Candida albicans stimulates formation of a multi-receptor complex that mediates epithelial cell invasion during oropharyngeal infection

Hyr1 enables C. albicans to resist killing by neutrophils.

“Previously, it was discovered that Hyr1 enables C. albicans to resist killing by neutrophils [24]. We verified this result with human neutrophils using hyr1Δ/Δ mutants constructed in both the SC5314 and SN250 strain backgrounds (Figs 8A and S5A).”

• cites [24] G Luo, 2010, Candida albicans Hyr1p confers resistance to neutrophil killing and is a potential vaccine target, J Infect Dis sourceSupported

Hyr1 is required for maximal virulence in an immunosuppressed mouse model of OPC.

“It has previously been found that Hyr1 also required for maximal virulence in an immunosuppressed mouse model of OPC [25].”

• cites [25] P Dwivedi, 2011, Role of Bcr1-activated genes Hwp1 and Hyr1 in Candida albicans oral mucosal biofilms and neutrophil evasion., PLoS ONE. sourceSupported

• AssumptionRests on an assumption: The mouse model of oropharyngeal candidiasis is predictive of human oropharyngeal candidiasis.

Previously identified C. albicans invasins Als3 and Ssa1 mediate invasion of oral epithelial cells by interacting with E-cadherin and EGFR.

“Previously, we identified two C. albicans invasins, Als3 and Ssa1 that mediate invasion of oral epithelial cells by interacting with E-cadherin and EGFR [16,17,19].”

• cites [16] QT Phan, 2007, Als3 is a Candida albicans invasin that binds to cadherins and induces endocytosis by host cells, PLoS Biol sourceSupported
• cites [17] W Zhu, 2012, EGFR and HER2 receptor kinase signaling mediate epithelial cell invasion by Candida albicans during oropharyngeal infection, Proc Natl Acad Sci USA sourceNot checked — no full text of the source
• cites [19] JN Sun, 2010, Host cell invasion and virulence mediated by Candida albicans Ssa1., PLoS Pathog. sourcePartly supported

  The Results sections on cadherin binding and Ssa1–Als3 interactions report that both invasins contribute to oral epithelial-cell invasion and link them to E-cadherin binding. The passages found do not identify EGFR as an interacting receptor (searched: EGFR and epidermal growth factor receptor), so that part of the claim is unsupported by this paper. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Hyr1 contributes to virulence by enabling C. albicans to resist being killed by neutrophils.

“Hyr1 has been found to contribute to virulence by enabling C. albicans to resist being killed by neutrophils [24].”

• cites [24] G Luo, 2010, Candida albicans Hyr1p confers resistance to neutrophil killing and is a potential vaccine target, J Infect Dis sourceSupported

siRNA knockdown of c-Met decreases endocytosis of C. albicans by approximately 50%.

“Both siRNA knockdown of c-Met and blockade of c-Met kinase activity with the specific tyrosine kinase inhibitor SGX523 decreased the endocytosis of C. albicans by approximately 50% (Fig 1D and 1E).”

E-cadherin knockdown reduces phosphorylation of EGFR in C. albicans-infected oral epithelial cells.

“When epithelial cell E-cadherin was knocked down with siRNA prior to C. albicans infection, there was reduced phosphorylation of both c-Met and EGFR (Fig 3A–3C).”

Although Hyr1 and Als3 interact with the same epithelial cell receptors, deletion of HYR1 and ALS3 has different effects on interactions of C. albicans with epithelial cells.

“Although Hyr1 and Als3 interacted with the same epithelial cell receptors, deletion of HYR1 and ALS3 had different effects on the interactions of C. albicans with epithelial cells.”

C. albicans infection induces c-Met autophosphorylation detectable within 5 min and persisting for at least 60 min.

“By immunoblotting of oral epithelial cell lysates with phosphospecific antibodies, we determined that C. albicans infection induced c-Met autophosphorylation that was detectable within 5 min and persisted for at least 60 min (Fig 1B and 1C).”

The hyr1Δ/Δ single mutant induces the same amount of epithelial cell damage as the wild-type strain.

