Biology subjects

Tomko, J.

Publications and source records attributed to Tomko, J..

9 recordsLinked to original sources

bioRxiv2026

Anisotropic Thermal Conductivity in Topologically Networked Protein-MXene Composites

Governing thermal transport in engineered materials creates opportunities to redirect and recover the excess heat generated in electronic and energy-conversion devices. Materials that pair low cross-plane thermal conductivity with high in-plane thermal conductivity are particularly valuable because they confine heat and channel it away from sensitive regions, preventing localized device failure. Two-dimensional crystals are efficient building blocks for such anisotropic thermal conductors, but they are brittle, and the polymer composites used to toughen them usually forfeit much of the intrinsic anisotropy: in conventional percolation-based design, filler fraction is the only handle available, and it governs both in-plane and cross-plane conduction. Here we report a composite of Ti3C2Tx (MXene) nanosheets and squid ring teeth (SRT) inspired recombinant tandem-repeat (TR) proteins in which the protein serves as a molecular template and bridge, setting the spacing between nanosheets with angstrom-level precision through the number of tandem-repeat units and independently of the filler fraction. This structural handle provides a second, independent design parameter. At a fixed MXene loading, the number of repeats tunes the cross-plane conductivity (0.30 to 0.93 W/mK) and, with it, the thermal anisotropy ratio over a wide range (from about 70 down to 17), while the in-plane conductivity stays high (16 to 21 W/mK). We rationalize these trends with a Gaussian Network Model (GNM) of the protein embedded in a two-phase layered medium, which reproduces the measured directional conductivities from a single structural parameter and identifies the protein gallery as the cross-plane bottleneck. Extending the model to a mechanically loaded five-period stack, we find that the anisotropy is robust to reversible compression and twist, changing by only a few percent, so the number of tandem repeats, not the applied strain, is the dominant design handle. Because anisotropy is tuned structurally rather than volumetrically, these protein-MXene composites decouple thermal anisotropy from filler content, pointing toward flexible thermal materials that are not bound by the rules of mixture and percolation.

bioengineering↗

bioRxiv2025

Antiretroviral treatment does not prevent extrapulmonary tuberculosis during SIV/Mtb co-infection in macaques

Co-infection with both HIV and M. tuberculosis (Mtb) results in disseminated tuberculosis (TB) and accelerated progression of HIV. Despite greater access to antiretroviral treatment (ART), it remains unclear whether suppression of HIV replication protects against severe Mtb infection. Here, using a macaque model of SIV/Mtb coinfection, we investigated whether treatment of SIV infection with ART influenced control of a subsequent Mtb challenge compared to SIV infected macaques who were not treated with ART. Using a macaque model of simian immunodeficiency virus (SIV)-Mtb co-infection, macaques were first infected with SIVB670, SIVB670 with ART, or saline followed by a low-dose Mtb inoculation with serial clinical, microbiological, PET CT imaging, and immunologic assessments. At necropsy, gross pathology, viremia, bacterial burden, and immunologic parameters were compared. SIV-TB animals had greater gross pathology and total bacterial burden than TB only and SIV/ART/TB groups. However, despite normal blood CD4 counts and undetectable SIV RNA, SIV/ART/TB macaques showed similar clinical parameters and extrapulmonary involvement as SIV/TB animals. Analysis of barcoded-Mtb suggests ART control of SIV replication does not prevent Mtb extrapulmonary dissemination. These data indicate that people living with HIV on ART remain at high risk of bacterial dissemination and extrapulmonary TB disease, particularly when methods to identify extrapulmonary disease are inconsistent. This highlights the importance of understanding the mechanism of extrapulmonary spread and disease severity in HIV/TB co-infected individuals.

immunology↗

bioRxiv2025

Rankings of tuberculosis antibiotic treatment regimens are sensitive to spatial scale, detection limit, and initial host bacterial burden

