Biology subjects

Lun, S.

Publications and source records attributed to Lun, S..

8 recordsLinked to original sources

bioRxiv2026

Intrinsic T-cell programming and immune spatial organization govern sex-biased tuberculosis immunity

Biological sex can profoundly influence the susceptibility to infectious diseases, yet the mechanisms behind the sex-dependent protective immunity against tuberculosis (TB) remain poorly understood. Here we show that sexually divergent immunity during chronic Mycobacterium tuberculosis (Mtb) infection is governed by both intrinsic T cell programming and pulmonary immune spatial organization. Using the Four Core Genotype (FCG) mouse model, adoptive cell transfer, pathway-specific blockade and B cell depletion, we demonstrate that CD4 T cells from gonadal females (XXF), but not XX males (XXM), confer enhanced protection to susceptible XY male recipients, independently of sex chromosome complement. Female-derived CD4 T cells reduce Mtb burdens while promoting pulmonary Bcl6 CD4 T cell responses and limiting neutrophilic inflammation. Mechanistically, blockade of CXCR3 or CD40L abrogates female-associated protection, with CD40L signaling additionally required to maintain organized pulmonary B cell structures. Although depletion of conventional B-2 B cells did not impair bacterial control, it disrupted tertiary lymphoid organization and revealed striking sex-specific functions of pulmonary B cells. Loss of B cell follicles (BCFs) primarily remodeled adaptive T cell responses in females, whereas in males it drove inflammatory myeloid activation, exaggerated neutrophil recruitment and widespread neutrophil extracellular trap (NET) formation. Together, these findings identify two complementary layers of sex-dependent immune regulation during TB: intrinsic programming of protective female CD4 T cells, and B cell-dependent spatial organization that coordinates adaptive immunity in females while restraining pathological inflammation in males. These findings establish immune tissue organization as a key determinant of the sexually dimorphic host defense during chronic TB.

immunology↗

bioRxiv2026

Gonadal regulation of sex-specific immunity in tuberculosis: enhanced lymphocyte function in females and dysfunctional myeloid responses in males

Tuberculosis (TB), the worlds deadliest infection, shows higher prevalence and mortality in males than females (M/F ratio >1.7). Using Four Core Genotype (FCG) mice to decouple gonadal from chromosomal sex (XX, XY gonadal males and XX, XY gonadal females), we show that gonadal males develop accelerated disease driven by dysfunctional myeloid responses rather than impaired bacterial recognition. Both XX and XY males exhibited increased mortality, higher Mycobacterium tuberculosis (Mtb) burden, and severe lung pathology. Mechanistically, gonadal male susceptibility involved early myeloid priming, excessive neutrophil recruitment, CCR2 monocyte accumulation, and hyperinflammation, with enhanced neutrophil extracellular trap (NET) formation and disorganized granulomas, implicating testes and androgens as key drivers of male susceptibility. While XY gonadal females were less susceptible, XX gonadal females showed the greatest resistance, associated with coordinated T- and B-cell responses and enhanced B-cell follicle formation. Together, these findings identify gonad-driven myeloid dysregulation as a central mechanism underlying male TB susceptibility.

immunology↗

bioRxiv2026

BCG vaccination mitigates tau pathology and restores cognitive function in PS19 mice.