“Although the als3Δ/Δ single mutant and the hyr1Δ/Δ als3Δ/Δ double mutant caused virtually no epithelial cell damage, the hyr1Δ/Δ single mutant induced the same amount of damage as the wild-type strain (Fig 7E).”

Candidalysin is dispensable for C. albicans to induce phosphorylation of c-Met.

“Although the ece1Δ/Δ mutant induced minimal phosphorylation of EGFR, it stimulated the phosphorylation of c-Met similarly to the wild-type strain, indicating that candidalysin is dispensable for c-Met activation (S4B–S4D Fig).”

C. albicans infection causes a modest but significant increase in association of c-Met with EGFR.

“When the epithelial cells were infected with C. albicans, there was a marked increase in the association of E-cadherin with both c-Met and EGFR, and a modest but still significant increase in the association of c-Met with EGFR.”

The phosphorylation and endocytosis defects of the hyr1Δ/Δ mutant are restored by complementing with a wild-type copy of HYR1.

“The phosphorylation and endocytosis defects of the hyr1Δ/Δ mutant were restored by complementing the mutant with a wild-type copy of HYR1.”

Deletion of HYR1 renders C. albicans more susceptible to killing by mouse neutrophils.

“Deletion of HYR1 also rendered C. albicans more susceptible to killing by mouse neutrophils (Fig 8B).”

The combination of SGX523 and gefitinib had no effect on invasion of C. albicans into fixed epithelial cells (active penetration).

“This reduction in epithelial cell uptake was due solely to inhibition of receptor-induced endocytosis because the combination of SGX523 and gefitinib had no effect on the invasion of C. albicans into fixed epithelial cells, which occurs by the process of active penetration (S2A and S2B Fig).”

c-Met interacts with C. albicans Ssa1.

“Proteomics analysis revealed that c-Met interacts with C. albicans Hyr1, Als3 and Ssa1.”

• Also stated in: § Hyr1 is a C. albicans ligand for c-Met · plain

  “Both Als3 and Ssa1 were detected in the band containing proteins from the wild-type strain, but not the als3Δ/Δ ssa1Δ/Δ mutant, thus validating the assay (Table 1).”

C. albicans infection causes a marked increase in association of E-cadherin with c-Met.

“When the epithelial cells were infected with C. albicans, there was a marked increase in the association of E-cadherin with both c-Met and EGFR, and a modest but still significant increase in the association of c-Met with EGFR.”

E-cadherin is necessary for C. albicans to activate c-Met in oral epithelial cells.

“E-cadherin is necessary for C. albicans to activate both c-Met and EGFR and to induce the endocytosis of C. albicans.”

• Also stated in: § E-cadherin interacts with both c-Met and EGFR · plain

  “When epithelial cell E-cadherin was knocked down with siRNA prior to C. albicans infection, there was reduced phosphorylation of both c-Met and EGFR (Fig 3A–3C).”

Als3 is required for C. albicans to stimulate EGFR in oral epithelial cells in vitro.

“Both Hyr1 and Als3 are required for C. albicans to stimulate c-Met and EGFR in oral epithelial cells in vitro and for full virulence during OPC in mice.”

• Also stated in: § Hyr1-mediated invasion is dispensable for epithelial cell damage · plain

  “Both the als3Δ/Δ single mutant and the hyr1Δ/Δ als3Δ/Δ double mutant induced minimal phosphorylation of c-Met and EGFR, similarly to the hyr1Δ/Δ single mutant (Fig 7A–7C).”

At day 1 post-infection, oral fungal burden of phagocyte-deficient mice infected with hyr1Δ/Δ als3Δ/Δ double mutant is similar to mice infected with wild-type strain.

“At day 1 post-infection, the oral fungal burden of the phagocyte-deficient mice infected with the hyr1Δ/Δ als3Δ/Δ double mutant was similar to mice infected with the wild-type strain (Fig 10C).”

C. albicans infection causes c-Met and EGFR to form a complex with E-cadherin.

“The proximity ligation and co-immunoprecipitation data showed that C. albicans infection cause c-Met and EGFR to form a complex with E-cadherin.”

C. albicans infection enhances formation of a multi-protein complex containing c-Met, EGFR, and E-cadherin.

“Taken together, these results indicate that C. albicans infection enhances the formation of a multi-protein complex that contains c-Met, EGFR, and E-cadherin.”

