Biology subjects

Shlezinger, N.

Publications and source records attributed to Shlezinger, N..

5 recordsLinked to original sources

bioRxiv2024

Aspergillus dsRNA virus drives fungal fitness and pathogenicity in the mammalian host

Fungal pathogens pose a significant threat to global health. Aspergillus fumigatus accounts for approximately 65% of all invasive fungal infections in humans, with mortality rates from invasive aspergillosis reaching nearly 50%. Mycoviruses, viruses that infect fungi, can modulate fungal virulence in plant pathogenic fungi, leading to either hypovirulence or hypervirulence. However, their impact on fungal pathogenesis in mammals has remained largely unexplored. Here, utilizing an A. fumigatus strain naturally infected with Aspergillus fumigatus polymycovirus-1M (AfuPmV-1M), we found that the mycovirus confers a significant survival advantage to the fungus under conditions of oxidative stress, heat stress, and within the murine lung. Thus, AfuPmV-1M modulates fungal fitness, resulting in increased virulence and the progression of exacerbated fungal disease. Moreover, antiviral treatment reverses the virus-mediated increase in virulence, representing a promising "antipathogenicity" therapy against virus-bearing pathogenic fungi. Collectively, these findings reveal that mycoviruses act as pivotalbackseat drivers in human fungal diseases, underscoring significant clinical implications and offering promising avenues for novel therapeutic strategies.

microbiology↗

bioRxiv2024

Competitive fungal commensalism mitigates candidiasis pathology

The mycobiota are a critical part of the gut microbiome, but host-fungal interactions and specific functional contributions of commensal fungi to host fitness remain incompletely understood. Here we report the identification of a new fungal commensal, Kazachstania heterogenica var. weizmannii, isolated from murine intestines. K. weizmannii exposure prevented Candida albicans colonization and significantly reduced the commensal C. albicans burden in colonized animals. Following immunosuppression of C. albicans colonized mice, competitive fungal commensalism thereby mitigated fatal candidiasis. Metagenome analysis revealed K. weizmannii presence among human commensals. Our results reveal competitive fungal commensalism within the intestinal microbiota, independent of bacteria and immune responses, that could bear potential therapeutic value for the management of C. albicans-mediated diseases.

immunology↗

bioRxiv2023

Dectin-1/CARD9-induction of the TFEB and TFE3 gene network is dispensable for phagocyte anti-Aspergillus activity in the lung

Myeloid phagocytes of the respiratory immune system, such as neutrophils, monocytes, and alveolar macrophages, are essential for immunity to Aspergillus fumigatus, the most common etiologic agent of mold pneumonia worldwide. Following engulfment of A. fumigatus conidia, fusion of the phagosome with the lysosome, is a critical process for killing conidia. TFEB and TFE3 are transcription factors that regulate lysosomal biogenesis under stress and are activated by inflammatory stimuli in macrophages, but it is unknown whether TFEB and TFE3 contribute to anti-Aspergillus immunity during infection. We found that lung neutrophils express TFEB and TFE3, and their target genes were upregulated during A. fumigatus lung infection. Additionally, A. fumigatus infection induced nuclear accumulation of TFEB and TFE3 in macrophages in a process regulated by Dectin-1 and CARD9 signaling. Genetic deletion of Tfeb and Tfe3 impaired macrophage killing of A. fumigatus conidia. However, in a murine immune competent Aspergillus infection model with genetic deficiency of Tfeb and Tfe3 in hematopoietic cells, we surprisingly found that lung myeloid phagocytes had no defects in conidial phagocytosis or killing. Loss of TFEB and TFE3 did not impact murine survival or clearance of A. fumigatus from the lungs. Our findings indicate that myeloid phagocytes activate TFEB and TFE3 in response to A. fumigatus, and while this pathway promotes macrophage fungicidal activity in vitro, genetic loss can be functionally compensated at the portal of infection in the lung, resulting in no measurable defect in fungal control and host survival.

immunology↗

bioRxiv2023

Maternal exposure to environmental levels of carbamazepine induces mild growth retardation in mouse embryos

As chemical pollution is constantly increasing, the impact on the environment and public health must be investigated. This study focuses on the anticonvulsant drug carbamazepine (CBZ), which is ubiquitously present in the environment. Due to its physicochemical properties and stability during wastewater treatment, CBZ is detected in reclaimed wastewater, surface water and groundwater. In water-scarce regions heavily relying on treated wastewater for crop irrigation, CBZ is detected in arable land, produce and even in humans consuming crops irrigated with recealimed wastewater. Aalthough environmental levels of CBZ are very low, risks associated with unintentional exposure to CBZ are essential to be revealed. In perinatal medicine, CBZ is a teratogen; its prescription to pregnant women increases the risk for fetal malformations. This raises the concern of whether environmental exposure to CBZ may also impact embryogenesis. Studies in zebrafish and chick embryos or in cell culture have indicated negative outcomes upon exposure to low CBZ levels. Yet, these systems do not recapitulate the manner by which human fetuses are exposed to pharmaceuticals via maternal uptake. Here, we employed the mouse model to determine whether maternal exposure to environmental-relevant doses of CBZ will impact embryonic development. No effects on fertility, number of gestation sacs, gross embryonic malformations or fetal survival were detected. Yet, embryos were growth-delayed compared to controls (p=0.0011), as manifested in lower embryonic stage and somite number, earlier morphological features and reduction in mitotically-active cells. This study provides the first evidence for the effect of environmental concentration of CBZ on the developmental kinetics of maternally-exposed mammalian embryos. While the developmental delay was relatively modest, its consistency in high number of biological replicates, together with the known implication of developmental delay on post-natal health, calls for further in-depth risk analyses to reveal the effects of pharmaceuticals released to the environment on public health.

developmental biology↗

bioRxiv2022

Quorum sensing peptidic inhibitor rescue host immune system eradication: a novel QS infectivity mechanism

Subverting the host immune system is a major task for any given pathogen to assure its survival and proliferation. For the opportunistic human pathogen Bacillus cereus (Bc), immune evasion enables the establishment of potent infections. In various species of the Bc group, the pleiotropic regulator PlcR and its cognate cell-cell signaling peptide PapR7 regulates virulence genes expression in response to fluctuations in population density, i.e., a quorum-sensing (QS) system. However, how QS exerts its effects during infections, and whether PlcR confers the immune evading ability remain unclear. Herein, we report how interception of the QS communication in Bc obliterates the ability to control the host immune system. Here we designed a peptide-based QS inhibitor that suppresses PlcR-dependent virulence factor expression and attenuates Bc infectivity in mouse models. We demonstrate that the QS peptidic inhibitor blocks host immune system-mediated eradication by reducing the expression of PlcR-regulated major toxins. Our findings provide the first evidence that Bc infectivity is regulated by QS circuit mediated destruction of the host immunity, thus reveal a new strategy to limit Bc virulence and enhance host defense. This peptidic quorum-quenching agent constitutes readily accessible chemical tool for studying how other pathogen QS systems modulate host immunity and forms a basis for development of anti-infective therapeutics.

microbiology↗