Biology subjects

Velu, V.

Publications and source records attributed to Velu, V..

7 recordsLinked to original sources

bioRxiv2026

Genomic Evolution of SARS-CoV-2 Delta Variants Pre- and Post-Omicron Emergence using Alignment-free Machine Learning models

The SARS-CoV-2 Delta variant (B.1.617.2), initially classified as a variant of concern due to its enhanced transmissibility and vaccine-escape mutations, underwent further genomic changes following the emergence of the Omicron variant (B.1.1.529). This study investigates the genomic differences in Delta variant spike gene sequences collected before and after the emergence of Omicron. A total of 190 sequences were analyzed using an alignment-free approach incorporating k-mer-based feature extraction and machine learning models, including convolutional neural networks (CNN), K-means clustering, and random forest classification. The random forest model achieved 93% accuracy, with significant F1 scores, effectively distinguishing the two Delta variant groups. Comparative analysis revealed 157 persistent mutations and four vanished mutations in the post-Omicron group. Cluster analysis showed notable shifts, indicating stable yet evolving genomic patterns over time. The study demonstrates the advantage of alignment-free methods in detecting subtle sequence variations that alignment-based approaches may overlook. These findings enhance our understanding of SARS-CoV-2 evolution and provide a framework for identifying key genomic signatures relevant to public health. The methodology and insights gained offer potential applications in variant surveillance, vaccine design, and viral evolutionary studies, supporting preparedness for future SARS-CoV-2 variant emergence.

genomics↗

bioRxiv2026

Interleukin-6 restricts pre-thymic T cell lineage commitment of progenitors driving loss of SIV control

Effective T cell reconstitution in people living with HIV is central to durable immune control and cure strategies. Sustained thymic output underpins T cell recovery and requires continuous seeding by T cell-committed progenitors originating in the bone marrow (BM). Using the SIV/rhesus macaque model, we identified a thymus-seeding progenitor (TSP; CD4-CD8-CD34CD38-CD7) in BM declining rapidly following SIV infection. This loss closely associated with reduction in T cell lineage committed differentiation of BM-derived hematopoietic stem and progenitor cells (HSPCs). Importantly, both the decline in TSPs and the impairment of pre-thymic T cell potential were strongly associated with early loss of viral control, independent of peripheral T cell dynamics. Plasma interleukin-6 (IL-6) levels robustly predicted the magnitude of TSP loss and the restriction of T cell-biased HSPC differentiation. Integrated transcriptomic and proteomic analyses revealed inflammatory imprinting of HSPCs characterized by activation of the IL-6-JAK-STAT axis, inflammasome engagement, and coordinated suppression of key T cell specification factors, including RUNX1, FYN, and ZAP70. In a nonanimal model of thymopoiesis, IL-6 exposure of rhesus macaque and human HSPCs inhibited their transition from DN1 (CD38-) to DN2 (CD38) TSP states, indicating an early block in T cell lineage commitment. Conversely, ex vivo IL-6 receptor blockade restored thymocyte differentiation to levels comparable to untreated controls. Collectively, these findings demonstrate that pathogenic inflammation restricts pre-thymic T cell development early after infection, directly contributing to loss of viral control. These findings have important implications for understanding the mediators of anti-viral T cell immunity and HIV cure.

immunology↗

bioRxiv2025

Identification and characterization of host-directed therapeutics for tuberculosis using a versatile human 3D tuberculoma bioplatform

