TY - JOUR
T1 - B Cell Chronic Lymphocytic Leukemia Development in Mice with Chronic Lung Exposure to Coccidioides Fungal Arthroconidia
AU - Coyne, Vanessa
AU - Mead, Heather L.
AU - Mongini, Patricia K.A.
AU - Barker, Bridget M.
N1 - Funding Information:
Received for publication March 1, 2023. Accepted for publication April 24, 2023. Address correspondence and reprint requests to: Dr. Patricia K. A. Mongini, Pathogen Microbiome Institute, Northern Arizona University, 1395 S Knowles Drive/ Building 56/STE 210, Flagstaff, AZ 86001. E-mail address: patricia.mongini@nau.edu 1P.K.A.M. and B.M.B. are cosenior authors. ORCIDs: 0000-0002-5680-0758 (H.L.M.); 0000-0002-4966-7741 (P.K.A.M.); 0000-0002-3439-4517 (B.M.B.). This work was supported by the Northern Arizona University Foundation. V.C. managed the in vitro growth, isolation, and fixation of Coccidioides arthroconidia, kept records of all mice used for these experiments, administered arthroconidia via the intranasal route, performed all blood collections, monitored mice for survival endpoint, performed euthanasia and necropsies, and contributed to the manuscript; H.L.M. was instrumental in training V.C. in all class II biological safety cabinet procedures involving manipulation of Coccidioides and in guiding early mouse manipulations; P.K.A.M. initiated the hypothesis, developed the project with B.M.B., managed all blood cell enumeration/staining, flow cytometric analyses, and data computation, and wrote the manuscript; and B.M.B. developed the project with P.K.A.M. and was responsible for coordinating all efforts involving Coccidioides and animal manipulation and helped write the manuscript. Abbreviations used in this article: AICDA, activation-induced cytosine deaminase; B-CLL, chronic lymphocytic leukemia; DT, doubling time; MBL, monoclonal B cell lymphocytosis; NET, neutrophil extracellular trap; PAMP, pathogen-associated molecular pattern; Tg, transgenic. The online version of this article contains supplemental material. This article is distributed under the terms of the CC BY-NC-ND 4.0 Unported license.
Publisher Copyright:
Copyright © 2023 The Authors.
PY - 2023/5/1
Y1 - 2023/5/1
N2 - Links between repeated microbial infections and B cell chronic lymphocytic leukemia (B-CLL) have been proposed but not tested directly. This study examines how prolonged exposure to a human fungal pathogen impacts B-CLL development in Em-hTCL1–transgenic mice. Monthly lung exposure to inactivated Coccidioides arthroconidia, agents of Valley fever, altered leukemia development in a species-specific manner, with Coccidioides posadasii hastening B-CLL diagnosis/progression in a fraction of mice and Coccidioides immitis delaying aggressive B-CLL development, despite fostering more rapid monoclonal B cell lymphocytosis. Overall survival did not differ significantly between control and C. posadasii–treated cohorts but was significantly extended in C. immitis–exposed mice. In vivo doubling time analyses of pooled B-CLL showed no difference in growth rates of early and late leukemias. However, within C. immitis–treated mice, B-CLL manifests longer doubling times, as compared with B-CLL in control or C. posadasii–treated mice, and/or evidence of clonal contraction over time. Through linear regression, positive relationships were noted between circulating levels of CD5+/B220low B cells and hematopoietic cells previously linked to B-CLL growth, albeit in a cohort-specific manner. Neutrophils were positively linked to accelerated growth in mice exposed to either Coccidioides species, but not in control mice. Conversely, only C. posadasii–exposed and control cohorts displayed positive links between CD5+/B220low B cell frequency and abundance of M2 anti-inflammatory monocytes and T cells. The current study provides evidence that chronic lung exposure to fungal arthroconidia affects B-CLL development in a manner dependent on fungal genotype. Correlative studies suggest that fungal species differences in the modulation of nonleukemic hematopoietic cells are involved. ImmunoHorizons, 2023, 7: 333–352.
AB - Links between repeated microbial infections and B cell chronic lymphocytic leukemia (B-CLL) have been proposed but not tested directly. This study examines how prolonged exposure to a human fungal pathogen impacts B-CLL development in Em-hTCL1–transgenic mice. Monthly lung exposure to inactivated Coccidioides arthroconidia, agents of Valley fever, altered leukemia development in a species-specific manner, with Coccidioides posadasii hastening B-CLL diagnosis/progression in a fraction of mice and Coccidioides immitis delaying aggressive B-CLL development, despite fostering more rapid monoclonal B cell lymphocytosis. Overall survival did not differ significantly between control and C. posadasii–treated cohorts but was significantly extended in C. immitis–exposed mice. In vivo doubling time analyses of pooled B-CLL showed no difference in growth rates of early and late leukemias. However, within C. immitis–treated mice, B-CLL manifests longer doubling times, as compared with B-CLL in control or C. posadasii–treated mice, and/or evidence of clonal contraction over time. Through linear regression, positive relationships were noted between circulating levels of CD5+/B220low B cells and hematopoietic cells previously linked to B-CLL growth, albeit in a cohort-specific manner. Neutrophils were positively linked to accelerated growth in mice exposed to either Coccidioides species, but not in control mice. Conversely, only C. posadasii–exposed and control cohorts displayed positive links between CD5+/B220low B cell frequency and abundance of M2 anti-inflammatory monocytes and T cells. The current study provides evidence that chronic lung exposure to fungal arthroconidia affects B-CLL development in a manner dependent on fungal genotype. Correlative studies suggest that fungal species differences in the modulation of nonleukemic hematopoietic cells are involved. ImmunoHorizons, 2023, 7: 333–352.
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UR - http://www.scopus.com/inward/citedby.url?scp=85159771051&partnerID=8YFLogxK
U2 - 10.4049/immunohorizons.2300013
DO - 10.4049/immunohorizons.2300013
M3 - Article
C2 - 37195872
AN - SCOPUS:85159771051
SN - 2573-7732
VL - 7
SP - 333
EP - 352
JO - ImmunoHorizons
JF - ImmunoHorizons
IS - 5
ER -