{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T07:00:06Z","timestamp":1790233206303,"version":"4.1.0"},"reference-count":47,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2017,6,13]],"date-time":"2017-06-13T00:00:00Z","timestamp":1497312000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2017,7,5]],"date-time":"2017-07-05T00:00:00Z","timestamp":1499212800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100003593","name":"MCTI | Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["302372\/2014-8"],"award-info":[{"award-number":["302372\/2014-8"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2012\/23942-9"],"award-info":[{"award-number":["2012\/23942-9"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2016\/12948-7"],"award-info":[{"award-number":["2016\/12948-7"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2013\/22375-6"],"award-info":[{"award-number":["2013\/22375-6"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2015\/17541-0"],"award-info":[{"award-number":["2015\/17541-0"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2017,7,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Aspergillus fumigatus<\/jats:italic>\n                    is an opportunistic fungal pathogen that causes invasive aspergillosis (IA), a life-threatening disease in immunocompromised humans. The echinocandin caspofungin, adopted as a second-line therapy in combating IA, is a \u03b2-1,3-glucan synthase inhibitor, which, when used in high concentrations, reverts the anticipated\n                    <jats:italic>A.\u00a0fumigatus<\/jats:italic>\n                    growth inhibition, a phenomenon called the \u201ccaspofungin paradoxical effect\u201d (CPE). The CPE has been widely associated with increased chitin content in the cell wall due to a compensatory upregulation of chitin synthase-encoding genes. Here, we demonstrate that the CPE is dependent on the cell wall integrity (CWI) mitogen-activated protein kinase MpkA\n                    <jats:sup>MPK1<\/jats:sup>\n                    and its associated transcription factor (TF) RlmA\n                    <jats:sup>RLM1<\/jats:sup>\n                    , which regulate chitin synthase gene expression in response to different concentrations of caspofungin. Furthermore, the calcium- and calcineurin-dependent TF CrzA binds to and regulates the expression of specific chitin synthase genes during the CPE. These results suggest that the regulation of cell wall biosynthetic genes occurs by several cellular signaling pathways. In addition, CrzA is also involved in cell wall organization in the absence of caspofungin. Differences in the CPE were also observed between two\n                    <jats:italic>A.\u00a0fumigatus<\/jats:italic>\n                    clinical isolates, which led to the identification of a novel basic leucine zipper TF, termed ZipD. This TF functions in the calcium-calcineurin pathway and is involved in the regulation of cell wall biosynthesis genes. This study therefore unraveled additional mechanisms and novel factors governing the CPE response, which ultimately could aid in developing more effective antifungal therapies.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    Systemic\n                    <jats:italic>Aspergillus fumigatus<\/jats:italic>\n                    infections are often accompanied by high mortality rates. The fungal cell wall is important for infection as it has immunomodulatory and immunoevasive properties. Paradoxical growth of\n                    <jats:italic>A.\u00a0fumigatus<\/jats:italic>\n                    in the presence of high concentrations of the cell wall-disturbing agent caspofungin has been observed for more than a decade, although the mechanistic nature of this phenomenon remains largely uncharacterized. Here, we show that the CWI pathway components MpkA and RlmA as well as the calcium\/calcineurin-responsive transcription factor CrzA regulate the expression of cell wall biosynthetic genes during the caspofungin paradoxical effect (CPE). Furthermore, an additional, novel calcium\/calcineurin-responsive transcription factor was identified to play a role in cell wall biosynthesis gene expression during the CPE. This work paints a crucial role for calcium metabolism in the CPE and provides further insight into the complex regulation of cell wall biosynthesis, which could ultimately lead to the development of more efficient antifungal therapies.\n                  <\/jats:p>","DOI":"10.1128\/mbio.00705-17","type":"journal-article","created":{"date-parts":[[2017,6,13]],"date-time":"2017-06-13T20:10:20Z","timestamp":1497384620000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":76,"title":["The\n                    <i>Aspergillus fumigatus<\/i>\n                    CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect"],"prefix":"10.1128","volume":"8","author":[{"given":"Laure Nicolas Annick","family":"Ries","sequence":"first","affiliation":[{"name":"Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo, Ribeir\u00e3o Preto, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina Campos","family":"Rocha","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica e Evolu\u00e7\u00e3o, Centro de Ci\u00eancias Biol\u00f3gicas e da Sa\u00fade, Universidade Federal de S\u00e3o Carlos, S\u00e3o Carlos, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia Alves","family":"de Castro","sequence":"additional","affiliation":[{"name":"Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo, Ribeir\u00e3o Preto, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Silva-Rocha","sequence":"additional","affiliation":[{"name":"Faculdade de Medicina de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo, Ribeir\u00e3o Preto, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto Nascimento","family":"Silva","sequence":"additional","affiliation":[{"name":"Faculdade de Medicina de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo, Ribeir\u00e3o Preto, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda Zanolli","family":"Freitas","sequence":"additional","affiliation":[{"name":"Universidade Estadual Paulista, UNESP, Instituto de Qu\u00edmica, Araraquara, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leandro Jos\u00e9","family":"de Assis","sequence":"additional","affiliation":[{"name":"Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo, Ribeir\u00e3o Preto, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C\u00e9lia","family":"Bertolini","sequence":"additional","affiliation":[{"name":"Universidade Estadual Paulista, UNESP, Instituto de Qu\u00edmica, Araraquara, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iran","family":"Malavazi","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica e Evolu\u00e7\u00e3o, Centro de Ci\u00eancias Biol\u00f3gicas e da Sa\u00fade, Universidade Federal de S\u00e3o Carlos, S\u00e3o Carlos, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo H.","family":"Goldman","sequence":"additional","affiliation":[{"name":"Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo, Ribeir\u00e3o Preto, S\u00e3o Paulo, 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