A C. albicans als3Δ/Δ ssa1Δ/Δ mutant induces minimal phosphorylation of both EGFR and c-Met.

“Because Als3 and Ssa1 are surface expressed only on hyphae and are required for C. albicans to activate EGFR in oral epithelial cells [17], we tested a C. albicans als3Δ/Δ ssa1Δ/Δ mutant and found that it induced minimal phosphorylation of both EGFR and c-Met (Fig 5D–5F), suggesting that Als3 and/or Ssa1 are required for the activation of both receptors.”

• cites [17] W Zhu, 2012, EGFR and HER2 receptor kinase signaling mediate epithelial cell invasion by Candida albicans during oropharyngeal infection, Proc Natl Acad Sci USA sourceNot checked — no full text of the source

Treating mice with small molecule inhibitors of c-Met and EGFR ameliorates OPC.

“Treating mice with small molecule inhibitors of c-Met and EGFR ameliorates OPC, demonstrating the potential therapeutic efficacy of blocking these host receptors for C. albicans.”

• Also stated in: § Hyr1 and Als3 are required for maximal virulence during OPC · plain

  “Thus, dual inhibition of EGFR and c-Met ameliorates OPC.”

At day 2 post-infection, oral fungal burden of phagocyte-depleted mice infected with hyr1Δ/Δ als3Δ/Δ double mutant is significantly lower than that of mice infected with wild-type strain.

“At day 2 post-infection, the oral fungal burden of the phagocyte-depleted mice infected with the hyr1Δ/Δ als3Δ/Δ double mutant was significantly lower than that of mice infected with the wild-type strain (Fig 10D).”

Hyr1 is required for full virulence during OPC in mice.

“Both Hyr1 and Als3 are required for C. albicans to stimulate c-Met and EGFR in oral epithelial cells in vitro and for full virulence during OPC in mice.”

• Also stated in: § Hyr1 and Als3 are required for maximal virulence during OPC · plain

  “After 2 d of infection, the oral fungal burden of mice infected with all three mutants was lower than the mice infected with the wild-type strain (Fig 10B).”

c-Met interacts with C. albicans Hyr1.

“Proteomics analysis revealed that c-Met interacts with C. albicans Hyr1, Als3 and Ssa1.”

• Also stated in: § Hyr1 is a C. albicans ligand for c-Met · plain

  “Notably, multiple Hyr1 peptides were identified in the bands from both strains.”

After 2 days of infection, oral fungal burden of mice infected with all three mutants is lower than mice infected with wild-type strain.

“After 2 d of infection, the oral fungal burden of mice infected with all three mutants was lower than the mice infected with the wild-type strain (Fig 10B).”

Multiple Hyr1 peptides were identified in the far Western bands from both wild-type and als3Δ/Δ ssa1Δ/Δ strains.

“Notably, multiple Hyr1 peptides were identified in the bands from both strains.”

The hyr1Δ/Δ mutant is still more susceptible to killing by c-Met deficient neutrophils than the wild-type strain.

“Although the c-Met deficient neutrophils had reduced capacity to kill C. albicans, the hyr1Δ/Δ mutant was still more susceptible to killing by these neutrophils than the wild-type strain (Fig 8B).”

Hyr1 is required for C. albicans to stimulate EGFR in oral epithelial cells in vitro.

“Both Hyr1 and Als3 are required for C. albicans to stimulate c-Met and EGFR in oral epithelial cells in vitro and for full virulence during OPC in mice.”

• Also stated in: § Hyr1 is a C. albicans ligand for c-Met · plain

  “This mutant also had reduced capacity to stimulate the phosphorylation of EGFR as compared to the wild-type strain (Fig 5H and 5J).”

c-Met interacts with C. albicans Als3.

“Proteomics analysis revealed that c-Met interacts with C. albicans Hyr1, Als3 and Ssa1.”

• Also stated in: § Hyr1 is a C. albicans ligand for c-Met · plain

  “Both Als3 and Ssa1 were detected in the band containing proteins from the wild-type strain, but not the als3Δ/Δ ssa1Δ/Δ mutant, thus validating the assay (Table 1).”

