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The multifactorial basis of therapeutic response can obscure the relation between antimicrobial drug susceptibility and clinical outcome. To discern the relationship between parasite susceptibility to meglumine antimoniate (SbV) and therapeutic outcome of cutaneous leishmaniasis, risk factors for treatment failure were considered in evaluating this relationship in ninety-one cutaneous leishmaniasis patients and corresponding clinical strains of Leishmania (Viannia) panamensis. Parasite susceptibility to 32 μg SbV/mL (plasma Cmax) was evaluated in primary human macrophages, PBMCs, and U937 macrophages. Early parasitological response to treatment was determined in lesions of a subgroup of patients, and pathogenicity of Sb-resistant and sensitive clinical strains was compared in BALB/c mice. Parasite survival in cell models and patient lesions was determined by qRT-PCR of Leishmania 7SLRNA transcript. Parasite loads in BALB/c mice were quantified by limiting dilution analysis. The disparate Sb-susceptibility of parasite subpopulations distinguished by isoenzyme profiles (zymodemes) was manifest in all cell models. Notably, Sb-resistance defined by parasite survival, was most effectively discerned in U937 macrophages compared with primary human host cells, significantly higher among strains from patients who failed treatment than cured and, significantly associated with treatment failure. Each unit increase in transformed survival rate corresponded to a 10.6-fold rise in the odds of treatment failure. Furthermore, treatment failure was significantly associated with naturally Sb-resistant zymodeme 2.3 strains, which also produced larger lesions and parasite burdens in BALB/c mice than Sb-sensitive zymodeme 2.2 strains. The confounding effect of host risk factors for treatment failure in discerning this association was evidenced in comparing strains from patients with and without the defined risk factors for treatment failure. These results establish the association of natural resistance to meglumine antimoniate with treatment failure, the importance of host risk factors in evaluating drug susceptibility and treatment outcome, and the clinical and epidemiological relevance of natural Sb-resistance in L. (V.) panamensis subpopulations.

Summary: Drug resistance threatens the effective control of infections, including parasitic diseases such as leishmaniases. Neutrophils are essential players in antimicrobial control, but their role in drug-resistant infections is poorly understood. Here, we evaluated human neutrophil response to clinical parasite strains having distinct natural drug susceptibility. We found that Leishmania antimony drug resistance significantly altered the expression of neutrophil genes, some of them transcribed by specific neutrophil subsets. Infection with drug-resistant parasites increased the expression of detoxification pathways and reduced the production of cytokines. Among these, the chemokine CCL3 was predominantly impacted, which resulted in an impaired ability of neutrophils to attract myeloid cells. Moreover, decreased myeloid recruitment when CCL3 levels are reduced was confirmed by blocking CCL3 in a mouse model. Collectively, these findings reveal that the interplay between naturally drug-resistant parasites and neutrophils modulates the infected skin immune microenvironment, revealing a key role of neutrophils in drug resistance.

ObjectiveArboviruses pose a challenge in ensuring the supply of pathogen-free blood components because they are not routinely screened in blood banks, and blood components from infected asymptomatic donors could be transfused. This study aimed to detect and characterize arboviral infections in Colombian blood donors.MethodsIn a cross-sectional study, the prevalence of dengue (DENV), Zika (ZIKV), and chikungunya (CHIKV) viruses and co-infections of blood donors were compared between an epidemic period (November 2019–February 2020, n = 462) and an endemic period (November 2021–August 2022, n = 1,119). Viral RNA from each donor serum was purified, and the viruses were detected using a previously standardized multiplex hemi-nested RT-PCR protocol. Subsequently, donors who tested positive were surveyed 15 days after the detection of the virus to identify clinical characteristics related to the arboviral infection. The prevalences of each virus were presented as percentages and compared between epidemic and endemic periods.ResultsSignificantly higher prevalences were found in the epidemic period compared with the endemic period for DENV (14.5 vs. 1.9%), ZIKV (7.8 vs. 0.3%), CHIKV (8 vs. 3.3%), and co-infections (4.3 vs. 0.2%). The survey response rate of positive donors in the two periods was 83/175 (47%). In total, 57% of the donors surveyed were asymptomatic. Symptomatic donors most frequently reported headache (31%), malaise (13%), arthralgia (10%), and fever/chills (8%).ConclusionThe prevalence observed in epidemic and endemic periods was higher than that reported in other studies in the Americas. The high proportion of asymptomatic cases found, in addition to the mild and nonspecific manifestations among the symptomatic, may limit the effectiveness of the donor selection criteria used to mitigate the risk of transfusion-transmitted arboviruses.