Host-directed therapies (HDT) represent a pivotal strategy in combating both drug-susceptible and drug-resistant tuberculosis (TB). Current evaluations, however, show limited success in animal models and clinical settings, emphasizing the need for more effective HDT candidates. With few druggable targets validated within granulomas, it is essential to verify the effectiveness of HDT candidates identified through traditional macrophage cultures in the context of the tuberculous granuloma milieus. Bioengineering a scalable, high-throughput screening (HTS) platform that replicates the physiological microenvironments in the hallmark tubercular lesions could significantly improve the identification of relevant HDT candidates and new treatment strategies. Here, we developed a facile, HTS-compatible bioplatform that generates tuberculoma-emulating structures, following three-dimensional (3D) co-cultures of human cells and pathogenic mycobacteria. Employing high-content imaging alongside immunological and transcriptomic approaches, we demonstrated that these 3D structures exhibit classic tuberculoma attributes and develop crucial transformations. Utilizing this system, we screened antibody biosimilars and potential HDT compounds. Our findings demonstrate the systems versatility in discovering antimicrobials and HDT candidates that effectively reduce mycobacterial burdens and granuloma lesions, while elucidating their immune mechanisms within 3D milieus. Many compounds effective in two-dimensional (2D) cultures were ineffective once granulomas formed in our 3D model. Notably, several promising compounds were found to induce rapid autophagy flux, and we validated the effectiveness of one such compound, the multi-kinase inhibitor AT9283, in a mouse model. Our findings highlight several HDT candidates for potential repurposing in TB treatment, offering a robust tool for accelerating therapeutic discoveries and advancing translational research for TB and other granulomatous diseases. SummarySafer and shorter treatment regimens for tuberculosis (TB) are urgently needed. Host-directed therapies (HDT) are being explored to enhance antibiotic regimens and address antimicrobial resistance. To expedite the discovery of HDT candidates and the development of new treatment strategies, scalable in vitro systems are needed that can replicate the critical features and microenvironments of TB lesions in a format compatible with high-throughput screening (HTS). We developed an HTS-compatible bioplatform using 3D co-cultures of human cells and fluorescent mycobacteria, creating tuberculoma-like structures with classic solid, necrotic, and cavitary transformations that exhibit crucial microenvironments. This facile system enabled us to screen antibody biosimilars and HDT compounds in 3D human in vitro tuberculomas, identifying candidates that inhibited mycobacterial growth and granuloma lesions while revealing potential innate immune mechanisms. The study revealed several promising HDT candidates that could be repurposed for TB treatment, introducing a versatile tool for screening therapeutic libraries. Additionally, it presents a framework for enhancing human in-vitro granuloma models, as advances in tissue-like systems emerge to recapitulate the architecture and multilineage differentiation in the lungs.

immunology↗

bioRxiv2025

Refined cell transfer model reveals roles for Ascl2 and Cxcr3 in splenic localization of mouse NK cells during virus infection

Cell transfer experiments complement the rigorous investigation of antiviral and antitumor functions of natural killer (NK) cells. Success in these endeavors is enhanced by expansion of small numbers of input NK cells driven by viral antigens or homeostatic proliferation in immunodeficient hosts. In contrast, analysis of other NK-cell functions, including immunoregulation, are non-proliferative and require an intact immune system in recipient mice. We reveal poor persistence of conventional congenic (CD45.1) BoyJ NK cells following adoptive transfer in comparison to CRISPR-generated CD45.1+ (JAXBoy) NK cells. Reciprocal transfers between C57BL/6 and JAXBoy mice substantially improve seeding and maintenance of donor NK cells. Using this system, we confirm that CXCR3 re-positions NK cells in the white pulp of the spleen after infection, which is vital for immunoregulation. Moreover, we discovered that the transcription factor ASCL2 is required for recruitment of NK cells into the spleen and white pulp. These results provide improved tools and novel insights into NK cell biology. Key pointsO_LIJAXBoy are superior to conventional BoyJ mice for NK cell persistence after transfer. C_LIO_LICXCR3 repositions donor NK cells in T/B-zones of the spleen after infection. C_LIO_LIThe transcription factor ASCL2 is required for NK-cell recruitment to spleen white pulp. C_LI

immunology↗

bioRxiv2024

Altered DNA methylation pattern contributes to differential epigenetic immune signaling in the upper respiratory airway of COVID-19 patients