Hyr1 is dispensable for C. albicans to induce a proinflammatory response by oral epithelial cells in vitro.

“Collectively, these data indicate that Hyr1 is dispensable for C. albicans to induce a proinflammatory response by oral epithelial cells in vitro.”

E-cadherin knockdown reduces phosphorylation of c-Met in C. albicans-infected oral epithelial cells.

“When epithelial cell E-cadherin was knocked down with siRNA prior to C. albicans infection, there was reduced phosphorylation of both c-Met and EGFR (Fig 3A–3C).”

E-cadherin is necessary for C. albicans to activate EGFR in oral epithelial cells.

“E-cadherin is necessary for C. albicans to activate both c-Met and EGFR and to induce the endocytosis of C. albicans.”

• Also stated in: § E-cadherin interacts with both c-Met and EGFR · plain

  “When epithelial cell E-cadherin was knocked down with siRNA prior to C. albicans infection, there was reduced phosphorylation of both c-Met and EGFR (Fig 3A–3C).”

Als3 is required for full virulence during OPC in mice.

“Both Hyr1 and Als3 are required for C. albicans to stimulate c-Met and EGFR in oral epithelial cells in vitro and for full virulence during OPC in mice.”

• Also stated in: § Hyr1 and Als3 are required for maximal virulence during OPC · plain

  “After 2 d of infection, the oral fungal burden of mice infected with all three mutants was lower than the mice infected with the wild-type strain (Fig 10B).”

An hyr1Δ/Δ deletion mutant induces minimal phosphorylation of c-Met.

“An hyr1Δ/Δ deletion mutant induced minimal phosphorylation of c-Met (Fig 5H and 5I).”

In response to C. albicans, c-Met forms a multi-protein complex with EGFR and E-cadherin.

“In response to C. albicans, c-Met forms a multi-protein complex with EGFR and E-cadherin that is required for the endocytosis of the organism in vitro and for maximal virulence during OPC.”

E-cadherin is necessary for C. albicans to induce endocytosis by oral epithelial cells.

“E-cadherin is necessary for C. albicans to activate both c-Met and EGFR and to induce the endocytosis of C. albicans.”

• Also stated in: § E-cadherin interacts with both c-Met and EGFR · plain

  “While E-cadherin knockdown also decreased the endocytosis of C. albicans, the combination of E-cadherin knockdown with either SGX523 or gefitinib did not inhibit endocytosis further (Fig 3D and 3E), and there was no effect on adherence (S2F and S2G Fig).”

The hyr1Δ/Δ mutant has reduced capacity to stimulate phosphorylation of EGFR compared to wild-type.

“This mutant also had reduced capacity to stimulate the phosphorylation of EGFR as compared to the wild-type strain (Fig 5H and 5J).”

C. albicans induces phosphorylation of c-Met independently of EGFR.

“Thus, C. albicans induces the phosphorylation of c-Met independently of EGFR.”

The presence of EGFR and HER2 is required for C. albicans to induce maximal phosphorylation of c-Met.

“Thus, the presence of EGFR and HER2 is required for C. albicans to induce maximal phosphorylation of c-Met.”

Both the als3Δ/Δ single mutant and the hyr1Δ/Δ als3Δ/Δ double mutant induce minimal phosphorylation of c-Met and EGFR, similarly to the hyr1Δ/Δ single mutant.

“Both the als3Δ/Δ single mutant and the hyr1Δ/Δ als3Δ/Δ double mutant induced minimal phosphorylation of c-Met and EGFR, similarly to the hyr1Δ/Δ single mutant (Fig 7A–7C).”

Blockade of c-Met kinase activity with SGX523 decreases endocytosis of C. albicans by approximately 50%.

“Both siRNA knockdown of c-Met and blockade of c-Met kinase activity with the specific tyrosine kinase inhibitor SGX523 decreased the endocytosis of C. albicans by approximately 50% (Fig 1D and 1E).”

Als3 is required for C. albicans to stimulate c-Met in oral epithelial cells in vitro.

“Both Hyr1 and Als3 are required for C. albicans to stimulate c-Met and EGFR in oral epithelial cells in vitro and for full virulence during OPC in mice.”

