Effect and Mechanism of Cotrimoxazole Against Talaromyces marneffei in vitro.

Humans Trimethoprim, Sulfamethoxazole Drug Combination / pharmacology Interleukin-10 / therapeutic use Tumor Necrosis Factor-alpha Interleukin-6 HIV Infections / complications Acquired Immunodeficiency Syndrome / complications Opportunistic Infections / complications
Cotrimoxazole Dectin-1 signaling pathway Dihydrofolate reductase Dihydropteroic acid synthetase HIV/AIDS Talaromyces marneffei

Journal

Mycopathologia
ISSN: 1573-0832
Titre abrégé: Mycopathologia
Pays: Netherlands
ID NLM: 7505689

Informations de publication

Date de publication:
Dec 2022
Historique:
received: 11 04 2022
accepted: 18 09 2022
pubmed: 2 11 2022
medline: 23 11 2022
entrez: 1 11 2022
Statut: ppublish

Résumé

Talaromyces marneffei (formerly Penicillium marneffei) is an important thermally dimorphic fungus endemic which is characterized by one of the most frequent opportunistic infections in HIV/AIDS patients, mainly prevalent in Southeast Asia, southern China, and northeastern India. Cotrimoxazole(CTX) inhibits folic acid synthesis which is important for the survival of many bacteria, protozoa, and fungi, thereby commonly used to prevent several opportunistic infections among HIV/AIDS patients. In addition to preventing other HIV-associated opportunistic infections, CTX prophylaxis are considered to have the potential to prevent T. marneffei infection in HIV/AIDS patients receiving antiretroviral therapy (ART). However, the effect of cotrimoxazole towards T. marneffei fungus in vitro remains unclear. Human THP-1 macrophages were used as cell model in vitro to explore the effect and mechanism of cotrimoxazole resistance towards T. marneffei. Cell viability assay and drug sensitivity colony forming units (CFU) experiments were conducted to determine the minimum inhibitory concentration (MIC) of cotrimoxazole inside and outside THP-1 macrophages respectively. Enzyme-linked immunosorbent assay (Elisa) was used to measure the concentration of Dihydropteroic acid synthetase (DHPS), Dihydrofolate synthetase (DHFS) and Dihydrofolate reductase (DHFR) between T. marneffei adding TMP/SMX and without adding TMP/SMX group respectively. Real-time fluorescence quantitative PCR(qPCR) was performed to detect the mRNA expression levels in Dectin-1 mediated signaling pathway and downstream inflammatory cytokines including IL-6, IL-10, IL-23A, CXCL8 and TNF-α released by T. marneffei-infected macrophages between adding TMP/SMX and without adding TMP/SMX group respectively. Cotrimoxazole can inhibit the proliferation of T. marneffei within safe concentration inside and outside THP-1 macrophages. Drug susceptibility results showed the minimal inhibit concentration(MIC) of 1:5 TMP/SMX was ranging from 14/70 to 68/340 μg/ml. The MIC of SMX was ranging from 100 to 360 μg/ml. The MIC of TMP was ranging from 240 to 400 μg/ml outside macrophages. The MIC of TMP/SMX was ranging from 36/180 to 68/340 μg/ml. The MIC of SMX was ranging from 340 to 360 μg/ml. The MIC of TMP was ranging from 320 to 400 μg/ml inside macrophages. The synergistic interaction of 1:5 TMP/SMX was more effective in inhibiting T. marneffei than separate SMX and TMP. DHPS, DHFS and DHFR can be inhibited by cotrimoxazole within safe and effective concentration. Dectin-1 expression is increased following T. marneffei infection, leading to the increase of IL-6, IL-10, IL-23A and the decrease of CXCL8 and TNF-α. Conversely, cotrimoxazole decrease the levels of Dectin-1, IL-6, IL-10, IL-23A and increase the levels of CXCL8 and TNF-α, thereby enhancing the intracellular killing-T. marneffei capacity of macrophages. Our findings indicated that cotrimoxazole directly inhibited T. marneffei growth by blocking DHPS, DHFS and DHFR and indirectly inhibited T. marneffei growth perhaps by regulating the Dectin-1 signaling pathway, which may effectively interfere with the defense ability of the host against T. marneffei infection.

