A non-canonical RNAi pathway controls virulence and genome stability in Mucorales

Pérez-Arques, Carlos; Navarro-Mendoza, María Isabel; Murcia, Laura; Navarro, Eusebio; Garre, Victoriano

doi:10.1101/2020.01.14.906289

Cited by 6 publications

(11 citation statements)

References 35 publications

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“…Transcriptomics on rdrp1 and r3b2 mutants demonstrated that these genes play important roles in regulating the fungal response to stressful environments, such as macrophage phagocytosis, as well as movement of TEs. These results that NCRIP play a role in controlling virulence in M. circinelloides (Pérez-Arques et al, 2020).…”

Section: Rnai Silencing Pathways In Mucoralesmentioning

confidence: 64%

Understanding Mucormycoses in the Age of “omics”

2020

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Mucormycoses are deadly invasive infections caused by several fungal species belonging to the subphylum Mucoromycotina, order Mucorales. Hallmarks of disease progression include angioinvasion and tissue necrosis that aid in fungal dissemination through the blood stream, causing deeper infections and resulting in poor penetration of antifungal agents to the site of infection. In the absence of surgical removal of the infected focus, antifungal therapy alone is rarely curative. Even when surgical debridement is combined with high-dose antifungal therapy, the mortality associated with mucormycoses is >50%. The unacceptably high mortality rate, limited options for therapy and the extreme morbidity of highly disfiguring surgical therapy provide a clear mandate to understand the molecular mechanisms that govern pathogenesis with the hopes of developing alternative strategies to treat and prevent mucormycoses. In the absence of robust forward and reverse genetic systems available for this taxonomic group of fungi, unbiased next generation sequence (NGS)-based approaches have provided much needed insights into our understanding of many aspects of Mucormycoses, including genome structure, drug resistance, diagnostic development, and fungus-host interactions. Here, we will discuss the specific contributions that NGSbased approaches have made to the field and discuss open questions that can be addressed using similar approaches.

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Section: Rnai Silencing Pathways In Mucoralesmentioning

confidence: 64%

Understanding Mucormycoses in the Age of “omics”

2020

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“…Later, new studies investigated the role of NCRIP in the regulation of these mucoralean retrotransposons. The lack of NCRIP in mutant strains triggered a strong overaccumulation of sRNAs and a complete depletion of mRNAs compared with wild-type strains [27]. These exciting results indicated a negative regulatory role of NCRIP over the canonical repression of transposons, similar to the repression of NCRIP over the epimutational RNAi pathway.…”

Section: Role Of Ncrip In the Integrity And Defense Of The Genomementioning

confidence: 85%

“…The role of R3B2 in the transgene-induced and the endogenous canonical RNAi pathways is independent of its duties in the NCRIP mechanism. However, recent studies have found a new role of R3B2 and the other components of NCRIP in the negative regulation of the expression of centromeric retrotransposons [27,61]. In these studies, a particular type of centromeres (mosaic centromeres) was identified in Mucorales.…”

Section: Role Of Ncrip In the Integrity And Defense Of The Genomementioning

confidence: 99%

“…The lack of an active NCRIP mechanism results in misregulation of the genetic response of mucoralean spores during the confrontation with macrophages, the first stage of the infection [27,65]. The studies confronting the sRNAs produced explicitly by the NCRIP mechanism with the genome sequence of M. lusitanicus found that this pathway regulates many genes [23].…”

Section: The Ncrip Mechanism Regulates Virulence In Mucoralesmentioning

confidence: 99%

“…In the absence of the target protein, the antifungal compound is unable of inhibiting the regular growth of the fungus. The non-canonical RNA interference pathway (NCRIP) was initially described as a non-specific RNA degradation mechanism, although further studies demonstrated its role in regulating several processes [23,26,27].…”

Section: Introductionmentioning

confidence: 99%

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Role of the Non-Canonical RNAi Pathway in the Antifungal Resistance and Virulence of Mucorales

Cánovas-Márquez¹,

Navarro-Mendoza²,

Pérez-Arques³

et al. 2021

Preprint

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Mucorales are the causal agents for the lethal disease known as mucormycosis. Mortality rates of mucormycosis can reach up to 90%, due to the mucoralean antifungal drug resistance and the lack of effective therapies. A concerning urgency among the medical and scientific community claims to find targets for the development of new treatments. Here, we reviewed different studies de-scribing the role and machinery of a novel non-canonical RNAi pathway (NCRIP) only conserved in Mucorales. Its non-canonical features are the independence of Dicer and Argonautes proteins. Conversely, NCRIP relies on RNA-dependent RNA Polymerases and an atypical ribonuclease III (RNaseIII). NCRIP regulates the expression of mRNAs by degrading them in a specific manner. Its mechanism binds dsRNA but only cuts ssRNA. NCRIP exhibits a diversity of functional roles. It represses the epimutational pathway and the lack of NCRIP increases the generation of drug resistant strains. NCRIP also regulates the control of retrotransposons expression, playing an essential role in genome stability. Finally, NCRIP regulates the response during phagocytosis, affecting the multifactorial process of virulence. These critical NCRIP roles in virulence and antifungal drug resistance, along with its exclusive presence in Mucorales, mark this pathway as a promising target to fight against mucormycosis.

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Integration of RNA‐seq and RNAi reveals the contribution of znuA gene to the pathogenicity of Pseudomonas plecoglossicida and to the immune response of Epinephelus coioides

Wang

Zhao

et al. 2021

Journal of Fish Diseases

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Pseudomonas plecoglossicida is an important pathogen in aquaculture and causes serious economic losses. Our previous study indicated that znuA gene might play an important role in the pathogenicity of P. plecoglossicida. Five shRNAs were designed and synthesized to silence the znuA gene of P. plecoglossicida. Two of the five mutants of P. plecoglossicida exhibited significant reduction in the expression level of znuA mRNA with different efficiencies. The mutant with the highest silencing efficiency of 89.2% was chosen for further studies. Intrapleural injection of the znuA‐RNAi strain at a dose of 105 cfu/fish did not cause the death of Epinephelus coioides, and no significant signs were observed at the spleen surface of infected E. coioides, while the counterpart E. coioides infected by the same dose of wild‐type strain of P. plecoglossicida all died in 5 days post‐infection (dpi). The expression of znuA gene of znuA‐RNAi strain in E. coioides was always lower than that in wild‐type strain of P. plecoglossicida. The pathogen load in the early stage of infection was higher than that in the later stage of infection. Although the infection of the znuA‐RNAi strain of P. plecoglossicida could induce the production of antibodies in E. coioides, it failed to produce a good immune protection against the infection of wild‐type strain of P. plecoglossicida. Compared with the transcriptome data of E. coioides infected by the wild‐type strain of P. plecoglossicida, the transcriptome data of E. coioides infected by the znuA‐RNAi strain of P. plecoglossicida have altered significantly. Among them, KEGG enrichment analysis showed that the focal adhesion pathway was significantly enriched and exhibited the largest number of 302 DEMs (differentially expressed mRNAs). These results showed that the immune response of E. coioides to P. plecoglossicida infection was significantly affected by the RNAi of znuA gene.

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A non-canonical RNAi pathway controls virulence and genome stability in Mucorales

Cited by 6 publications

References 35 publications

Understanding Mucormycoses in the Age of “omics”

Understanding Mucormycoses in the Age of “omics”

Role of the Non-Canonical RNAi Pathway in the Antifungal Resistance and Virulence of Mucorales

Integration of RNA‐seq and RNAi reveals the contribution of znuA gene to the pathogenicity of Pseudomonas plecoglossicida and to the immune response of Epinephelus coioides

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