• Also stated in: § Hyr1-mediated invasion is dispensable for epithelial cell damage · plain

  “Both the als3Δ/Δ single mutant and the hyr1Δ/Δ als3Δ/Δ double mutant induced minimal phosphorylation of c-Met and EGFR, similarly to the hyr1Δ/Δ single mutant (Fig 7A–7C).”

C. albicans infection causes a marked increase in association of E-cadherin with EGFR.

“When the epithelial cells were infected with C. albicans, there was a marked increase in the association of E-cadherin with both c-Met and EGFR, and a modest but still significant increase in the association of c-Met with EGFR.”

Hyr1 is required for C. albicans to stimulate c-Met in oral epithelial cells in vitro.

“Both Hyr1 and Als3 are required for C. albicans to stimulate c-Met and EGFR in oral epithelial cells in vitro and for full virulence during OPC in mice.”

• Also stated in: § Hyr1 is a C. albicans ligand for c-Met · plain

  “An hyr1Δ/Δ deletion mutant induced minimal phosphorylation of c-Met (Fig 5H and 5I).”

c-Met binds to a single broad band in cell wall proteins from hyphae of wild-type or als3Δ/Δ ssa1Δ/Δ mutant, but not wild-type yeast.

“We found that c-Met bound to a single broad band in lanes containing cell wall proteins from hyphae of the wild-type strain or the als3Δ/Δ ssa1Δ/Δ mutant, but not wild-type yeast (Fig 5G).”

Phosphorylation of c-Met and EGFR is induced by C. albicans hyphae but not by yeast-phase organisms.

“The phosphorylation of c-Met and EGFR was induced by C. albicans hyphae, but not by yeast-phase organisms, indicating that the C. albicans ligand for c-Met must be expressed predominantly by hyphae (Fig 5A–5C).”

c-Met functions as a host cell receptor for C. albicans.

“Here, we report that c-Met functions as a host cell receptor for C. albicans.”

• Also stated in: § Discussion · hedged

  “The data presented here indicate that C. albicans interacts with c-Met on oral epithelial cells and that this interaction is required for the normal endocytosis of the fungus.”

C. albicans infection of oral epithelial cells induces c-Met to form a multi-protein complex with E-cadherin and EGFR.

“We found that C. albicans infection of oral epithelial cells induces c-Met to form a multi-protein complex with E-cadherin and the epidermal growth factor receptor (EGFR).”

• Also stated in: § E-cadherin interacts with both c-Met and EGFR · hedged

  “Taken together, these results indicate that C. albicans infection enhances the formation of a multi-protein complex that contains c-Met, EGFR, and E-cadherin.”

E-cadherin knockdown decreases endocytosis of C. albicans.

“While E-cadherin knockdown also decreased the endocytosis of C. albicans, the combination of E-cadherin knockdown with either SGX523 or gefitinib did not inhibit endocytosis further (Fig 3D and 3E), and there was no effect on adherence (S2F and S2G Fig).”

The hyr1Δ/Δ mutant invades fixed epithelial cells similarly to the wild-type strain.

“To test this possibility, we assessed the invasion of the hyr1Δ/Δ mutant into fixed epithelial cells and found that it was similar to the wild-type strain (Figs 7F and S4F).”

c-Met deficient neutrophils have reduced capacity to kill C. albicans.

“Although the c-Met deficient neutrophils had reduced capacity to kill C. albicans, the hyr1Δ/Δ mutant was still more susceptible to killing by these neutrophils than the wild-type strain (Fig 8B).”

c-Met forms a complex with EGFR and E-cadherin.

“forms a complex with EGFR and E-cadherin”

• AssumptionRests on an assumption: The antibodies used in immunofluorescence, proximity ligation, immunoprecipitation, and immunoblotting specifically detect their intended targets.

The c-Met/EGFR/E-cadherin complex interacts with Hyr1.

“this complex interacts with Hyr1”

• AssumptionRests on an assumption: The antibodies used in immunofluorescence, proximity ligation, immunoprecipitation, and immunoblotting specifically detect their intended targets.

c-Met is required for maximal killing of C. albicans by neutrophils.