Retrospective studies in patients with non-muscle invasive bladder cancer (NMIBC) have reported a significant reduction in Alzheimers disease (AD) incidence (12-78%) among Bacillus Calmette-Guerin (BCG) recipients versus controls. To investigate the underlying mechanisms, we evaluated BCG in the PS19 mouse model of tauopathy. We found that BCG administration reduced hippocampal phospho-tau and microgliosis while preserving neuronal markers. In vivo volumetric T2-MRI demonstrated attenuation of brain atrophy accompanied by increased glutamate-weighted CEST-MRI signals. Functionally, BCG-treated mice showed improved performance in the novel object recognition test (NORT), as well as improved body-weight maintenance and survival. Transcriptomic profiling of the hippocampus revealed near complete normalization of the PS19 disease-associated gene expression signature towards that of healthy controls. Flow cytometric profiling of brain myeloid populations demonstrated a reduction in activated resident microglia, but total microglia cells remain elevated. Moreover, an increase of the co-stimulatory marker CD80 on the recruited peripheral myeloid cells ensues following BCG treatment. Consistent with this shift in myeloid state, primary brain myeloid cells from BCG-treated mice also exhibited enhanced phagocytosis of FITC-labeled tau fibrils and increased lactate production. Together, these findings indicate that BCG induces systemic and CNS myeloid cell reprogramming that limits neuroinflammation, enhances tau clearance, and rescues cognitive and neurodegenerative phenotypes in a tauopathy model. BCG is a safe, readily available therapy that merits consideration as a preventive agent against dementia. One sentence summaryBCG therapy prevents tauopathy in PS19 mouse model.

neuroscience↗

bioRxiv2025

Loss of the ESX-5 secretion locus in Mycobacterium tuberculosis reshapes the mycomembrane and enhances ESX-1 substrate secretion

The ESX-5 secretion system, uniquely found in slow-growing mycobacteria, is predicted to secrete over 150 proteins across the inner membrane of Mycobacterium tuberculosis (M.tb). Although many of these substrates are believed to promote M.tb virulence, most remain poorly characterized. Here, we use a complete locus deletion strain of ESX-5 in M.tb to examine the molecular changes caused by a broad loss in ESX-5 secretory substrates. We confirmed the selective loss of PE/PPE proteins secreted by ESX-5 into both the culture filtrate (CF) and outer mycomembrane (OMM) fractions of the M.tb {Delta}esx5 mutant. In examining other ESX systems, we found that ESX-1 substrate levels were increased in both the CF and OMM fractions of the {Delta}esx5 mutant. Conversely, the ESX-3 locus was transcriptionally repressed upon ESX-5 deletion. We noted that the {Delta}esx5 mutant had altered morphology in the form of wrinkled distortions of the bacterial surface. Likewise, we identified increased susceptibility of the {Delta}esx5 mutant to a variety of large (molecular weight >550 g/mol) antimicrobial compounds, suggesting that an intact ESX-5 system is required for M.tb to exclude such molecules. Our findings suggest that removing the ESX-5 system from M.tb fundamentally alters the properties of the mycobacterial OMM and impacts the expression and secretion activity of other ESX systems. Significance StatementMycobacterium tuberculosis (M.tb) uses the ESX-5 secretion system to export numerous proteins that shape host-pathogen interactions. Here, we found that deleting ESX-5 from M.tb not only prevented the secretion of many ESX-5 substrates but also impacted other ESX systems. The M.tb {Delta}esx5 mutant had increased ESX-1 substrate secretion but reduced ESX-3 expression. In addition, the M.tb {Delta}esx5 mutant displayed altered cell surface morphology and increased vulnerability to large antibiotic drugs, suggesting a critical role for ESX-5 for maintaining outer membrane integrity. These findings highlight ESX-5 as a central modulator of secretion and cell envelope composition with implications for drug targeting and vaccine development.

microbiology↗

bioRxiv2023

Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis

As one of the most successful human pathogens, Mycobacterium tuberculosis (Mtb) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a novel glutamine metabolism antagonist, JHU083, inhibits Mtb proliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomics analysis of lungs from JHU083-treated Mtb-infected mice revealed reduced glutamine levels, citrulline accumulation suggesting elevated NOS activity, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. When tested in an immunocompromised mouse model of Mtb infection, JHU083 lost its therapeutic efficacy suggesting the drugs host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis.

microbiology↗

bioRxiv2022

Adjunctive inhibition of the integrated stress response pathway accelerates bacterial clearance in a mouse model of tuberculosis

