Gene expression patterns associated with Leishmania panamensis infection in macrophages from BALB/c and C57BL/6 mice

Restrepo, Carlos M.; Llanes, Alejandro; Herrera, Lizzi; Ellis, E. M.; Lleonart, Ricardo; Fernández, Patricia L.

doi:10.1371/journal.pntd.0009225

Cited by 7 publications

(5 citation statements)

References 53 publications

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“…Besides, the gene expression was calculated by the ΔΔCt method [ 42 ]. To find up-regulated and down-regulated genes, log Fold-changes were calculated in the log2 scale (equal to ΔΔCt) that log2 > 0 indicates up-regulation and log2 < 0 indicates down-regulation of genes [ 43 , 44 ].…”

Section: Methodsmentioning

confidence: 99%

The issue beyond resistance: Methicillin-resistant Staphylococcus epidermidis biofilm formation is induced by subinhibitory concentrations of cloxacillin, cefazolin, and clindamycin

et al. 2022

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Staphylococcus epidermis is one of the most frequent causes of device-associated infections due to biofilm formation. Current reports noted that subinhibitory concentrations of antibiotics induce biofilm production in some bacteria. Accordingly, we evaluated the effect of exposure of different subinhibitory concentrations of cloxacillin, cefazolin, clindamycin, and vancomycin on the biofilm formation of methicillin-resistant S. epidermidis (MRSE). Antimicrobial susceptibility testing and minimum inhibitory/bactericidal concentration of antimicrobial agents were determined. MRSE isolates were selected, and their biofilm formation ability was evaluated. The effect of subinhibitory concentrations of cloxacillin, cefazolin, clindamycin, and vancomycin, antibiotics selected among common choices in the clinic, on MRSE biofilm formation was determined by the microtitre method. Besides, the effect of subinhibitory concentrations of cloxacillin, cefazolin, clindamycin, and vancomycin on the expression of the biofilm-associated genes icaA and atlE was evaluated by Reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR). Antimicrobial susceptibility patterns of MRSE strains showed a high level of resistance as follows: 80%, 53.3%, 33.3%, 33.3%, and 26.6%, for erythromycin, trimethoprim-sulfamethoxazole, tetracycline, clindamycin, and gentamicin, respectively. Besides, 73.3% of S. epidermidis strains were Multidrug-resistant (MDR). Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values were in the range of 0.5 to512 μg/mL and 1 to1024 μg/mL for cloxacillin, 0.125 to256 μg/mL and 1 to512 μg/mL for cefazolin, 0.125 to64 μg/mL and 4 to>1024 μg/mL for clindamycin, and 2 to32 μg/mL and 4 to32 μg/mL for vancomycin, respectively. The findings showed that subinhibitory concentrations of cloxacillin, cefazolin, and clindamycin induce biofilm production in MRSE strains. In particular, the OD values of strains were in the range of 0.09–0.95, 0.05–0.86, and 0.06–1 toward cloxacillin, cefazolin, and clindamycin, respectively. On the other hand, exposure to subinhibitory vancomycin concentrations did not increase the biofilm formation in MRSE strains. The findings also demonstrated that sub-MIC of antibiotics up-regulated biofilm-associated genes. In particular, atlE and icaA were up-regulated 0.062 to 1.16 and 0.078 to 1.48 folds, respectively, for cloxacillin, 0.11 to 0.8, and 0.1 to 1.3 folds for cefazolin, 0.18 to 0.98, and 0.19 to 1.4 folds, respectively, for clindamycin. In contrast, the results showed that sub-MIC of vancomycin did not increase the biofilm-associated genes. These findings overall show that exposure to sub-MIC of traditional antibiotics can cause biofilm induction in MRSE, thereby increasing the survival and persistence on various surfaces that worsen the condition of comorbid infections.

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Section: Methodsmentioning

confidence: 99%

The issue beyond resistance: Methicillin-resistant Staphylococcus epidermidis biofilm formation is induced by subinhibitory concentrations of cloxacillin, cefazolin, and clindamycin

et al. 2022

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“…These effects are also dependent on Leishmania spp., which modulate macrophage immunity, adding another level of complexity. For instance, in a recent study, infection with L. panamensis induced a potent activation of classical M1 macrophages in C57BL/6 mice but only an intermediate response in BALB/c mice [ 51 ]. Hence, it would be of interest to study the effects of genetic iron overload using different mouse and Leishmania spp.…”