“our data with c-Met deficient neutrophils indicate that c-Met is required for maximal killing of C. albicans”

• AssumptionRests on an assumption: The c-Met deficient neutrophils used are specifically deficient in c-Met and have no other relevant functional defects.

The c-Met/EGFR/E-cadherin complex mediates endocytosis of C. albicans by epithelial cells.

“to mediate the endocytosis of C. albicans”

• Also stated in: § Discussion · plain

  “and induces epithelial cell endocytosis”

• AssumptionRests on an assumption: The antibodies used in immunofluorescence, proximity ligation, immunoprecipitation, and immunoblotting specifically detect their intended targets.

Hyr1 mediates resistance to neutrophil killing independently of c-Met.

“they also show that Hyr1 mediates resistance to neutrophil killing independently of c-Met”

• AssumptionRests on an assumption: In vitro neutrophil killing assays reflect phagocyte-mediated killing in vivo.
• AssumptionRests on an assumption: The c-Met deficient neutrophils used are specifically deficient in c-Met and have no other relevant functional defects.

Hyr1 is required for maximal virulence during OPC in immunocompetent mice.

“The results of the current studies indicate that Hyr1 is required for maximal virulence in during OPC in immunocompetent mice.”

• AssumptionRests on an assumption: The mouse model of oropharyngeal candidiasis is predictive of human oropharyngeal candidiasis.

c-Met is a novel oral epithelial cell receptor.

“this work identifies c-Met as a novel oral epithelial cell receptor”

In immunosuppressed mice, combined inhibition of EGFR and c-Met ameliorated the severity of OPC.

“We also found that in immunosuppressed mice, the combined inhibition of EGFR and c-Met ameliorated the severity of OPC”

• AssumptionRests on an assumption: The mouse model of oropharyngeal candidiasis is predictive of human oropharyngeal candidiasis.

Hyr1 and Als3 mediate virulence during OPC in mice by functioning in the same pathway.

“As predicted by our in vitro results, we found that Hyr1 and Als3 mediate virulence during OPC in mice by functioning in the same pathway.”

• AssumptionRests on an assumption: The mouse model of oropharyngeal candidiasis is predictive of human oropharyngeal candidiasis.

In response to C. albicans infection, c-Met and EGFR are activated independently of each other.

“By contrast, we found that inhibition of c-Met with SGX523 did not block C. albicans-induced phosphorylation of EGFR, and that inhibition of EGFR with gefitinib did not reduce phosphorylation of c-Met. These results suggest that in response to C. albicans infection, each of these receptors is activated independently of the other.”

Contact with C. albicans hyphae activates c-Met similarly to EGFR.

“Collectively, these results indicate that contact with C. albicans hyphae activates c-Met similarly to EGFR.”

The c-Met/EGFR/E-cadherin complex is required for maximal virulence during OPC.

“In response to C. albicans, c-Met forms a multi-protein complex with EGFR and E-cadherin that is required for the endocytosis of the organism in vitro and for maximal virulence during OPC.”

The presence of EGFR is necessary for c-Met to induce endocytosis.

“Collectively, these results indicate that the presence of EGFR is necessary for c-Met to induce endocytosis.”

E-cadherin is a common member of the c-Met and EGFR signaling pathways that mediate endocytosis of C. albicans.

“Collectively, these results support the model that E-cadherin is a common member of the c-Met and EGFR signaling pathways that mediate the endocytosis of C. albicans.”

In phagocyte-replete mice, reduced virulence of hyr1Δ/Δ als3Δ/Δ double mutant at day 1 is due mainly to increased susceptibility to phagocyte killing.

“The absence of a virulence defect of the hyr1Δ/Δ als3Δ/Δ double mutant in the phagocyte-deficient mice suggests that in phagocyte-replete mice, the reduced virulence of this mutant at this time point is due mainly to its increased susceptibility to phagocyte killing.”

Dual inhibition of EGFR and c-Met ameliorates OPC.

“Thus, dual inhibition of EGFR and c-Met ameliorates OPC.”

Both Hyr1 and Als3 mediate virulence during OPC.

“Collectively, these results indicated that both Hyr1 and Als3 mediate virulence during OPC.”