The emergence of SARS-CoV-2 has had a profound adverse impact on global health and continues to remain a threat worldwide. The disease spectrum of COVID-19 ranges from asymptomatic to fatal clinical outcomes especially in the elderly population and in individuals with underlying medical conditions. The impact of COVID-19 on host immune responses and immune cells at the protein and DNA levels remains largely ambiguous. In a case-control study, here we explored the impact of COVID-19 on DNA methylation patterns in the upper respiratory airway to determine how SARS-CoV-2 infection altered the immune status of individuals requiring hospitalization for COVID-19. We performed DNA methylation arrays on nasopharyngeal swabs at inclusion/hospitalization as well as 6 weeks post-inclusion. Our study reveals a distinct DNA methylation pattern in COVID-19 patients compared to healthy controls, characterized by 317 779 differentially methylated CpGs. Notably, within the transcription start sites and gene body, COVID-19 patients exhibited a higher number of genes/CpGs with elevated methylation levels. Enrichment analysis of methylated genes at transcription start sites highlighted the impact on genes associated with inflammatory responses and immune functions. Some SARS-CoV-2 -induced CpG methylations were transient, returning to normal levels by 6 weeks post-inclusion. Enriched genes of interest included IL-17A, a pivotal cytokine implicated with inflammation and healing, and NUP93, associated with antiviral innate immunity. Further, six genes in our data set, OAS1, CXCR5, APP, CCL20, CNR2, and C3AR1, were found in enrichment analysis with previous COVID-19 studies. Additionally, RNAse1 and RNAse2 emerged as key regulators, while IL-18 played a role in various biological processes in COVID-19 patients. Overall, our results demonstrates that COVID-19 has a major impact on the upper airway by modifying the methylation pattern of many genes and this could have implications for the conditioning of the airways and how the individual response to future airway infections.

microbiology↗

bioRxiv2021

Deciphering the role of mucosal immune responses and cervicovaginal microbiome in resistance to HIV infection in HIV-exposed seronegative (HESN) women

The female genital tract (FGT) is an essential site of HIV infection. Discerning the nature of HIV-specific local immune responses is crucial for identifying correlates of protection in HIV-exposed seronegative (HESN) individuals. The present study involved a comprehensive analysis of soluble immune mediators, secretory immunoglobulins (sIg) and levels of natural killer (NK) cells, CXCR5+ CD8+T cells, T follicular helper cells (Tfh) and T regulatory cells (T regs) in the vaginal mucosa, as well as the nature and composition of the cervicovaginal microbiome in HESN women. We found significantly elevated antiviral cytokines, soluble immunoglobulins, and increased frequencies of activated NK cells, CXCR5+ CD8+ T cells and Tfh cells in HESN females as compared to HIV unexposed healthy (UH) women. Analysis of the genital microbiome of HESN women revealed a greater bacterial diversity and increased abundance of Gardnerella spp in the mucosa of HESN women. The findings suggest the female genital tract of HESN females represents a microenvironment equipped with innate immune factors, antiviral mediators and critical T cells subsets that protect against HIV infection.

immunology↗

bioRxiv2020

Control of Mycobacterium tuberculosis Infection in Lungs is Associated with Recruitment of Antigen-Specific Th1 and Th17 cells Co-expressing CXCR3 and CCR6.

Mycobacterium tuberculosis (Mtb)-specific T cell responses associated with immune control during asymptomatic latent tuberculosis infection (LTBI) remain poorly understood. Using a non-human primate (NHP) aerosol model, we studied the kinetics, phenotypes and functions of Mtb antigen-specific T cells in peripheral and lung compartments of Mtb-infected asymptomatic rhesus macaques by longitudinally sampling blood and bronchoalveolar lavage (BAL), for up to 24 weeks post-infection. We found significantly higher frequencies of Mtb-specific effector and memory CD4 and CD8 T cells producing IFN-{gamma} in the airways compared to peripheral blood, which were maintained throughout the study period. Moreover, Mtb-specific IL-17+ and IL-17/IFN-{gamma} double-positive T cells were present in the airways but were largely absent in the periphery, suggesting that balanced mucosal Th1/Th17 responses are associated with LTBI. The majority of Mtb-specific CD4 T cells that homed to the airways expressed the chemokine receptor CXCR3 and co-expressed CCR6. Notably, CXCR3+CD4+ cells were found in granulomatous and non-granulomatous regions of the lung and inversely correlated with Mtb burden. Our findings provide novel insights into antigen-specific T cell responses associated with asymptomatic Mtb infection that are relevant for developing better strategies to control TB.

immunology↗