Biology subjects

Zhang, R. Z.

Publications and source records attributed to Zhang, R. Z..

7 recordsLinked to original sources

bioRxiv2026

Determinants in gammaretroviral Env dictate the production of neutralizing antibodies

Protective immune responses are shaped by the nature of the infectious pathogen. Some viral infections are self-limiting and stimulate lasting immunity, while others activate poor responses that fail to control the infection or prevent development of disease. Little is known concerning the specific viral determinants that control whether a given viral infection will result in protective immunity. Here, we demonstrate that strains of the gammaretrovirus, murine leukemia virus, differ in their ability to stimulate neutralizing antibody production via a noncanonical pathway. Additionally, we show that virus-specific production of neutralizing immune responses is unique to infection, suggesting that the activation of alternative antibody responses is triggered by the infectious process rather than the unique nature of specific viral antigens. Viral chimeras indicate that activation of neutralizing antiviral antibody production is determined by the receptor-binding domain, and that the surface subunit controls binding to and infection of various cell types. The ability of specific viral factors to determine the outcome of infection and the induction of distinctive immune responses between closely related retroviral strains provides an ideal model for the dissection of both host and viral determinants underlying the control of viral infection and the production of neutralizing antibodies. SUMMARYWe report here that retroviral envelope glycoprotein determines stimulation of GC B cell responses and the production of neutralizing antibodies in the absence of IFN{gamma}-signaling, thus defining the factors that stimulate non-canonical immune responses and further developing the knowledge required for vaccine development.

immunology↗

bioRxiv2026

TLR7-independent control of retroviral infection

Development of effective immune responses against any pathogen requires efficient activation of the innate immune system followed by induction of an appropriate adaptive immune response using specific signaling pathways tailored to each infection. The sole innate immune receptor implicated in the induction of adaptive immunity to retroviral infection is Toll like receptor 7 (TLR7). We have found that germinal center responses, neutralizing antibody production, and clearance of murine leukemia virus (MLV) infection in BALB.J and C57BL/6N (B6N) mice occurs in the absence of TLR7 signaling. This suggests that a previously unknown alternative sensing pathway exists for the activation of protective immune responses upon retroviral infection. Genetic crosses indicate that the ability to control retroviral infection in the absence of TLR7 signaling is determined by the same recessive mechanism in both B6N and BALB.J mice, suggesting that TLR7-independent responses do not result from a gain-of-function of an alternative pattern recognition receptor. Additionally, we observed that TLR7-deficient BALB.J mice produce neutralizing antibodies against mouse mammary tumor virus (MMTV) infection, indicating that this alternative sensing pathway is active against retroviruses of multiple genera. Finally, we determined that the alternative sensing pathway is also independent of both MyD88 and STING signaling. The ability of mice of two genetic backgrounds to control retroviral infection in the absence of TLR7 signaling provides a valuable tool for the identification of a novel mechanism of retrovirus control. The dissection of this pathway has the potential to alter our understanding of the requirements for the stimulation of antigen-specific neutralizing immunity. Significance StatementInnate immune sensors are required for induction of pathogen-specific immune responses, and the development of novel vaccines requires an understanding of the basic mechanisms by which the immune system detects and responds to pathogens. While multiple innate immune receptors have been implicated in the sensing of retroviral infection, only Toll-like receptor 7 (TLR7) has been found to upregulate adaptive immune responses. Here, we demonstrate that an additional TLR7-independent mechanism for the activation of antiretroviral antibody responses is present in inbred mice from two genetic backgrounds. This finding has implications for the selection of mouse models for the study of antiviral immune responses and has the potential to alter our understanding of the requirements for the stimulation of antigen-specific neutralizing immunity.

microbiology↗

bioRxiv2026

BiLO: Bilevel Local Operator Learning for PDE Inverse Problems

We propose a new neural network based method for solving inverse problems for partial differential equations (PDEs) by formulating the PDE inverse problem as a bilevel optimization problem. At the upper level, we minimize the data loss with respect to the PDE parameters. At the lower level, we train a neural network to locally approximate the PDE solution operator in the neighborhood of a given set of PDE parameters, which enables an accurate approximation of the descent direction for the upper level optimization problem. The lower level loss function includes the least-square penalty of both the residual and its derivative with respect to the PDE parameters. We apply gradient descent simultaneously on both the upper and lower level optimization problems, leading to an effective and fast algorithm. The method, which we refer to as BiLO (Bilevel Local Operator learning), is also able to efficiently infer unknown functions in the PDEs through the introduction of an auxiliary variable. We provide a theoretical analysis that justifies our approach. Through extensive experiments over multiple PDE systems, we demonstrate that our method enforces strong PDE constraints, is robust to sparse and noisy data, and eliminates the need to balance the residual and the data loss, which is inherent to the soft PDE constraints in many existing methods.

systems biology↗

bioRxiv2026

Bayesian BiLO: Bilevel Local Operator Learning for Efficient Uncertainty Quantification of Bayesian PDE Inverse Problems with Low-Rank Adaptation