Hyr1 reduces susceptibility to neutrophil killing by a mechanism independent of c-Met.

“These results suggest that although c-Met is required for maximal neutrophil fungicidal activity, Hyr1 reduces susceptibility to neutrophil killing by a mechanism that is independent of this receptor.”

c-Met activity partially governs the endocytosis of C. albicans.

“Therefore, c-Met activity partially governs the endocytosis of C. albicans.”

Invasion mediated by Hyr1 is dispensable for inducing epithelial cell damage.

“These results suggest that invasion mediated by Hyr1 is dispensable for inducing epithelial cell damage.”

The c-Met/EGFR/E-cadherin complex is required for endocytosis of C. albicans in vitro.

“In response to C. albicans, c-Met forms a multi-protein complex with EGFR and E-cadherin that is required for the endocytosis of the organism in vitro and for maximal virulence during OPC.”

Blocking c-Met and EGFR has potential therapeutic efficacy for C. albicans OPC.

“Treating mice with small molecule inhibitors of c-Met and EGFR ameliorates OPC, demonstrating the potential therapeutic efficacy of blocking these host receptors for C. albicans.”

The additive inhibitory effect of gefitinib and SGX523 on endocytosis is consistent with the model that both c-Met and EGFR are required for maximal uptake of C. albicans.

“The additive inhibitory effect of gefitinib and SGX523 on the endocytosis of C. albicans is consistent with the model that both c-Met and EGFR are required for maximal uptake of this organism.”

The C. albicans ligand for c-Met must be expressed predominantly by hyphae.

“The phosphorylation of c-Met and EGFR was induced by C. albicans hyphae, but not by yeast-phase organisms, indicating that the C. albicans ligand for c-Met must be expressed predominantly by hyphae (Fig 5A–5C).”

Three different epithelial cell pathogens have evolved independent strategies that target c-Met.

“Thus, three different epithelial cell pathogens have evolved independent strategies that target c-Met.”

Als3 and Hyr1 are required to activate both c-Met and EGFR during OPC in mice.

“Thus, Als3 and Hyr1 are required to activate both c-Met and EGFR during OPC in mice.”

Als3 induces resistance to neutrophil killing by functioning in the same pathway as Hyr1.

“Our data support this finding and also suggest that Als3 induces resistance to neutrophil killing by functioning in the same pathway as Hyr1.”

C. glabrata cells engineered to express C. albicans Als3 have enhanced resistance to neutrophil killing.

“Previously, we found that C. glabrata cells that were engineered to express C. albicans Als3 had enhanced resistance to neutrophil killing, thus supporting this novel function of Als3 [41].”

• cites [41] Y Fu, 2013, Investigation of the function of Candida albicans Als3 by heterologous expression in Candida glabrata, Infect Immun sourceNot checked — no full text of the source

In contrast to the als3Δ/Δ mutant, it is likely that the hyr1Δ/Δ mutant can still form an invasion pocket via active penetration into which candidalysin can accumulate to sufficient levels to stimulate and damage oral epithelial cells.

“In contrast to the als3Δ/Δ mutant, it is likely that the hyr1Δ/Δ mutant can still form an invasion pocket via active penetration into which candidalysin can accumulate to sufficient levels to stimulate and damage oral epithelial cells.”

Hyr1 functions as an invasin.

“thus demonstrating that Hyr1 functions as an invasin”

The host cell targets of Hyr1, EGFR and c-Met are potential therapeutic targets.

“The current data suggest that the host cell targets of Hyr1, EGFR and c-Met are also potential therapeutic targets.”

• AssumptionRests on an assumption: The mouse model of oropharyngeal candidiasis is predictive of human oropharyngeal candidiasis.

After 1 day of infection, Hyr1 and Als3 contribute to virulence by reducing susceptibility to phagocyte killing.

“The results with phagocyte-depleted mice also suggest that after 1 day of infection, Hyr1 and Als3 contribute to virulence by reducing susceptibility to phagocyte killing”

• AssumptionRests on an assumption: The mouse model of oropharyngeal candidiasis is predictive of human oropharyngeal candidiasis.
• AssumptionRests on an assumption: In vitro neutrophil killing assays reflect phagocyte-mediated killing in vivo.