Section: Discussionmentioning

confidence: 99%

Genetic Iron Overload Hampers Development of Cutaneous Leishmaniasis in Mice

Charlebois

Wagner

et al. 2023

IJMS

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The survival, growth, and virulence of Leishmania spp., a group of protozoan parasites, depends on the proper access and regulation of iron. Macrophages, Leishmania’s host cell, may divert iron traffic by reducing uptake or by increasing the efflux of iron via the exporter ferroportin. This parasite has adapted by inhibiting the synthesis and inducing the degradation of ferroportin. To study the role of iron in leishmaniasis, we employed Hjv−/− mice, a model of hemochromatosis. The disruption of hemojuvelin (Hjv) abrogates the expression of the iron hormone hepcidin. This allows unrestricted iron entry into the plasma from ferroportin-expressing intestinal epithelial cells and tissue macrophages, resulting in systemic iron overload. Mice were injected with Leishmania major in hind footpads or intraperitoneally. Compared with wild-type controls, Hjv−/− mice displayed transient delayed growth of L. major in hind footpads, with a significant difference in parasite burden 4 weeks post-infection. Following acute intraperitoneal exposure to L. major, Hjv−/− peritoneal cells manifested increased expression of inflammatory cytokines and chemokines (Il1b, Tnfa, Cxcl2, and Ccl2). In response to infection with L. infantum, the causative agent of visceral leishmaniasis, Hjv−/− and control mice developed similar liver and splenic parasite burden despite vastly different tissue iron content and ferroportin expression. Thus, genetic iron overload due to hemojuvelin deficiency appears to mitigate the early development of only cutaneous leishmaniasis.

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“…The activation of ASS1 in BMdMs derived from resistant mice could be driven by a decreased uptake of available extracellular arginine by these macrophages. Indeed, previous studies reported reduced expression of the arginine transporter (Slc7a2), in C57BL/6 macrophages (compared to BALB/c) (7) resulting in decreased uptake of available extracellular arginine in response to cytokines (56). Our transcriptomic results show that Leishmania infection also induced a more robust expression of Slc7a2 mRNA in BMdMs derived from BALB/c (data not shown).…”

Section: Furthermore Mif Polymorphism Is Associated With Cutaneous Le...mentioning

confidence: 99%

“…Previous studies have compared the differential responses of macrophages from resistant and susceptible mice induced by Leishmania (6,7). However, to the best of our knowledge, no study has focused on the impact of the basal transcriptomic profile of macrophages, from different host backgrounds, on their response to Leishmania infection.…”

Section: Introductionmentioning

confidence: 99%

Host M-CSF induced gene expression drives changes in susceptible and resistant mice-derived BMdMs upon Leishmania major infection

et al. 2023

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Leishmaniases are a group of diseases with different clinical manifestations. Macrophage-Leishmania interactions are central to the course of the infection. The outcome of the disease depends not only on the pathogenicity and virulence of the parasite, but also on the activation state, the genetic background, and the underlying complex interaction networks operative in the host macrophages. Mouse models, with mice strains having contrasting behavior in response to parasite infection, have been very helpful in exploring the mechanisms underlying differences in disease progression. We here analyzed previously generated dynamic transcriptome data obtained from Leishmania major (L. major) infected bone marrow derived macrophages (BMdMs) from resistant and susceptible mouse. We first identified differentially expressed genes (DEGs) between the M-CSF differentiated macrophages derived from the two hosts, and found a differential basal transcriptome profile independent of Leishmania infection. These host signatures, in which 75% of the genes are directly or indirectly related to the immune system, may account for the differences in the immune response to infection between the two strains. To gain further insights into the underlying biological processes induced by L. major infection driven by the M-CSF DEGs, we mapped the time-resolved expression profiles onto a large protein-protein interaction (PPI) network and performed network propagation to identify modules of interacting proteins that agglomerate infection response signals for each strain. This analysis revealed profound differences in the resulting responses networks related to immune signaling and metabolism that were validated by qRT-PCR time series experiments leading to plausible and provable hypotheses for the differences in disease pathophysiology. In summary, we demonstrate that the host’s gene expression background determines to a large degree its response to L. major infection, and that the gene expression analysis combined with network propagation is an effective approach to help identifying dynamically altered mouse strain-specific networks that hold mechanistic information about these contrasting responses to infection.

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Gene expression patterns associated with Leishmania panamensis infection in macrophages from BALB/c and C57BL/6 mice

Cited by 7 publications

References 53 publications

The issue beyond resistance: Methicillin-resistant Staphylococcus epidermidis biofilm formation is induced by subinhibitory concentrations of cloxacillin, cefazolin, and clindamycin

The issue beyond resistance: Methicillin-resistant Staphylococcus epidermidis biofilm formation is induced by subinhibitory concentrations of cloxacillin, cefazolin, and clindamycin

Genetic Iron Overload Hampers Development of Cutaneous Leishmaniasis in Mice

Host M-CSF induced gene expression drives changes in susceptible and resistant mice-derived BMdMs upon Leishmania major infection

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