Pulmonary infection after inhalation of Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB). TB presents with lung granulomas - complex spheroidal structures composed of immune cells and bacteria. Granulomas often have centralized caseum (necrotic tissue) where mycobacteria are quarantined, complicating and prolonging multi-antibiotic regimens. Determining which antibiotic regimens are optimal for reducing treatment time and toxicity is a goal of recent TB eradication campaigns. Clinical trials are expensive and challenging, making it difficult to untangle which host-pathogen interactions drive the heterogeneous infection and treatment outcomes observed at between-host and within-host scales. To determine responses to antibiotic regimens, we simulate treatments in HostSim, our whole-host mechanistic, multi-scale computational model of Mtb-infection. HostSim tracks dynamics of pulmonary Mtb-infection over molecular, cellular, tissue, organ, and whole-host scales. We create a heterogenous virtual cohort, comprising distinct hosts, for virtual clinical trials. We represent drug treatments by newly-integrating pharmacokinetics / pharmacodynamics into HostSim, simulating treatment with commonly-prescribed TB antibiotic regimens (e.g., HRZE or BPaL). Our approach allows us to identify both (1) which hosts/granulomas most improve with treatment, and (2) which mechanisms influence outcome heterogeneity. By tracking experimental and clinical measurements, we virtually recreate several drug rankings from literature. We find that many methods of ranking treatment efficacy are strongly influenced by the definition of improvement used and, in some cases, the detection threshold of CFU. Other rankings depend on initial bacterial burden of hosts/granulomas. Our work suggests that metrics for regimen optimality may be orthogonal, which could explain seemingly-contradictory findings from prior studies.

systems biology↗

bioRxiv2024

CD4 T cells and CD8α+ lymphocytes are necessary for intravenous BCG-induced protection against tuberculosis in macaques

Tuberculosis (TB) is a major cause of morbidity and mortality worldwide despite widespread intradermal (ID) BCG vaccination in newborns. We previously demonstrated that changing the route and dose of BCG vaccination from 5{xi}105 CFU ID to 5{xi}107 CFU intravenous (IV) resulted in prevention of infection and disease in a rigorous, highly susceptible non-human primate model of TB. Identifying the immune mechanisms of protection for IV BCG will facilitate development of more effective vaccines against TB. Here, we depleted select lymphocyte subsets in IV BCG vaccinated macaques prior to Mtb challenge to determine the cell types necessary for that protection. Depletion of CD4 T cells or all CD8 expressing lymphoycytes (both innate and adaptive) resulted in loss of protection in most macaques, concomitant with increased bacterial burdens ([~]4-5 log10 thoracic CFU) and dissemination of infection. In contrast, depletion of only adaptive CD8{beta}+ T cells did not significantly reduce protection against disease. Our results demonstrate that CD4 T cells and innate CD8+ lymphocytes are critical for IV BCG-induced protection, supporting investigation of how eliciting these cells and their functions can improve future TB vaccines. One Sentence SummaryAntibody depletion of lymphocytes in rhesus macques demonstrates key roles for CD4 T cells and innate-like CD8+ lymphocytes in conferring sterilizing immunity against tuberculosis following intravenous BCG vaccination.

immunology↗

bioRxiv2024

Markov Field network integration of multi-modal data predicts effects of immune system perturbations on intravenous BCG vaccination in macaques

Analysis of multi-modal datasets can identify multi-scale interactions underlying biological systems, but can be beset by spurious connections due to indirect impacts propagating through an unmapped biological network. For example, studies in macaques have shown that BCG vaccination by an intravenous route protects against tuberculosis, correlating with changes across various immune data modes. To eliminate spurious correlations and identify critical immune interactions in a public multi-modal dataset (systems serology, cytokines, cytometry) of vaccinated macaques, we applied Markov Fields (MF), a data-driven approach that explains vaccine efficacy and immune correlations via multivariate network paths, without requiring large numbers of samples (i.e. macaques) relative to multivariate features. Furthermore, we find that integrating multiple data modes with MFs helps to remove spurious connections. Finally, we used the MF to predict outcomes of perturbations at various immune nodes, including a B-cell depletion that induced network-wide shifts without reducing vaccine protection, which we validated experimentally.

