bioRxiv Science⌕ Search

Biology subjects

Araveti, P. B.

Publications and source records attributed to Araveti, P. B..

3 recordsLinked to original sources
bioRxiv2026

IFN and IFN mimetics prevent IFN-I-mediated TB susceptibility by regulating iron metabolism and lipid peroxidation

Type I interferons (IFN-I) and IFN{gamma} exert divergent effects during tuberculosis, but the mechanisms that determine whether macrophage activation promotes host defense or inflammatory pathology remain incompletely understood. Here, we dissect the interplay between IFN-I and IFN{gamma} in macrophage activation using genetically susceptible B6.Sst1S macrophages. We show that, during tumor necrosis factor (TNF) stimulation, susceptible macrophages enter a persistent pathological activation state (pPAS) characterized by sustained lipid peroxidation and super-induction of IFN-I responses. This pathological state is maintained by autocrine IFN-I signaling. In contrast, IFN{gamma} priming prevents pPAS development by enhancing macrophage resilience to oxidative stress, in part through regulation of iron metabolism and induction of ferritin expression. Computational cell state transition assessment and regulation (cSTAR) analysis identified pathways and small molecules predicted to promote the transition of susceptible macrophages toward an IFN{gamma}-induced, Mtb-resistant state. Consistent with these predictions, the CDK4/6 inhibitor trilaciclib reduced lipid peroxidation by regulating iron metabolism, whereas retinoic acid signaling enhanced GPX4 expression and lipid biosynthesis programs. Combined CDK4/6 inhibition and retinoic acid receptor activation efficiently prevented the pathological activation state. Together, these findings delineate a mechanism of IFN-I/IFN{gamma} crosstalk during macrophage activation and identify pharmacologic strategies to prevent IFN-I-dominant, lipid peroxidation-driven macrophage pathology.

immunology↗
bioRxiv2024

Myc Dysregulation in Activated Macrophages Initiates Iron-Mediated Lipid Peroxidation that Fuels Type I Interferon and Compromises TB Resistance

A quarter of human population is infected with Mycobacterium tuberculosis, but less than 10% of those infected develop pulmonary TB. We developed a genetically defined sst1-susceptible mouse model that uniquely reproduces a defining feature of human TB: the development of necrotic lung granulomas and determined that the sst1-susceptible phenotype was driven by the aberrant macrophage activation. This study demonstrates that the aberrant response of the sst1-susceptible macrophages to prolonged stimulation with TNF is primarily driven by conflicting Myc and antioxidant response pathways leading to a coordinated failure 1) to properly sequester intracellular iron and 2) to activate ferroptosis inhibitor enzymes. Consequently, iron-mediated lipid peroxidation fueled Ifn{beta} superinduction and sustained the Type I Interferon (IFN-I) pathway hyperactivity that locked the sst1-susceptible macrophages in a state of unresolving stress and compromised their resistance to Mtb. The accumulation of the aberrantly activated, stressed, macrophages within granuloma microenvironment led to the local failure of anti-tuberculosis immunity and tissue necrosis. The upregulation of Myc pathway in peripheral blood cells of human TB patients was significantly associated with poor outcomes of TB treatment. Thus, Myc dysregulation in activated macrophages results in an aberrant macrophage activation and represents a novel target for host-directed TB therapies.

immunology↗
bioRxiv2022

Identification of a novel interaction between Theileria Prohibitin (TaPHB-1) and bovine RUVBL-1

Bovine tropical theileriosis causes huge economic loss worldwide. It is a tick borne disease of bovine caused by the parasite Theileria annulata. T. annulata is an intracellular parasite that belongs to the phylum Apicomplexa. The sporozoites of T. annulata are released by the tick into the bloodstream of the host during the blood meal that invades bovine B cells, macrophages, or monocytes. This infection leads to the transformation of the host cells and brings cancer-like phenotype in the host cells. The parasite proteins play a vital role in the transformation of the host cell. However, the parasite factors involved in the host cell transformation are not well explored. Previously, TaPIN1, a peptidyl-prolyl isomerase of T. annulata, was shown to be secreted to the host cytosol and play a role in the host cell transformation. The present study was carried out to explore the parasite-host interactions that may play an important role in the host cell transformation. We identified the parasite proteins that are expressed in the schizont stage with a signal peptide. We narrow down our search to a parasite prohibitin. The in silico analysis of T. annulata prohibitin (TA04375, TaPHB-1) showed that TaPHB-1 shares homology with the mammalian prohibitin 1. With the localization experiments, we confirmed that TaPHB-1 is exported to the parasite surface and also to the host cell cytosol. Further, we observed that the localization of host prohibitin differs in the parasite-infected cells and could not be reverted back by the elimination of the parasite in the infected cells. We found through the yeast-two-hybrid studies that bovine RUVBL1 (BoRUVBL-1) interacts with TaPHB-1. The interaction between BoRUVBL1 and TaPHB-1 was predominantly observed on the parasite surface in the infected bovine cells. The interaction was further confirmed with immunoprecipitation and LC-MS/MS analysis. Further, the LC-MS/MS based TaPHB-1 interactome study reveals that it interacts with proteins that regulate actin cytoskeleton organization, protein folding, mRNA processing, and metabolic processes. Our finding suggests that the parasite releases prohibitin protein into the cytoplasm of the host cell where it interacts with the host RUVBL-1. This finding has implications not only in the understanding of Theileria parasite biology in greater depth but also in the cancer biology where previously differential localization of prohibitin proteins was observed but its interaction partner was not known. Author summaryTheileria annulata, an apicomplexan, is a unique parasite which can transform host leucocytes. This parasite uses this strategy for its own multiplication. The cells infected with this parasite, when treated with buparvaquone, an anti-theilerial drug, cannot survive without the parasite. This observation suggests that the parasite derived factors are required to maintain the cancerous phenotype of the host cell. We mined the parasite proteome to find out the proteins with signal sequence that may be secreted to the host cell cytosol and being expressed in the schizont stage. The parasite prohibitin (TaPHB-1) chosen for this study was found to be secreted to the host cytoplasm and on the parasite surface. Interestingly, we observed a noticeable change in the localization of the host prohibitin in the parasite infected cells. The host prohibitin that is normally localized to the mitochondria in the uninfected cells was observed in the host cell nucleus similar to the cancerous cells. Since the parasite protein is exported to the host cytoplasm we looked for its interacting partner. We performed yeast-two-hybrid screening with TaPHB-1 with in-house prepared the cDNA library of the infected bovine leucocytes. We identified bovine RUVBL1 as the interacting partner of TaPHB-1. Interestingly, the interaction between parasite prohibitin and bovine RUVBL1 was observed on the parasite surface. Further, analysis of the parasite prohibitin interactome in the infected cells shows that it might be involved with those proteins which regulate actin cytoskeleton organization, protein folding, mRNA processing and metabolic process. Since parasite infected cells have cancer like phenotype, the identification of this novel interaction will open up new avenues not only in the arena of parasite biology but also in the domain of cancer biology.

microbiology↗