Bacterial Peptidoglycan Triggers Candida albicans Hyphal Growth by Directly Activating the Adenylyl Cyclase Cyr1p

Abstract

Human serum potently induces hyphal development of the polymorphic fungal pathogen Candida albicans, a phenotype that contributes critically to infections. The fungal adenylyl cyclase Cyr1p is a key component of the cAMP/PKA-signaling pathway that controls diverse infection-related traits, including hyphal morphogenesis. However, identity of the serum hyphal inducer(s) and its fungal sensor remain unknown. Our initial analyses of active serum fractions revealed signs of bacterial peptidoglycan (PGN)-like molecules. Here, we show that several purified and synthetic muramyl dipeptides (MDPs), subunits of PGN, can strongly promote C. albicans hyphal growth. Analogous to PGN recognition by the mammalian sensors Nod1 and Nod2 through their leucine-rich-repeat (LRR) domain, we show that MDPs activate Cyr1p by directly binding to its LRR domain. Given the abundance of PGN in the intestine, a natural habitat and invasion site for C. albicans, our findings have important implications for the mechanisms of infection by this pathogen.

Do Genetic Susceptibility, Toll-like Receptors, and Pathogen-associated Molecular Patterns Modulate the Effects of Wear?

“…For example, dental bacteria can cause episodic bacteremia and release LPS into the circulation and may also seed biofilm formation on orthopaedic implants [29,77,78]. Moreover, there is extensive evidence that PAMPs can translocate from the gastrointestinal tract to distant organs, including the bone marrow, and systemically prime the innate immune system in the absence of infection [14,18,25,28,42,63,70,71,84,101,115]. This translocation of PAMPs from the gut can be increased by minor surgical procedures, such as colonoscopy, a high-fat diet, or even a single high-fat meal [3,14,52,71,84].…”

“…The local effects of the PAMPs can also include increased corrosion of titanium surfaces, which in turn can increase PAMP binding to the surface [6]. Alternatively, gut-derived PAMPs could induce chronic low-level inflammation systemically [14,18,25,28,42,52,63,70,71,84,101,115], as appears to occur in the synovium during rheumatoid arthritis [12,106]. In this regard, it has recently been proposed that systemic low-level inflammation may contribute to aseptic loosening [81].…”

Sensing of mammalian IL-17A regulates fungal adaptation and virulence

“…2f). Cyr1p is a key component of the cAMP/PKA signaling pathway directly involved in signal sensing and in controlling hyphal morphogenesis in C. albicans 21 .…”

Linking cellular actin status with cAMP signaling inCandida albicans

“…[10][11][12] However, how these cyclases sense and integrate distinct signals to produce a contextually appropriate amount of cAMP remains largely unknown. Recent studies [6][7][8] of C. albicans response to hyphal-inducing signals raise a fascinating possibility: sensors for various signals might be embedded in the different domains of Cyr1, and the signal integration may thus be achieved by a combined allosteric effect on the catalytic domain. To investigate this hypothesis, we performed affinity-purification of Cyr1 under non-denaturing conditions to determine whether purified Cyr1 was capable of sensing various hyphal-inducing signals and consequently increasing cAMP synthesis.…”

“…3,4 A variety of host-associated factors have been found to promote C. albicans hyphal growth such as serum, bacterial-derived peptidoglycan, certain amino acids, CO 2 , and neutral pH. [5][6][7][8] These signals promote hyphal growth by activating the single adenylyl cyclase Cyr1, resulting a sharp rise in the cellular cAMP level. cAMP activates protein kinase A (PKA) which in turn causes transcriptional activation of hyphaspecific genes leading to hyphal growth.…”