systems biology↗

bioRxiv2023

CD4+ T cells are homeostatic regulators during Mtb reinfection

Immunological priming - either in the context of prior infection or vaccination - elicits protective responses against subsequent Mycobacterium tuberculosis (Mtb) infection. However, the changes that occur in the lung cellular milieu post-primary Mtb infection and their contributions to protection upon reinfection remain poorly understood. Here, using clinical and microbiological endpoints in a non-human primate reinfection model, we demonstrate that prior Mtb infection elicits a long-lasting protective response against subsequent Mtb exposure and that the depletion of CD4+ T cells prior to Mtb rechallenge significantly abrogates this protection. Leveraging microbiologic, PET-CT, flow cytometric, and single-cell RNA-seq data from primary infection, reinfection, and reinfection-CD4+ T cell depleted granulomas, we identify differential cellular and microbial features of control. The data collectively demonstrate that the presence of CD4+ T cells in the setting of reinfection results in a reduced inflammatory lung milieu characterized by reprogrammed CD8+ T cell activity, reduced neutrophilia, and blunted type-1 immune signaling among myeloid cells, mitigating Mtb disease severity. These results open avenues for developing vaccines and therapeutics that not only target CD4+ and CD8+ T cells, but also modulate innate immune cells to limit Mtb disease.

immunology↗

bioRxiv2022

Optimizing tuberculosis treatment efficacy: comparing the standard regimen with Moxifloxacin-containing regimens

Tuberculosis (TB) continues to be one of the deadliest infectious diseases in the world, causing ~1.5 million deaths every year. The World Health Organization initiated an End TB Strategy that aims to reduce TB-related deaths in 2035 by 95%. Recent research goals have focused on discovering more effective and more patient-friendly antibiotic drug regimens to increase patient compliance and decrease emergence of resistant TB. Moxifloxacin is one promising antibiotic that may improve the current standard regimen by shortening treatment time. Clinical trials and in vivo mouse studies suggest that regimens containing moxifloxacin have better bactericidal activity. However, testing every possible combination regimen with moxifloxacin either in vivo or clinically is not feasible due to experimental and clinical limitations. To identify better regimens more systematically, we simulated pharmacokinetics/pharmacodynamics of various regimens (with and without moxifloxacin) to evaluate efficacies, and then compared our predictions to both clinical trials and nonhuman primate studies performed herein. We used GranSim, our well-established hybrid agent-based model that simulates granuloma formation and antibiotic treatment, for this task. In addition, we established a multiple-objective optimization pipeline using GranSim to discover optimized regimens based on treatment objectives of interest, i.e., minimizing total drug dosage and lowering time needed to sterilize granulomas. Our approach can efficiently test many regimens and successfully identify optimal regimens to inform pre-clinical studies or clinical trials and ultimately accelerate the TB regimen discovery process. Author summaryTuberculosis (TB) is a top global health concern and treatment for TB requires multiple antibiotics taken for long periods of time, which is challenging for TB patients. Therefore, identifying regimens that are more effective and more patient-friendly than the standard treatment is urgently needed. It is also known that non-compliance leads to the development of drug resistant TB. In this work, we pair computational and experimental models to predict new regimens for the treatment of TB that optimize how fast bacteria are cleared using minimal dosage. We apply novel approaches to this goal and validate our predictions using a non-human primate model. Our findings suggest that systems pharmacological modeling should be employed as a method to narrow the design space for drug regimens for tuberculosis and other diseases as well.

pharmacology and toxicology↗

bioRxiv2022

T cell transcription factor expression evolves as adaptive immunity matures in granulomas from Mycobacterium tuberculosis-infected cynomolgus macaques

