Biology subjects

Nemeth, J.

Publications and source records attributed to Nemeth, J..

7 recordsLinked to original sources

bioRxiv2025

Interdependent Dynamics of mRNA Expression and HIV-1 Viral Load: Insights from Transcriptomics and Mendelian Randomization

The interaction between HIV-1 and the host immune system plays a crucial role in the natural control and progression of the infection. Previous studies have identified APOBEC3G, Tetherin, SAMHD1, and SERINC5 as HIV-1 host restriction factors, which are counteracted by the viral proteins Vif, Vpu, and Nef, respectively. The blood expression levels of some of these host proteins are correlated with HIV load, suggesting that interindividual differences in the spontaneous control of HIV infection might lead to the identification of novel HIV restriction factors. Our study enrolled 150 participants from the Swiss HIV Cohort Study with human genome-wide genotyping data, pre-antiretroviral treatment peripheral blood mononuclear cells (PBMC) aliquots and HIV load measurements. Using BrB-seq, we quantified mRNA expression of all protein-coding genes and found significant associations between 792 genes and HIV load. Pathway analysis revealed that higher viral load associated with the upregulation of innate immune response, proteasome complex, mitochondrial and cell-cycle related activity, and with the downregulation of ribosomal transcripts and genes involved in cytokine-cytokine receptor interaction, including IL4R, IL7R, and TCF7. Mendelian Randomization confirmed the viral restriction activity of TRABD2A and identified new candidates as potential restriction factors. These findings provide novel insights into the host-virus interplay and suggest additional genes that may contribute to the natural control of HIV-1 infection.

immunology↗

bioRxiv2025

c-Myc inhibits macrophage antimycobacterial response in Mycobacterium tuberculosis infection

Mycobacterium tuberculosis (MTB) is a major global cause of mortality worldwide, responsible for over a million deaths annually. Despite this burden, natural immunity prevents disease in more than 90% of exposed individuals. Previous studies have identified interferon-gamma (IFN-{gamma}) as a key regulator of innate immune defense against MTB. Here, we investigate the impact of IFN-{gamma} timing on macrophage-mediated control of MTB infection. We demonstrate that IFN-{gamma} exposure before infection enhances macrophage antibacterial activity, whereas post-infection exposure does not. Further investigation into this phenotype revealed a strong association between c-Myc signaling and macrophage function in MTB control, as identified using unbiased in vitro systems approaches. Given the challenge of perturbing c-Myc in primary cells, we developed a lentiviral system for c-Myc inhibition and overexpression. Using a tetracycline-inducible Omomyc system - a small peptide inhibitor of c-Myc - we show that c-Myc inhibition promotes a pro-inflammatory macrophage phenotype with enhanced antimycobacterial activity. Mechanistically, c-Myc inhibition induces metabolic reprogramming via increased mTORC1 activity, leading to upregulated inducible nitric oxide synthase and improved bacterial control. In vivo analyses, including murine models and human clinical histopathology, reveal a strong correlation between c-Myc expression and MTB persistence, as well as active tuberculosis (TB), suggesting a role for c-Myc in immune evasion. These findings reveal c-Myc as a potential mediator of immune privilege in MTB infection and highlight its role as a promising target for novel TB therapies aimed at enhancing macrophage function.

immunology↗

bioRxiv2024

Antibiotic lethality dictates mycobacterial infection outcomes

Antibiotic development and treatment focus on bacterial growth inhibition, often with limited success. Here, we introduce Antimicrobial Single-Cell Testing (ASCT), an advanced imaging strategy to assess bacterial killing in real-time. By tracking 140 million bacteria and generating over 20,000 in vitro time-kill curves, we can predict Mycobacterium tuberculosis treatment outcomes in mice and humans and link strain-specific survival (drug tolerance) in Mycobacterium abscessus to clinical responses. Using ASCT, we reveal drug tolerance as a distinct genetically encoded bacterial trait conserved across drugs with similar targets and, via genome-wide associations, uncover molecular mechanisms that govern bacterial killing. This study establishes the technical framework and in vivo validation for large-scale bacterial killing assessments to advance our understanding of bacterial survival, antibiotic development and clinical decision-making.

microbiology↗

bioRxiv2023

Mycobacterium tuberculosis infection associated immune perturbations correlate with antiretroviral immunity

Infection with Mycobacterium tuberculosis (MTB) remains one of the most important opportunistic infections in people with HIV-1 (PWH). While active Tuberculosis (TB) leads to rapid progression of immunodeficiency in PWH, the interaction between MTB and HIV-1 during the asymptomatic phase of both infections remains poorly understood. In a cohort of individuals with HIV (PWH) with and without suppressed HIV-1 viral load, the transcriptomic profiles of peripheral blood mononuclear cells (PBMC) clustered in individuals infected with Mycobacterium tuberculosis (MTB) compared to carefully matched controls. Subsequent functional annotation analysis disclosed alterations in the IL-6, TNF, and KRAS pathways. Notably, MTB-associated genes demonstrated an inverse correlation with HIV-1 viremia, evident at both on individual gene level and when employed as a gene score. In sum, our data show that MTB infection in PWH is associated with a shift in the activation state of the immune system, displaying an inverse relationship with HIV-1 viral load. These results could provide an explanation for the observed increased antiretroviral control associated with MTB infection in PWH.

