Mechanobiology of immune cells: Messengers, receivers and followers in leishmaniasis aiding synthetic devices

Khandibharad, Shweta; Nimsarkar, Prajakta; Singh, Shailza

doi:10.1016/j.crimmu.2022.08.007

Cited by 4 publications

(5 citation statements)

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“…M2 subtypes which include M2a, M2b, M2c and M2d were characterized by markers. Parameters for M2a were set as log2 CCl24>1 and log2 SOCS3>1, for M2b log2 TNF>1 and log2 CCl1>1 for M2c, log2 TGFB>1 and log2CD163>1 and for M2d log2 NOS2>1 and log2 CCl5>1 (Khandibharad et al, 2022) (Figure 1 (2)). We could see the shift in macrophage population with time points of infection where M2 and M2a population was most dominant in all the samples, M1 was most dominant in 6hr infected sample, M2d was enriched in 6hr infected sample as well.…”

Section: Resultsmentioning

confidence: 99%

“…Epigenetic modifications and chromatin remodeling framework of macrophages with respect to L.major infection that causes CL is still poorly understood. Macrophage being the most prime target of infection may dictate disease fate and the modular characteristics of parasite may influence the host macrophage plasticity for survival (Khandibharad et al, 2022). Fine balance between different types of macrophages such as M1 which mediates Th1-type response and M2 macrophages having different subsets such as M2a, M2b, M2c and M2d that elevates Th2-type response regulates the parasite clearance (Tomiotto-Pellissier et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Single cell ATAC sequencing identifies sleepy macrophages during reciprocity of cytokines inL.majorinfection

Khandibharad¹,

Kharat²,

Singh³

2023

Preprint

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Hallmark for macrophages is their ability to possess plasticity which enables them to respond to changing microenvironment. Leishmania takes use of the phenotypic plasticity of macrophages to create favorable position for intracellular survival and persistent infection through regulatory cytokine like IL10. However, these effector cells can eliminate infection through modulation of critical cytokines such as IL12 and key players involved in its production. Using sophisticated tool of single cell ATAC sequencing we analyzed the regulatory axis of IL10 and IL12 in time dependent manner for L.major infection in macrophages. We recognized the cellular heterogeneity post infection with the regulators of IL10 and IL12 and observed a reciprocal relationship between them. Our prominent findings also exposed sleepy macrophages and its role in IL10 and IL12 reciprocity. To summarize, role of NFAT5 was vital in identification of sleepy macrophages which is a transient state where transcription factors controlled the epigenetic remodeling and expression of genes involved in pro-inflammatory cytokine production and recruitment of immune cells.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Single cell ATAC sequencing identifies sleepy macrophages during reciprocity of cytokines inL.majorinfection

Khandibharad¹,

Kharat²,

Singh³

2023

Preprint

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“…For instance, researchers have utilized synthetic biology to manipulate T cells, enabling them to express chimeric antigen receptors (CARs) designed to recognize leishmanial antigens ( Arya and Arora, 2021 ). Similarly, immune cells can be modulated using engineered synthetic circuits to detect and eliminate parasites by inducing the production of pro-inflammatory cytokines, which can stimulate NO production ( Khandibharad et al, 2022 ). The optimization of synthetic circuit delivery is a critical aspect of advancing immunotherapy and synthetic biology applications.…”

Section: Discussionmentioning

confidence: 99%

Synthetic biology for combating leishmaniasis

Khandibharad,

Singh

2024

Front. Microbiol.

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Leishmaniasis is a neglected tropical disease caused by protozoan parasites of the Leishmania genus. Despite the efforts to control and treat the disease, it still remains a major public health problem in many countries. Synthetic biology is a rapidly evolving interdisciplinary field that combines biology, engineering, and computer science to design and construct novel biological systems. In recent years, synthetic biology approaches have shown great promise for developing new and effective strategies to combat leishmaniasis. In this perspective, we summarize the recent advances in the use of synthetic biology for the development of vaccines, diagnostic tools, and novel therapeutics for leishmaniasis.

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“…Epigenetic modifications and chromatin remodeling framework of macrophages with respect to L. major infection that causes CL are still poorly understood. Macrophage being the most prime target of infection may dictate disease fate, and the modular characteristics of parasite may influence the host macrophage plasticity for survival ( 23 ). A fine balance exists between different types of macrophages such as pro-inflammatory cytokine-expressing macrophages which mediate Th1-type response and anti-inflammatory cytokine-expressing macrophages having different subsets such as M2a, M2b, M2c, and M2d that elevate Th2-type response which regulates the parasite clearance ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

Single-cell ATAC sequencing identifies sleepy macrophages during reciprocity of cytokines in L. major infection

Khandibharad,

Singh

2024

Microbiol Spectr

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The hallmark characteristic of macrophages lies in their inherent plasticity, allowing them to adapt to dynamic microenvironments. Leishmania strategically modulates the phenotypic plasticity of macrophages, creating a favorable environment for intracellular survival and persistent infection through regulatory cytokine such as interleukin (IL)-10. Nevertheless, these effector cells can counteract infection by modulating crucial cytokines like IL-12 and key components involved in its production. Using sophisticated tool of single-cell assay for transposase accessible chromatin (ATAC) sequencing, we systematically examined the regulatory axis of IL-10 and IL-12 in a time-dependent manner during Leishmania major infection in macrophages Our analysis revealed the cellular heterogeneity post-infection with the regulators of IL-10 and IL-12, unveiling a reciprocal relationship between these cytokines. Notably, our significant findings highlighted the presence of sleepy macrophages and their pivotal role in mediating reciprocity between IL-10 and IL-12. To summarize, the roles of cytokine expression, transcription factors, cell cycle, and epigenetics of host cell machinery were vital in identification of sleepy macrophages, which is a transient state where transcription factors controlled the epigenetic remodeling and expression of genes involved in pro-inflammatory cytokine expression and recruitment of immune cells. IMPORTANCE Leishmaniasis is an endemic affecting 99 countries and territories globally, as outlined in the 2022 World Health Organization report. The disease’s severity is compounded by compromised host immune systems, emphasizing the pivotal role of the interplay between parasite and host immune factors in disease regulation. In instances of cutaneous leishmaniasis induced by L. major , macrophages function as sentinel cells. Our findings indicate that the plasticity and phenotype of macrophages can be modulated to express a cytokine profile involving IL-10 and IL-12, mediated by the regulation of transcription factors and their target genes post -L. major infection in macrophages. Employing sophisticated methodologies such as single-cell ATAC sequencing and computational genomics, we have identified a distinctive subset of macrophages termed “sleepy macrophages.” These macrophages exhibit downregulated housekeeping genes while expressing a unique set of variable features. This data set constitutes a valuable resource for comprehending the intricate host-parasite interplay during L. major infection.

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Mechanobiology of immune cells: Messengers, receivers and followers in leishmaniasis aiding synthetic devices

Cited by 4 publications

References 135 publications

Single cell ATAC sequencing identifies sleepy macrophages during reciprocity of cytokines inL.majorinfection

Single cell ATAC sequencing identifies sleepy macrophages during reciprocity of cytokines inL.majorinfection

Synthetic biology for combating leishmaniasis

Single-cell ATAC sequencing identifies sleepy macrophages during reciprocity of cytokines in L. major infection

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