Biology subjects

Kashanchi, F.

Publications and source records attributed to Kashanchi, F..

4 recordsLinked to original sources

bioRxiv2024

Epigenetic silencing and blockade of latency reversal by an HIV-1 encoded antisense transcript

The mechanisms that regulate human immunodeficiency virus 1 (HIV-1) latency are not fully elucidated. We reported that an HIV-1 antisense transcript (AST) induces epigenetic modifications at the HIV-1 promoter causing a closed chromatin state that suppresses viral transcription. Here we show that ectopic expression of AST in CD4+ T-cells from people with HIV-1 under antiretroviral therapy blocks latency reversal in response to pharmacologic and T-cell receptor stimulation, enforcing transcriptional silencing. We define structural domains and sequence motifs of AST contributing to its latency-promoting functions. Finally, we report an unbiased proteomics screen of AST interactors that revealed an array of previously known and potential new HIV-1-suppressive factors. Our studies identify AST as a first-in-class biological molecule capable of enforcing HIV-1 latency and with actionable curative potential.

molecular biology↗

bioRxiv2024

Activation of Macrophages by Extracellular Vesicles Derived from Babesia-infected Red Blood Cells

Babesia microti is the primary cause of human babesiosis in North America. Despite an emergence of the disease in recent years, the pathogenesis and immune response to B. microti infection remain poorly understood. Studies in laboratory mice have shown a critical role for macrophages in the elimination of parasites and infected red blood cells (iRBCs). Importantly, the underlying mechanisms that activate macrophages are still unknown. Recent evidence identified the release of extracellular vesicles (EVs) from Babesia iRBCs. EVs are spherical particles released from cell membranes under natural or pathological conditions that have been suggested to play roles in host-pathogen interactions among diseases caused by protozoan parasites. The present study examined whether EVs released from cultured Babesia iRBCs activated macrophages resulting in changes in the secretion of cytokines. An analysis of vesicle size in EV fractions from Babesia iRBCs showed diverse populations in the <100 nm size range compared to EVs from uninfected RBCs. Uptake of EVs released from B. microti-iRBCs was observed in macrophages in vitro. In addition, incubation of macrophages with EVs isolated from Babesia iRBC culture supernatants resulted in the activation of NF-{kappa}B and modulation of pro-inflammatory cytokines. These results support a role for EVs in the activation of macrophage functions and provide new insights into the mechanisms involved in the induction of the innate immune response during babesiosis.

microbiology↗

bioRxiv2021

Retroviral Infection of Human Neurospheres and Use of Stem Cell EVs to Repair Cellular Damage

HIV-1 remains an incurable infection that is associated with substantial economic and epidemiologic impacts. HIV-associated neurocognitive disorders (HAND) are commonly linked with HIV-1 infection; despite the development of combination antiretroviral therapy (cART), HAND is still reported to affect at least 50% of HIV-1 infected individuals. It is believed that the over-amplification of inflammatory pathways, along with release of toxic viral proteins from infected cells, are primarily responsible for the neurological damage that is observed in HAND; however, the underlying mechanisms are not well-defined. Therefore, there is an unmet need to develop more physiologically relevant and reliable platforms for studying these pathologies. In recent years, neurospheres derived from induced pluripotent stem cells (iPSCs) have been utilized to model the effects of different neurotropic viruses. Here, we report the generation of neurospheres from iPSC-derived neural progenitor cells (NPCs) and we show that these cultures are permissive to retroviral (e.g. HIV-1, HTLV-1) replication. In addition, we also examine the potential effects of stem cell derived extracellular vesicles (EVs) on HIV-1 damaged cells as there is abundant literature supporting the reparative and regenerative properties of stem cell EVs in the context of various CNS pathologies. Consistent with the literature, our data suggests that stem cell EVs may modulate neuroprotective and anti-inflammatory properties in damaged cells. Collectively, this study demonstrates the feasibility of NPC-derived neurospheres for modeling HIV-1 infection and, subsequently, highlights the potential of stem cell EVs for rescuing cellular damage induced by HIV-1 infection.

cell biology↗

bioRxiv2019

ZIKA VIRUS INFECTION DURING PREGNANCY AND INDUCED BRAIN PATHOLOGY IN BECLIN1-DEFICIENT MOUSE MODEL

We investigated the role of the autophagy protein, Beclin1, in the replication and disease of Zika virus (ZIKV) in pregnant dams and their offspring using Beclin1-deficient (Atg6+/-) and wild-type (Atg6+/+) mouse model infected with the Honduran (R103451), Puerto Rican (PRVABC59), and the Uganda (MR766) strains of ZIKV. Pregnant dams infected subcutaneously at embryonic stage (E)9 showed viral RNA in serum harvested at E13 and in various organs removed postmortem at E17. Subcutaneous infections with ZIKV also showed the vertical transmission of ZIKV from the placenta to embryos removed postmortem at E17. From the three isolates, R103451-infected Atg6+/- dams had the lowest mortality rate while 30 % of their offspring containing the hemizygous beclin1 allele (Atg6+/-) were smaller in size and had smaller and underdeveloped brain. Growth impairment in the pups became noticeable after two weeks post-birth. After 21-days, pups were sacrificed and brain tissues removed postmortem showed expression of the envelope (E) and the non-structural (NS)-1 proteins, along with signs of neuronal injury, despite an absence in viral RNA detection. A significant decrease in the mRNA expression levels of the insulin-like growth factor-1 (IGF-1) by 8-fold and a decrease in the mRNA expression levels of several microcephaly related genes along with an increase in the secretion of several inflammatory molecules may have contributed to the observed phenotype. Since autophagy regulates cytokines and chemokines production, a dysregulation in this pathway may have further exacerbated the pathology of ZIKV. IMPORTANCEPups delivered from ZIKV-infected dams showed significant growth impairments in the body and the brain. We believe that the reduction in insulin growth factor together with the increase secretion of inflammatory molecules may have triggered neuronal injury and the downregulation of the microcephalic genes, while reduced expression of the autophagy protein, Beclin1 further exacerbated the pathology. Although the mechanism is still unknown, the autophagy pathway seems to play a key role in ZIKV pathology. It is therefore of great significance to study the role of autophagy during viral infection with the goal to identify potential targets for anti-ZIKV therapeutic intervention.

immunology↗