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Article

Evaluation of Sex Differences in Murine Diabetic Ketoacidosis and Neutropenic Models of Invasive Mucormycosis

by
Teclegiorgis Gebremariam
1,
Sondus Alkhazraji
1,
Abdullah Alqarihi
1,
Nathan P. Wiederhold
2,
Laura K. Najvar
2,3,
Thomas F. Patterson
2,3,
Scott G. Filler
1,4 and
Ashraf S. Ibrahim
1,4,*
1
The Division of Infectious Diseases, The Lundquist Institute for Biomedical Innovation at Harbor-University of California at Los Angeles (UCLA) Medical Center, Torrance, CA 90502, USA
2
University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
3
South Texas Veterans Health Care System, San Antonio, TX 78229, USA
4
David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
*
Author to whom correspondence should be addressed.
J. Fungi 2021, 7(4), 313; https://doi.org/10.3390/jof7040313
Submission received: 8 April 2021 / Revised: 15 April 2021 / Accepted: 16 April 2021 / Published: 18 April 2021
(This article belongs to the Section Fungal Pathogenesis and Disease Control)
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Abstract

There is increased concern that the quality, generalizability and reproducibility of biomedical research can be influenced by the sex of animals used. We studied the differences between male and female mice in response to invasive pulmonary mucormycosis including susceptibility to infection, host immune reaction and responses to antifungal therapy. We used diabetic ketoacidotic (DKA) or neutropenic mice infected with either Rhizopus delemar or Mucor circinelloides. The only difference detected was that when DKA mice were infected with M. circinelloides, female mice were more resistant to infection than male mice (median survival time of 5 vs. 2 days for female and male mice, respectively). However, a 100% lethality was detected among infected animals of both sexes. Treatment with either liposomal amphotericin B (L-AMB) or posaconazole (POSA) protected mice from infection and eliminated the difference seen between infected but untreated female and male mice. Treatment with L-AMB consistently outperformed POSA in prolonging survival and reducing tissue fungal burden of DKA and neutropenic mice infected with R. delemar or M. circinelloides, in both mouse sexes. While little difference was detected in cytokine levels among both sexes, mucormycosis infection in the DKA mouse model induced more inflammatory cytokines/chemokines involved in neutrophil (CXCL1) and macrophage (CXCL2) recruitment vs. uninfected mice. As expected, this inflammatory response was reduced in the neutropenic mouse model. Our studies show that there are few differences between female and male DKA or neutropenic mice infected with mucormycosis with no effect on the outcome of treatment or host immune response.
Keywords: Rhizopus; Mucor; mucormycosis; murine; sex Rhizopus; Mucor; mucormycosis; murine; sex

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MDPI and ACS Style

Gebremariam, T.; Alkhazraji, S.; Alqarihi, A.; Wiederhold, N.P.; Najvar, L.K.; Patterson, T.F.; Filler, S.G.; Ibrahim, A.S. Evaluation of Sex Differences in Murine Diabetic Ketoacidosis and Neutropenic Models of Invasive Mucormycosis. J. Fungi 2021, 7, 313. https://doi.org/10.3390/jof7040313

AMA Style

Gebremariam T, Alkhazraji S, Alqarihi A, Wiederhold NP, Najvar LK, Patterson TF, Filler SG, Ibrahim AS. Evaluation of Sex Differences in Murine Diabetic Ketoacidosis and Neutropenic Models of Invasive Mucormycosis. Journal of Fungi. 2021; 7(4):313. https://doi.org/10.3390/jof7040313

Chicago/Turabian Style

Gebremariam, Teclegiorgis, Sondus Alkhazraji, Abdullah Alqarihi, Nathan P. Wiederhold, Laura K. Najvar, Thomas F. Patterson, Scott G. Filler, and Ashraf S. Ibrahim. 2021. "Evaluation of Sex Differences in Murine Diabetic Ketoacidosis and Neutropenic Models of Invasive Mucormycosis" Journal of Fungi 7, no. 4: 313. https://doi.org/10.3390/jof7040313

APA Style

Gebremariam, T., Alkhazraji, S., Alqarihi, A., Wiederhold, N. P., Najvar, L. K., Patterson, T. F., Filler, S. G., & Ibrahim, A. S. (2021). Evaluation of Sex Differences in Murine Diabetic Ketoacidosis and Neutropenic Models of Invasive Mucormycosis. Journal of Fungi, 7(4), 313. https://doi.org/10.3390/jof7040313

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