Uncertainty quantification in PDE inverse problems is essential in many applications. Scientific machine learning and AI enable data-driven learning of model components while preserving physical structure, and provide the scalability and adaptability needed for emerging imaging technologies and clinical insights. We develop a Bilevel Local Operator Learning framework for Bayesian inference in PDEs (B-BiLO). At the upper level, we sample parameters from the posterior via Hamiltonian Monte Carlo, while at the lower level we fine-tune a neural network via low-rank adaptation (LoRA) to approximate the solution operator locally. B-BiLO enables efficient gradient-based sampling without synthetic data or adjoint equations and avoids sampling in high-dimensional weight space, as in Bayesian neural networks, by optimizing weights deterministically. We analyze errors from approximate lower-level optimization and establish their impact on posterior accuracy. Numerical experiments across PDE models, including tumor growth, demonstrate that B-BiLO achieves accurate and efficient uncertainty quantification. MSC Classification: 65M32, 62F15, 68T07

systems biology↗

bioRxiv2022

Genetic differences between 129S substrains affect antiretroviral immune responses

Inbred mouse lines vary in their ability to mount protective antiretroviral immune responses, and even closely related strains can exhibit opposing phenotypes upon retroviral infection. Here, we found that 129S mice inherit a previously unknown mechanism for the production of anti-murine leukemia virus (MLV) antibodies and control of infection. The resistant phenotype is controlled by two dominant loci that are independent from known MLV-resistance genes. We also show that production of anti-MLV antibodies in 129S7, but not 129S1 mice is independent of interferon gamma (IFN{gamma}) signaling. Thus, our data indicate that 129S mice inherit an unknown mechanism for control of MLV infection and demonstrate that there is genetic variability in 129S substrains that affects their ability to mount antiviral immune responses. ImportanceUnderstanding the genetic basis for production of protective antiviral immune responses is crucial for the development of novel vaccines and adjuvants. Additionally, characterizing the genetic and phenotypic variability in inbred mice has implications for the selection of strains for targeted mutagenesis, choice of controls, and for broader understanding of the requirements for protective immunity.

microbiology↗

bioRxiv2022

Group A Streptococcus Induces Lysosomal Dysfunction in THP-1 Macrophages

The human-specific bacterial pathogen Group A Streptococcus (GAS) is a significant cause of morbidity and mortality. Macrophages are important to control GAS infection, but previous data indicate that GAS can persist in macrophages. In this study, we detail the molecular mechanisms by which GAS survives in THP-1 macrophages. Our fluorescence microscopy studies demonstrate that GAS are readily phagocytosed by macrophages, but persist within phagolysosomes. These phagolysosomes are not acidified, which is in agreement with our findings that GAS cannot survive in low pH environments. We find that the secreted pore-forming toxin Streptolysin O (SLO) perforates the phagolysosomal membrane, allowing leakage of not only protons, but large proteins including the lysosomal protease cathepsin B. Additionally, GAS blocks the activity of vacuolar ATPase (v-ATPase) to prevent acidification of the phagolysosome. Thus, while GAS does not inhibit fusion of the lysosome with the phagosome, it has multiple mechanisms to prevent proper phagolysosome function, allowing for persistence of the bacteria within the macrophage. This has important implications for not only the initial response but the overall functionality of the macrophages, which may lead to the resulting pathologies in GAS infection. Our data suggests that therapies aimed at improving macrophage function may positively impact patient outcomes in GAS infection.

microbiology↗

bioRxiv2019

Fractal dimension, occupancy and hotspot analyses of B cell spatial distribution predict clinical outcome in breast cancer

While the density of tumor-infiltrating lymphocytes (TILs) is now well known to correlate with clinical outcome, the clinical significance of spatial distribution of TILs is not well characterized. We have developed novel statistical techniques (including fractal dimension differences, a hotspot analysis, a box counting method that we call occupancy and a way to normalize cell density that we call thinning) to analyze the spatial distribution (at different length scales) of various types of TILs in triple negative breast tumors. Consistent with prior reports, the density of CD20+ B cells within tumors is not correlated with clinical outcome. However, we found that their spatial distribution differs significantly between good clinical outcome (no recurrence within at least 5 years of diagnosis) and poor clinical outcome (recurrence with 3 years of diagnosis). Furthermore, CD20+ B cells are more spatially dispersed in good outcome tumors and are more likely to infiltrate into cancer cell islands. Lastly, we found significant correlation between the spatial distributions of CD20+ B cells and CD8+ (cytotoxic) T cells (as well as CD3+ T cells), regardless of outcome. These results highlight the significance of the spatial distribution of TILs, especially B cells, within tumors.\n\nSignificance StatementImmune cells can fight cancer. For example, a patient has a good prognosis when a high density of killer T cells, a type of immune cell that can kill cancer cells, infiltrates into a tumor. However, there is no clear association between prognosis and the density of B cells, another type of immune cell, in a tumor. We developed several statistical techniques to go beyond cell density and look at the spatial distribution, i.e., the pattern or arrangement of immune cells, in tumors that have been removed from patients with triple negative breast cancer. We find that B cells and killer T cells tend to be more spread out in the tumors of patients whose cancer did not recur.

cancer biology↗