Biology subjects

Tikoo, S.

Publications and source records attributed to Tikoo, S..

3 recordsLinked to original sources

bioRxiv2026

Explaining the pathogenesis of African swine fever using knowledge-driven regulatory network modeling

A lethal DNA virus with significant economic impact on livestock farmers worldwide, the pathogenesis of African swine fever virus (ASFV) infection is complex and continues to challenge the development of effective vaccine candidates. The requirement for high-containment conditions further complicates its study, resulting in limitations in sample size and marker assessment that challenge conventional statistical analysis. In this work we demonstrate how prior knowledge of immune biology and pathogen-host proteome interactions can be leveraged and reconciled with sparse experimental data to deliver plausible mechanistically informed hypotheses describing ASFV illness progression. We apply large-scale automated mining of literature and pathway schema together with generative artificial intelligence (AI) to create closed-loop regulatory network models consisting of 133 pathogen and host proteins linked by 676 regulatory interactions. Immune regulatory tuning of these networks is reverse engineered to explain two distinct experimentally observed illness progression trajectories in only 5 markers measured every second day over a maximum of 8 days. Comparison of network model pools specific to each progression phenotype suggest that these significantly different outcomes may arise from altered regulatory tuning of genes coding for interleukin (IL)1{beta}, tumor necrosis factor (TNF) and Forkhead box protein (FOX)O4, potentially as a result of epigenetic adaptations. Simulated challenges with individual ASFV protein confirm broadly delayed interferon (IFN)-{gamma}I response in both phenotypes, with multigene family (MGF)505-3R offering the earliest induction and only in the more severe phenotype. Paradoxically, predictions suggest that this delay is preceded by an early IL-10 induction by this same viral protein. While added model granularity and validation is needed, we propose that this proof-of-concept knowledge driven approach offers an attractive solution to mechanistic hypothesis generation in data poor environments.

Systems Biology↗

bioRxiv2021

A distinct CD115- erythro-myeloid precursor present at the maternal-embryonic interface and in the bone marrow of adult mice

During ontogeny, macrophages develop from CD115+ precursors, including erythro-myeloid progenitors (EMP). EMP arise in the embryonic yolk sac, the primary site of early haematopoiesis. In adults, CD115+ bone marrow-derived monocytes represent essential macrophage precursors. Herein, we identify a CD115- macrophage precursor within the adult bone marrow that is unrelated to the classical monocyte lineage but rather shares transcriptomic and functional characteristics of embryonic EMP. These EMPROR (for Erythro Myeloid Precursor) cells are capable of efficiently generating macrophages in disease settings. During early development, EMPROR cells were largely absent from the yolk sac but were instead found at the embryonic-maternal interface in the uterine wall. Unexpectedly, the latter site contains robust haematopoietic activity and harbours defined embryonic haematopoietic progenitor cells, including classical CD115+ EMP. Our data suggest the existence of an alternative pathway of macrophage generation in the adult. Further, we uncover a hitherto unknown site of earliest blood cell development.

immunology↗

bioRxiv2019

Abrogation of RAB27A expression transiently affects melanoma cell proliferation

The role of the small GTPase RAB27A as an essential melanosome trafficking regulator in melanocytes is well-accepted. A decade ago, RAB27A was identified as a tumor dependency gene that promotes melanoma cell proliferation. RAB27A has since been linked to another propeller of cancer progression: exosome secretion. We have recently demonstrated that RAB27A is overexpressed in a subset of melanomas. High RAB27A gene and protein expression correlates with poor prognosis in melanoma patients. Mechanistic investigations revealed that the generation of pro-invasive exosomes was RAB27A-dependent and, therefore, silencing RAB27A reduced melanoma cell invasion in vitro and in vivo. However, previous studies have implicated RAB27A to be involved in both proliferation and invasion of melanoma cells. In this study, we demonstrate that the effects of abrogating RAB27A expression on proliferation are temporary, in contrast to the previously reported persistent effects on tumor invasion and metastasis. Therefore, we assist in the dissection of the short-term versus long-term effects of RAB27A knockdown on melanoma cell proliferation, invasion, and metastasis. We believe that our findings provide novel insights into the effects of RAB27A blockade. SignificanceRAB27A is known to serve as an essential regulator for melanosome trafficking. However, to date its role in melanoma biology has not been completely deciphered. While there are consistent independent reports on the pro-invasive effects of RAB27A, there are conflicting data on its impact on cell proliferation. Here we show that indeed abrogation of RAB27A does reduce cellular proliferation; however, this effect is only transient, while the impact on invasion as reported previously is persistent. This finding offers an explanation for the apparent contradiction in the literature and provides a deeper understanding of RAB27A function in melanoma cell biology.

cancer biology↗