Tuberculosis (TB) is a devastating infectious disease that continues to cause millions of human deaths every year. Even though most cases of TB can be cured with a 6-month antibiotic combination therapy, these long treatment durations have led to the emergence of multi-drug resistance and pose a major hurdle to global TB control. Despite numerous advances in TB drug development, a substantially shortened treatment time has yet to be achieved. Given the rise in antibiotic resistance, an alternative strategy to the direct targeting of M. tuberculosis (M.tb) is the development of host-directed therapies (HDTs) that promote bacterial clearance and/or lung health when given adjunctive to standard TB antibiotics. We recently discovered that a small molecule inhibitor of the Integrated Stress Response (ISR), which is abnormally activated in TB and associated with the formation of necrotic granulomas, reduced M.tb numbers and lung inflammation in mice. Here, we evaluated the therapeutic potential of adjunctive ISR inhibition in the context of standard TB therapy. Throughout the course of treatment, ISR inhibition robustly lowered bacterial burdens compared to standard TB therapy alone and accelerated the time-to-sterility in mice, as demonstrated by significantly reduced relapse rates after 4 months of treatment. In addition, mice receiving adjunctive ISR inhibition tended to have reduced lung necrosis and inflammation. Together, our findings identify the ISR pathway as a promising therapeutic target with the potential of shortening TB treatment durations and improving lung health.

microbiology↗

bioRxiv2020

Effective host-directed therapy for tuberculosis by targeted depletion of myeloid-derived suppressor cells using a diphtheria toxin-based fusion protein

Myeloid-derived suppressor cells (MDSCs) are present in elevated numbers in TB patients and have been found to be permissive for Mycobacterium tuberculosis (Mtb) proliferation. To determine whether depletion of MDSCs may improve host control of TB, we used a novel diphtheria toxin-based fusion protein known as DABIL-4 that targets and depletes IL-4-receptor positive cells. We show that DABIL-4 depletes both PMN-MDSCs and M-MDSC in the mouse TB model, and that it reduces the lung bacillary burden of Mtb. These results indicate that MDSC-depleting therapies targeting the IL4 receptor are beneficial in TB and offer an avenue towards host-directed TB therapy.

microbiology↗

bioRxiv2018

The integrated stress response mediates type I interferon driven necrosis in Mycobacterium tuberculosis granulomas

Necrosis in the tuberculous granuloma is a hallmark of tuberculosis that enables pathogen survival and transmission. Susceptibility to tuberculosis and several other intracellular bacteria is controlled by a mouse genetic locus, sst1, and mice carrying the sst1-suscepible (sst1S) genotype develop necrotic inflammatory lung lesions, similar to human TB granulomas. Our previous work established that increased disease severity in sst1S mice reflects dysfunctional macrophage effector or tolerance mechanisms, but the molecular mechanisms have remained unclear. Here we demonstrate that sst1S macrophages develop aberrant, biphasic responses to TNF characterized by super-induction of stress and type I interferon pathways after prolonged TNF stimulation with this late-stage response being initiated by oxidative stress and Myc activation and driven via a JNK - IFN{beta} - PKR circuit. This circuit leads to induction of the integrated stress response (ISR) mediated by eIF2 phosphorylation and the subsequent hyper-induction of ATF3 and ISR-target genes Chac1, Trib3, Ddit4. The administration of ISRIB, a small molecule inhibitor of the ISR, blocked the development of necrosis in lung granulomas of M. tuberculosis-infected sst1S mice and concomitantly reduced the bacterial burden revealing that induction of the ISR and the locked-in state of escalating stress driven by type I IFN pathway in sst1S macrophages plays a causal role in the development of necrosis. Our data support a generalizable paradigm in intracellular pathogen-host interactions wherein host susceptibility emerges within inflammatory tissue due to imbalanced macrophage responses to growth, differentiation, activation and stress stimuli. Successful pathogens such as M. tuberculosis may exploit this aberrant response in susceptible hosts to induce necrotic lesions that favor long-term pathogen survival and transmission. Interruption of the aberrant stress response with inhibitors such as ISRIB may offer novel therapeutic strategies.

immunology↗