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a global health concern, yearly resulting in 10 million new cases of active TB. Immunologic investigation of lung granulomas is essential for understanding host control of bacterial replication. We identified and compared the pathological, cellular, and functional differences in granulomas at 4, 12, and 20 weeks post-infection in Chinese cynomolgus macaques. Original granulomas differed in transcription factor expression within adaptive lymphocytes with those at 12 weeks showing higher frequencies of CD8+T-bet+ T cells, while increases in CD4+T-bet+ T cells were observed at 20 weeks post-infection. The appearance of T-bet+ adaptive T cells at 12 and 20 weeks was coincident with a reduction in bacterial burden, suggesting their critical role in Mtb control. This study highlights the evolution of T cell responses within lung granulomas, suggesting that vaccines promoting the development and migration of T-bet+ T cells would enhance mycobacterial control.

immunology↗

bioRxiv2020

Pre-existing SIV infection increases expression of T cell markers associated with activation during early Mycobacterium tuberculosis co-infection and impairs TNF responses in granulomas

Tuberculosis (TB) is the leading infectious cause of death among people living with HIV (PLHIV). PLHIV are more susceptible to contracting Mycobacterium tuberculosis (Mtb) infection and often have worsened TB disease. Understanding the immunologic defects caused by HIV and the consequences it has on Mtb co-infection is critical in combating this global health epidemic. We previously established a model of simian immunodeficiency virus (SIV) and Mtb co-infection in Mauritian cynomolgus macaques (MCM), and showed that SIV/Mtb co-infected MCM had rapidly progressive TB. We hypothesized that pre-existing SIV infection impairs early T cell responses to Mtb infection. To test our hypothesis, we infected MCM with SIVmac239 intrarectally followed by co-infection with a low dose of Mtb Erdman 6 months later. SIV-naive MCM were infected with Mtb alone as controls. Six weeks after Mtb infection, animals were necropsied and immune responses were measured by multiparameter flow cytometry. While the two groups exhibited similar TB progression at time of necropsy (Nx), longitudinal sampling of the blood (PBMC) and airways (BAL) revealed a significant reduction in circulating CD4+ T cells and an influx of CD8+ T cells in airways following Mtb co-infection of SIV+ animals. Differences in the activation markers CD69, PD-1, and TIGIT were observed. At sites of Mtb infection (i.e. granulomas), SIV/Mtb co-infected animals had a higher proportion of CD4+ and CD8+ T cells expressing PD-1 and TIGIT. In addition, there were fewer TNF-producing CD4+ and CD8+ T cells in granulomas and airways of SIV/Mtb co-infected animals. Taken together, we show that concurrent SIV infection alters T cell phenotypes in granulomas during the early stages of TB disease. As it is critical to establish control of Mtb replication soon after infection, these phenotypic changes may distinguish the immune dysfunction that arises from pre-existing SIV infection which promotes TB progression. Author SummaryPeople living with HIV are incredibly susceptible to TB and, when co-infected with Mtb, often develop serious TB disease. We do not yet understand precisely how HIV infection impairs the early stages of the adaptive immune response against Mtb bacilli. We employed a non-human primate model of HIV, using SIV as a surrogate for HIV, followed by Mtb co-infection to investigate the immunologic defects associated with pre-existing SIV infection over the first six weeks of Mtb co-infection. Our study focused on CD4+ and CD8+ T cells as these cells are known to play an important role in Mtb control. We found more CD8+ T cells in granulomas, the sites of Mtb infection, from SIV/Mtb co-infected animals, with little difference in CD4+ T cells. SIV/Mtb co-infected animals and animals infected with SIV alone had a higher proportion of both CD4+ and CD8+ T cells expressing activation markers compared to SIV-naive animals, consistent with SIV-dependent immune activation. Notably, we observed a lower proportion of TNF-producing T cells, a cytokine critical for Mtb control, in granulomas and airways of SIV/Mtb co-infected animals. Taken together, these data show that pre-existing SIV alters T cell phenotypes and reduces TNF responses early in Mtb infection.

immunology↗