rescued the increased sensitivity to P. aeruginosa observed in ExoSGAP-expressing flies suggesting that Rac2 is the main host factor whose function is inhibited by the GAP domain of the ExoS toxin.

Pathogen-Derived Effectors Trigger Protective Immunity via Activation of the Rac2 Enzyme and the IMD or Rip Kinase Signaling Pathway

“…Further suggesting a potential role for Rac2, both J96 and J96-ΔCNF1 showed comparable growth in flies lacking Rac2 (Rac2Δ) (Supplementary Figure SF1a), an observation that was in keeping with the possibility that the immune response triggered by CNF1 was mediated by Rac2. However, consistent with previous reports (Avet-Rochex et al, 2007), and independent of CNF1, Rac2Δ flies showed increased susceptibility to infection with J96 (Supplementary Figure SF1b) and other pathogens and somewhat confounded interpretation of these data.…”

TM9SF4 is required forDrosophilacellular immunity via cell adhesion and phagocytosis

“…Indeed, TM9SF4 ectopic expression might interfere with unknown signalling pathways as suggested by the observation that tissue-directed expression of TM9SF4 induces strong morphogenesis defects (unpublished observations). Similarly, increased sensitivity was observed when Rac2 was overexpressed in the haemocyte lineage (Avet-Rochex et al, 2007). These observations indicate that expression of TM9SF4 must be finely tuned in phagocytic cells to preserve their function.…”

Mechanisms of Drosophila Immunity - An Innate Immune System at Work

“…Small GTPases are also required for the morphological changes of plasmatocytes and lamellocytes during encapsulation as well as for phagocytosis [132][133][134][135]. Both bacterial and eukaryotic virulence factors with similarity to RhoGAPs might target GTPases in immune tissues [136].…”