immunology↗

bioRxiv2019

Latent Mycobacterium tuberculosis infection provides protection for the host by changing the activation state of the innate immune system

An efficacious vaccine against adult tuberculosis (TB) remains elusive. Progress is hampered by an incomplete understanding of the immune mechanisms that protect against infection with Mycobacterium tuberculosis (Mtb), the causative agent of TB1. Over 90% of people who become infected with Mtb mount an immune response that contains the bacteria indefinitely, leading to a state known as "latent TB infection" (LTBI)2. A significant body of epidemiologic evidence indicates that LTBI protects against active TB after re-exposure, offering an intriguing avenue to identifying protective mechanisms3, 4. We show that in a mouse model, LTBI is highly protective against infection with Mtb for up to 100 days following aerosol challenge. LTBI mice are also protected against heterologous bacterial challenge (Listeria monocytogenes) and disseminated melanoma suggesting that protection is in part mediated by alterations in the activation state of the innate immune system. Protection is associated with elevated activation of alveolar macrophages (AM), the first cells that respond to inhaled Mtb, and accelerated recruitment of Mtb-specific T cells to the lung parenchyma upon aerosol challenge. Systems approaches, including transcriptome analysis of both naive and infected AMs, as well as ex vivo functional assays, demonstrate that LTBI reconfigures the response of tissue resident AMs.. Furthermore, we demonstrate that both LTBI mice and latently infected humans show similar alterations in the relative proportions of circulating innate immune cells, suggesting that the same cellular changes observed in the LTBI mouse model are also occurring in humans. Therefore, we argue that under certain circumstances, LTBI could be beneficial to the host by providing protection against subsequent Mtb exposure.

immunology↗

bioRxiv2019

Alveolar macrophages up-regulate a non-classical innate response to Mycobacterium tuberculosis infection in vivo

Alveolar macrophages (AMs) are the first cells to be infected during Mycobacterium tuberculosis (Mtb) infection. Thus the AM response to infection is the first of many steps leading to initiation of the adaptive immune response, which is required for efficient control of infection. A hallmark of Mtb infection is the delay of the adaptive response, yet the mechanisms responsible for this delay are largely unknown. We developed a system to identify, sort and analyze Mtb-infected AMs from the lung within the first 10 days of infection. In contrast to what has been previously described using in vitro systems, we find that Mtb-infected AMs up-regulate a cell-protective antioxidant transcriptional signature that is dependent on the lung environment and not dependent on bacterial virulence. Computational approaches including pathway analysis and transcription factor binding motif enrichment analysis identify Nrf2 as a master regulator of the response of AMs to Mtb infection. Using knock-out mouse models, we demonstrate that Nrf2 drives the expression of the cell protective transcriptional program and impairs the ability of the host to control bacterial growth over the first 10 days of infection. Mtb-infected AMs exhibit a highly delayed pro-inflammatory response, and comparisons with uninfected AMs from the same infected animals demonstrate that inflammatory signals in the lung environment are blocked in the Mtb-infected cells. Thus, we have identified a novel lung-specific transcriptional response to Mtb infection that impedes AMs from responding rapidly to intracellular infection and thereby hinders the overall immune response.\n\nOne Sentence SummaryIn response to Mtb infection in vivo, alveolar macrophages fail to up-regulate the canonical pro-inflammatory innate response and instead induce an Nrf2-dependent cell protective transcriptional program, which in turn impairs the hosts control of bacterial growth.

immunology↗

bioRxiv2018

Targeting neuronal and glial cell types with synthetic promoter AAVs in mice, non-human primates, and humans

Targeting genes to specific neuronal or glial cell types is valuable both for understanding and for repairing brain circuits. Adeno-associated viral vectors (AAVs) are frequently used for gene delivery, but targeting expression to specific cell types is a challenge. We created a library of 230 AAVs, each with a different synthetic promoter designed using four independent strategies. We show that ~11% of these AAVs specifically target expression to neuronal and glial cell types in the mouse retina, mouse brain, non-human primate retina in vivo, and in the human retina in vitro. We demonstrate applications for recording, stimulation, and molecular characterization, as well as the intersectional and combinatorial labeling of cell types. These resources and approaches allow economic, fast, and efficient cell-type targeting in a variety of species, both for fundamental science and for gene therapy.

neuroscience↗