Sections du résumé

BACKGROUND BACKGROUND
Talaromyces marneffei (formerly Penicillium marneffei) is an important thermally dimorphic fungus endemic which is characterized by one of the most frequent opportunistic infections in HIV/AIDS patients, mainly prevalent in Southeast Asia, southern China, and northeastern India. Cotrimoxazole(CTX) inhibits folic acid synthesis which is important for the survival of many bacteria, protozoa, and fungi, thereby commonly used to prevent several opportunistic infections among HIV/AIDS patients. In addition to preventing other HIV-associated opportunistic infections, CTX prophylaxis are considered to have the potential to prevent T. marneffei infection in HIV/AIDS patients receiving antiretroviral therapy (ART). However, the effect of cotrimoxazole towards T. marneffei fungus in vitro remains unclear.
METHODS METHODS
Human THP-1 macrophages were used as cell model in vitro to explore the effect and mechanism of cotrimoxazole resistance towards T. marneffei. Cell viability assay and drug sensitivity colony forming units (CFU) experiments were conducted to determine the minimum inhibitory concentration (MIC) of cotrimoxazole inside and outside THP-1 macrophages respectively. Enzyme-linked immunosorbent assay (Elisa) was used to measure the concentration of Dihydropteroic acid synthetase (DHPS), Dihydrofolate synthetase (DHFS) and Dihydrofolate reductase (DHFR) between T. marneffei adding TMP/SMX and without adding TMP/SMX group respectively. Real-time fluorescence quantitative PCR(qPCR) was performed to detect the mRNA expression levels in Dectin-1 mediated signaling pathway and downstream inflammatory cytokines including IL-6, IL-10, IL-23A, CXCL8 and TNF-α released by T. marneffei-infected macrophages between adding TMP/SMX and without adding TMP/SMX group respectively.
RESULTS RESULTS
Cotrimoxazole can inhibit the proliferation of T. marneffei within safe concentration inside and outside THP-1 macrophages. Drug susceptibility results showed the minimal inhibit concentration(MIC) of 1:5 TMP/SMX was ranging from 14/70 to 68/340 μg/ml. The MIC of SMX was ranging from 100 to 360 μg/ml. The MIC of TMP was ranging from 240 to 400 μg/ml outside macrophages. The MIC of TMP/SMX was ranging from 36/180 to 68/340 μg/ml. The MIC of SMX was ranging from 340 to 360 μg/ml. The MIC of TMP was ranging from 320 to 400 μg/ml inside macrophages. The synergistic interaction of 1:5 TMP/SMX was more effective in inhibiting T. marneffei than separate SMX and TMP. DHPS, DHFS and DHFR can be inhibited by cotrimoxazole within safe and effective concentration. Dectin-1 expression is increased following T. marneffei infection, leading to the increase of IL-6, IL-10, IL-23A and the decrease of CXCL8 and TNF-α. Conversely, cotrimoxazole decrease the levels of Dectin-1, IL-6, IL-10, IL-23A and increase the levels of CXCL8 and TNF-α, thereby enhancing the intracellular killing-T. marneffei capacity of macrophages.
CONCLUSIONS CONCLUSIONS
Our findings indicated that cotrimoxazole directly inhibited T. marneffei growth by blocking DHPS, DHFS and DHFR and indirectly inhibited T. marneffei growth perhaps by regulating the Dectin-1 signaling pathway, which may effectively interfere with the defense ability of the host against T. marneffei infection.

Identifiants

DOI: 10.1007/s11046-022-00673-2 PMID: 36318375
pubmed: 36318375
doi: 10.1007/s11046-022-00673-2
pii: 10.1007/s11046-022-00673-2
doi:

Substances chimiques

Trimethoprim, Sulfamethoxazole Drug Combination 8064-90-2
Interleukin-10 130068-27-8
Tumor Necrosis Factor-alpha 0
Interleukin-6 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

579-593

Subventions

Organisme : Science Fund for Distinguished Young Scholars of Guangxi Province
ID : 2018GXNSFFA281001
Organisme : China National Funds for Distinguished Young Scientists
ID : 8197081279
Organisme : China National Funds for Distinguished Young Scientists
ID : 81960602
Organisme : China National Funds for Distinguished Young Scientists
ID : 81971935
Organisme : Guangxi Key Research and Development Plan
ID : GuikeAB18050022
Organisme : Guangxi Youth Science Foundation of Guangxi Medical University
ID : GXMUYSF201906

Informations de copyright

© 2022. The Author(s), under exclusive licence to Springer Nature B.V.

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Auteurs

Jie Chen (J)

Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China.
Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.
Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning, 530021, Guangxi, China.

Rongfeng Chen (R)

Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China.
Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.

Wudi Wei (W)

Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China.
Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.

Fengxiang Qin (F)

Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China.
Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.

Xiu Chen (X)

Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China.
Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.

Jinhao He (J)

Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China.

Hong Zhang (H)

Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China.

Gang Wang (G)

Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China.
Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.

Minjuan Shi (M)

Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China.
Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.

Tongxue Qin (T)

Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China.
Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.

Yinlu Liao (Y)

Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China.
Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.

Yuting Wu (Y)

Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China.
Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.

Beibei Lu (B)

Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China.
Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.

Xing Tao (X)

Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China.
Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China.

Li Ye (L)

Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China. yeli@gxmu.edu.cn.
Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China. yeli@gxmu.edu.cn.

Hao Liang (H)

Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China. lianghao@gxmu.edu.cn.
Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China. lianghao@gxmu.edu.cn.

Junjun Jiang (J)

Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China. jiangjunjun@gxmu.edu.cn.
Guangxi-ASEAN Collaborative Innovation Center for Major Disease Prevention and Treatment, Life Sciences Institute, Guangxi Medical University, Nanning, 530021, Guangxi, China. jiangjunjun@gxmu.edu.cn.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Effect and Mechanism of Cotrimoxazole Against...
questionsmedicales.fr › Préparations pharmaceutiques › Association médicamenteuse › Association triméthoprime-sulfaméthoxazole › Effect and Mechanism of Cotrimoxazole Against...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Interleukines › Interleukine-10 › Effect and Mechanism of Cotrimoxazole Against...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Facteurs de nécrose tumorale › Facteur de nécrose tumorale alpha › Effect and Mechanism of Cotrimoxazole Against...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Interleukines › Interleukine-6 › Effect and Mechanism of Cotrimoxazole Against...
questionsmedicales.fr › Maladies du système immunitaire › Déficits immunitaires › Infections à VIH › Effect and Mechanism of Cotrimoxazole Against...
questionsmedicales.fr › Maladies du système immunitaire › Déficits immunitaires › Infections à VIH › Syndrome d'immunodéficience acquise › Effect and Mechanism of Cotrimoxazole Against...
questionsmedicales.fr › Infection › Infections opportunistes › Effect and Mechanism of Cotrimoxazole Against...