RESUMEN

Mycobacterium tuberculosis ( Mtb) is one of the leading infectious causes of death worldwide. There is no available licensed therapeutic vaccine that shortens active tuberculosis (TB) disease drug treatment and prevents relapse, despite the World Health Organization's calls. Here, we show that an intranasal DNA vaccine containing a fusion of the stringent response rel Mtb gene with the gene encoding the immature dendritic cell-targeting chemokine, MIP-3α/CCL20, shortens the duration of curative TB treatment in immunocompetent mice. Compared to the first-line regimen for drug-susceptible TB alone, our novel adjunctive vaccine induced greater Rel Mtb -specific T-cell responses associated with optimal TB control in spleen, blood, lungs, mediastinal lymph nodes, and bronchoalveolar lavage (BAL) fluid. These responses were sustained, if not augmented, over time. It also triggered more effective dendritic cell recruitment, activation, and colocalization with T cells, implying enhanced crosstalk between innate and adaptive immunity. Moreover, it potentiated a 6-month TB drug-resistant regimen, rendering it effective across treatment regimens, and also showed promising results in CD4+ knockout mice, perhaps due to enhanced Rel-specific CD8+ T-cell responses. Notably, our novel fusion vaccine was also immunogenic in nonhuman primates, the gold standard animal model for TB vaccine studies, eliciting antigen-specific T-cell responses in blood and BAL fluid analogous to those observed in protected mice. Our findings have critical implications for therapeutic TB vaccine clinical development in immunocompetent and immunocompromised populations and may serve as a model for defining immunological correlates of therapeutic vaccine-induced protection. One sentence summary: A TB vaccine shortens curative drug treatment in mice by eliciting strong TB-protective immune responses and induces similar responses in macaques.

RESUMEN

Candida auris is an emerging human fungal pathogen, first described in Japan in 2009, and first detected in the United States in 2016. Here, we report the first-ever description of C. auris colonizing a human pet, the first identification of C. auris in a non-human mammal in the United States and the first C. auris isolate from the state of Kansas. While analyzing the oral mycobiome of dogs from a shelter in Kansas, the oral swab from one dog was found to contain C. auris as well as three other fungal species. The presence of C. auris in a dog suggests the possibility of zoonotic transmission to humans. The isolate is a member of Clade IV, which has been found in patients in Chicago and Florida, while Clades I and III are the most prevalent in the United States. The isolate is resistant to fluconazole, terbinafine, and amphotericin B but susceptible to caspofungin, consistent with the drug-resistant characteristics of many human C. auris isolates. The source of C. auris transient colonization in this dog is unknown, and there is no evidence that it was further transmitted to humans, other dogs in the shelter, or pets in its adopted household. Isolation of C. auris from a dog in Kansas has public health implications as a potential emerging source for the zoonotic spread of this pathogenic fungus, and for the development of antifungal resistance.IMPORTANCECandida auris is an emerging fungal infection of humans and is particularly problematic because it is multi-drug resistant and difficult to treat. It is also known to be spread from person to person by contact and can remain on surfaces for long periods of time. In this report, a dog in a shelter in Kansas is found to be colonized with Candida auris. This is the first study to document the presence of Candida auris on a pet, the first to document C. auris presence on a non-human mammal in the United States, and the first to report an isolate of C. auris within the state of Kansas. The presence of C. auris in a pet dog raises the possibility of zoonotic transmission from pets to human or vice versa.

Asunto(s)

Antifúngicos , Candidiasis , Perros , Humanos , Animales , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Candida , Candidiasis/microbiología , Candida auris , Kansas , Boca , Mamíferos , Pruebas de Sensibilidad Microbiana

RESUMEN

The purpose of this study was to characterize the variety and diversity of the oral mycobiome of domestic dogs and to identify the commensal and potentially pathogenic fungi present. Two hundred fifty-one buccal swabs from domestic dogs were obtained and struck onto a chromogenic fungal growth medium that distinguishes between fungal species based on colony color and morphology. After isolating and harvesting single colonies, genomic DNA was extracted from pure cultures. PCR was used to amplify a fungal-specific variable rDNA region of the genome, which was then sent for sequencing. Sequencing results were input into the NCBI BLAST database to identify individual components of the oral mycobiome of tested dogs. Of the 251 dogs swabbed, 73 had cultivable fungi present and 10 dogs had multiple fungal species isolated. Although the dogs did not show signs of oral infections at the time, we did find fungal species that cause pathogenicity in animals and humans. Among fungal isolates, Malassezia pachydermatis and species from the genus Candida were predominant. Following fungal isolate identification, antifungal drug susceptibility tests were performed on each isolate toward the medically important antifungal drugs including fluconazole, ketoconazole, and terbinafine. Drug susceptibility test results indicated that a large number of isolates had high MIC values for all three drugs. Exploring the oral mycobiome of dogs, as well as the corresponding drug susceptibility profiles, can have important implications for canine dental hygiene, health, and medical treatment. Identifying the microorganisms within the canine mouth can illustrate a common pathway for fungal pathogens of One Health concern to spread from our canine companions to humans.